FLUOXETINE

Main information

  • Trade name:
  • FLUOXETINE Capsules Hard 60 Milligram
  • Dosage:
  • 60 Milligram
  • Pharmaceutical form:
  • Capsules Hard
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FLUOXETINE Capsules Hard 60 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1364/001/001
  • Authorization date:
  • 03-10-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Fluoxetine60mgHardCapsules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachcapsulecontains60mgoffluoxetine(ashydrochloride)

Eachcapsulealsocontainsthecolouringagents,Tartrazine(E102)[0.37mg]andSunsetYellowFCF(E110)

[0.0009mg].

Forafulllistofexcipients,seeSection6.1

3PHARMACEUTICALFORM

Capsule,Hard

Hardgelatincapsuleswithyellowcapandwhitebodyimprintedwith‘FLX’oncapand‘60’onbodywithblackink.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Majordepression

Obsessive-compulsivedisorder

Bulimianervosa:fluoxetineisindicatedasacomplementtopsychotherapyforreductionofbingeeatingandpurging

activity.

4.2Posologyandmethodofadministration

Fororaladministrationtoadultsonly

Majordepression–Adultsandtheelderly:therecommendeddoseis20mgdaily.Dosageshouldbereviewedand

adjustedifnecessarywithin3to4weeksofinitiationoftherapyandthereafterasjudgedclinicallyappropriate.

Althoughtheremaybeincreasedpotentialforundesirableeffectsathigherdosesinsomepatientswithinsufficient

responseto20mg,thedosemaybeincreasedgraduallyuptoamaximumof60mg(seesection5.1).Dosage

adjustmentsshouldbemadecarefullyonanindividualpatientbasis,tomaintainthepatientsatthelowesteffective

dose.

Patientswithdepressionshouldbetreatedforasufficientperiodofatleast6monthstoensurethattheyarefreefrom

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/02/2012 CRN 2085601 page number: 1

Obsessive-compulsivedisorder–Adultsandtheelderly:therecommendeddoseis20mgdaily.Althoughtheremaybe

increasedpotentialforundesirableeffectsathigherdosesinsomepatients,ifaftertwoweeksthereisinsufficient

responseto20mg,thedosemaybeincreasedgraduallyuptoamaximumof60mg.Ifnoimprovementisobserved

within10weeks,treatmentwithfluoxetineshouldbereconsidered.Ifagoodtherapeuticresponsehasbeenobtained,

treatmentcanbecontinuedatadosageadjustedonanindividualbasis.Whiletherearenosystematicstudiestoanswer

thequestionofhowlongtocontinuefluoxetinetreatment,OCDisachronicdisorderanditisreasonabletoconsider

continuationbeyond10weeksinrespondingpatients.Dosageadjustmentsshouldbemadecarefullyonanindividual

patientbasis,tomaintainthepatientatthelowesteffectivedose.Theneedfortreatmentshouldbereassessed

periodically.Somecliniciansadvocateconcomitantbehaviouralpsychotherapyforpatientwhohavedonewellon

pharmacotherapy.

Long-termefficacy(morethan24weeks)hasnotbeendemonstratedinOCD.

Bulimianervosa–Adultsandtheelderly:adoseof60mg/dayisrecommended.

Long-termefficacy(morethan3months)hasnotbeendemonstratedinbulimianervosa.

Adults,allindications:Therecommendeddosemaybeincreasedordecreased.Dosesabove80mg/dayhavenotbeen

systematicallyevaluated.

Fluoxetinemaybeadministeredasasingleordivideddose,duringorbetweenmeals.

Whendosingisstopped,activedrugsubstancewillpersistinthebodyforweeks.Thisshouldbeborneinmindwhen

startingorstoppingtreatment.

Childrenandadolescentsaged8yearsandabove(moderatetoseveremajordepressiveepisode):Fluoxetine60mg

capsulesarenotlicensedandarenotappropriateforuseinchildrenoradolescents.Othersuitableformulations(20mg

capsules,liquidformulation)areavailableforthispatientpopulation.

Elderly:Cautionisrecommendedwhenincreasingthedoseandthedailydoseshouldgenerallynotexceed40mg.

Maximumrecommendeddoseis60mg/day.

Alowerorlessfrequentdose(e.g.20mgeverysecondday)shouldbeconsideredinpatientswithhepaticimpairment

(seeSection5.2),orinpatientswhereconcomitantmedicationhasthepotentialforinteractionswithfluoxetine(see

Section4.5).

Withdrawalsymptomsseenondiscontinuationoffluoxetine:Abruptdiscontinuationshouldbeavoided.Whenstopping

treatmentwithfluoxetinethedoseshouldbegraduallyreducedoveraperiodofatleastonetotwoweeksinorderto

reducetheriskofwithdrawalreactions(seeSection4.4andSection4.8).Ifintolerablesymptomsoccurfollowinga

decreaseinthedoseorupondiscontinuationoftreatment,thenresumingthepreviouslyprescribeddosemaybe

considered.Subsequently,thephysicianmaycontinuedecreasingthedose,butatamoregradualrate.

4.3Contraindications

Hypersensitivitytofluoxetineortoanyofitsexcipients

MonoamineOxidaseInhibitors:Casesofseriousandsometimesfatalreactionshavebeenreportedinpatientsreceiving

anSSRIincombinationwithamonoamineoxidaseinhibitor(MAOI),andinpatientswhohaverecentlydiscontinued

anSSRIandhavebeenstartedonaMAOI.Treatmentwithfluoxetineshouldonlybestarted2weeksafter

discontinuationofanirreversibleMAOIandthefollowingdayafterdiscontinuationofareversibleMAOI-A.

Serotoninsyndrome

Somecasespresentedwithfeaturesresemblingserotoninsyndrome(whichmayresembleandbediagnosedas

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/02/2012 CRN 2085601 page number: 2

SymptomsofadruginteractionwithaMAOIinclude:hyperthermia,rigidity,myoclonus,autonomicinstabilitywith

possiblerapidfluctuationsofvitalsigns,mentalstatuschangesthatincludeconfusion,irritabilityandextremeagitation

progressingtodeliriumandcoma.

Therefore,fluoxetineiscontra-indicatedincombinationwithanon-selectiveMAOI.Similarly,atleast5weeksshould

elapseafterdiscontinuingfluoxetinetreatmentbeforestartingaMAOI.Iffluoxetinehasbeenprescribedchronically

and/oratahighdose,alongerintervalshouldbeconsidered.

ThecombinationoffluoxetinewithareversibleMAOI(e.g.,moclobemide)isnotrecommended.Treatmentwith

fluoxetinecanbeinitiatedthefollowingdayafterdiscontinuationofareversibleMAOI.

4.4Specialwarningsandprecautionsforuse

Warnings

Rashandallergicreactions:Rash,anaphylactoideventsandprogressivesystemicevents,sometimeserious(involving

skin,kidney,liverorlung)havebeenreported.Upon,theappearanceofrashorofotherallergicphenomenaforwhich

analternativeaetiologycannotbeidentified,fluoxetineshouldbediscontinued.

Thecapsulescontainthecolouringagents,Tartrazine(E102)andSunsetYellowFCF(E110),asexcipients.These

colouringagentsmaycauseallergicreactions.

Precautions

Seizures:Seizuresareapotentialriskwithantidepressantdrugs.Therefore,aswithotherantidepressants,fluoxetine

shouldbeintroducedcautiouslyinpatientswhohaveahistoryofseizures.Treatmentshouldbediscontinuedinany

patientwhodevelopsseizuresorwherethereisanincreaseinseizurefrequency.Fluoxetineshouldbeavoidedin

patientswithunstableseizuresdisorders/epilepsyandpatientswithcontrolledepilepsyshouldbecarefullymonitored.

Mania:Antidepressantsshouldbeusedwithcautioninpatientswithahistoryofmania/hypomania.Aswithall

antidepressants,fluoxetineshouldbediscontinuedinanypatiententeringamanicphase.

Hepatic/RenalFunction:Fluoxetineisextensivelymetabolisedbytheliverandexcretedbythekidneys.Alowerdose,

e.g.,alternatedaydosing,isrecommendedinpatientswithsignificanthepaticdysfunction.whengivenfluoxetine20

mg/dayfor2months,patientswithsevererenalfailure(GFR<10ml/min)requiringdialysisshowednodifferencein

plasmalevelsoffluoxetineornorfluoxetinecomparedtocontrolswithnormalrenalfunction.

CardiacDisease:NoconductionabnormalitiesthatresultedinheartblockwereobservedintheECGof312patients

whoreceivedfluoxetineindouble-blindclinicaltrials.However,clinicalexperienceinacutecardiacdiseaseislimited,

thereforecautionisadvisable.

WeightLoss:Weightlossmayoccurinpatientstakingfluoxetinebutitisusuallyproportionaltobaselinebodyweight.

Diabetes:Inpatientswithdiabetes,treatmentwithanSSRImayalterglycaemiccontrol.Hypoglycaemiahasoccurred

duringtherapywithfluoxetineandhyperglycaemiahasdevelopedfollowingdiscontinuation.Insulinand/ororal

hypoglycaemicdosagemayneedtobeadjusted.

Suicide/Suicidalthoughtsorclinicalworsening:

Depressionisassociatedwithanincreasedriskofsuicidalthoughts,selfharmandsuicide(suicide-relatedevents).This

riskpersistsuntilsignificantremissionoccurs.Asimprovementmaynotoccurduringthefirstfewweeksormoreof

treatment,patientsshouldbecloselymonitoreduntilsuchimprovementoccurs.Itisgeneralclinicalexperiencethatthe

riskofsuicidemayincreaseintheearlystagesofrecovery.

OtherpsychiatricconditionsforwhichFluoxetine60mgcapsulesareprescribedcanalsobeassociatedwithan

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/02/2012 CRN 2085601 page number: 3

Thesameprecautionsobservedwhentreatingpatientswithmajordepressivedisordershouldthereforebeobserved

whentreatingpatientswithotherpsychiatricdisorders.

Patientswithahistoryofsuicide-relatedevents,orthoseexhibitingasignificantdegreeofsuicidalideationpriorto

commencementoftreatmentareknowntobeatgreaterriskofsuicidalthoughtsorsuicideattempts,andshouldreceive

carefulmonitoringduringtreatment.Ameta-analysisofplacebo-controlledclinicaltrialsofantidepressantdrugsin

adultpatientswithpsychiatricdisordersshowedanincreasedriskofsuicidalbehaviourwithantidepressantscompared

toplaceboinpatientslessthan25yearsold.

Closesupervisionofpatientsandinparticularthoseathighriskshouldaccompanydrugtherapyespeciallyinearly

treatmentandfollowingdosechanges.Patients(andcaregiversofpatients)shouldbealertedabouttheneedtomonitor

foranyclinicalworsening,suicidalbehaviourorthoughtsandunusualchangesinbehaviourandtoseekmedicaladvice

immediatelyifthesesymptomspresent.

Akathisia/psychomotorrestlessness:Theuseoffluoxetinehasbeenassociatedwiththedevelopmentofakathisia,

characterisedbyasubjectivelyunpleasantordistressingrestlessnessandneedtomoveoftenaccompaniedbyan

inabilitytositorstandstill.Thisismostlikelytooccurwithinthefirstfewweeksoftreatment.Inpatientswhodevelop

thesesymptoms,increasingthedosemaybedetrimental.

WithdrawalsymptomsseenondiscontinuationofSSRItreatment:Withdrawalsymptomswhentreatmentis

discontinuedarecommon,particularlyifdiscontinuationisabrupt(seeSection4.8).Inclinicaltrialsadverseevents

seenontreatmentdiscontinuationoccurredinapproximately60%ofpatientsinboththefluoxetineandplacebogroups.

Oftheseadverseevents,17%inthefluoxetinegroupand12%intheplacebogroupweresevereinnature.

Theriskofwithdrawalsymptomsmaybedependentonseveralfactors,includingthedurationanddoseoftherapyand

therateofdosereduction.Dizziness,sensorydisturbances(includingparaesthesia),sleepdisturbances(including

insomniaandintensedreams),asthenia,agitationoranxiety,nauseaand/orvomiting,tremor,andheadachearethe

mostcommonlyreportedreactions.Generally,thesesymptomsaremildtomoderate;however,insomepatientsthey

maybesevereinintensity.Theyusuallyoccurwithinthefirstfewdaysofdiscontinuingtreatment.Generally,these

symptomsareself-limitingandusuallyresolvewithin2weeks,thoughinsomeindividualstheymaybeprolonged(2-3

monthsormore).Itisthereforeadvisedthatfluoxetineshouldbegraduallytaperedwhendiscontinuingtreatmentover

aperiodofatleastonetotwoweeks,accordingtothepatient'sneeds(seeSection4.2).

Haemorrhage:Therehavebeenreportsofcutaneousbleedingabnormalitiessuchasecchymosisandpurpurawith

SSRI’s.Ecchymosishasbeenreportedasaninfrequenteventduringtreatmentwithfluoxetine.Otherhemorrhagic

manifestations(e.g.,gynaecologicalhaemorrhages,gastrointestinalbleedingsandothercutaneousormucous

bleedings)havebeenreportedrarely.CautionisadvisedinpatientstakingSSRI’s,particularlyinconcomitantusewith

oralanticoagulants,drugsknowntoaffectplateletfunction(e.g.,atypicalantipsychoticssuchasclozapine,

phenothiazines,mostTCA’s,aspirin,NSAID’s)orotherdrugsthatmayincreaseriskofbleedingaswellasinpatients

withahistoryofbleedingdisorders.

ElectroconvulsiveTherapy(ECT):Therehavebeenrarereportsofprolongedseizuresinpatientsonfluoxetine

receivingECTtreatment,thereforecautionisadvisable.

Onrareoccasionsdevelopmentofaserotoninsyndromeorneurolepticmalignantsyndrome-likeeventshavebeen

reportedinassociationwithtreatmentoffluoxetine,particularlywhengivenincombinationwithotherserotonergic

(amongothersL-tryptophan)and/orneurolepticdrugs.Asthesesyndromesmayresultinpotentiallylife-threatening

conditions,treatmentwithfluoxetineshouldbediscontinuedifsuchevents(characterisedbyclustersofsymptomssuch

ashyperthermia,rigidity,myoclonus,andautonomicinstabilitywithpossiblerapidfluctuationsofvitalsigns,mental

statuschangesincludingconfusion,irritability,extremeagitationprogressingtodeliriumandcoma)occurand

supportivesymptomatictreatmentshouldbeinitiated.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/02/2012 CRN 2085601 page number: 4

Half-life:thelongeliminationhalf-livesofbothfluoxetineandnorfluoxetineshouldbeborneinmind(seeSection5.2)

whenconsideringpharmacodynamicorpharmacokineticdruginteractions(e.g.whenswitchingfromfluoxetineto

otherantidepressants).

Monoamineoxidaseinhibitors:(see‘Contraindications’).

Notrecommendedcombinations;MAOI-A(seeSection4.3)

Combinationsrequiringprecautionsforuse:MAOI-B(selegeline):riskofserotoninsyndrome:Clinicalmonitoringis

recommended.

Phenytoin:Changesinbloodlevelhavebeenobservedwhencombinedwithfluoxetine.Insomecasesmanifestations

oftoxicityhaveoccurred.Considerationshouldbegiventousingconservativetitrationschedulesoftheconcomitant

drugandtomonitoringclinicalstatus.

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

serotoninsyndrome.Usewithtriptanscarriestheadditionalriskofcoronaryvasoconstrictionandhypertension.

Lithiumandtryptophan:TherehavebeenreportsofserotoninsyndromewhenSSRIshavebeengivenwithlithiumor

tryptophan,andtherefore,theconcomitantuseoffluoxetinewiththesedrugsshouldbeundertakenwithcaution.When

fluoxetineisusedincombinationwithlithium,closerandmorefrequentclinicalmonitoringisrequired.

CYP2D6isoenzyme:Becausefluoxetine’smetabolism(liketricyclicantidepressantsandotherselectiveserotonin

antidepressants)involvesthehepaticcytochromeCYP2D6isoenzymesystem,concomitanttherapywithdrugsalso

metabolisedbythisenzymesystemmayleadtodruginteractions.Concomitanttherapywithdrugspredominantly

metabolisedbythisisoenzyme,andwhichhaveanarrowtherapeuticindex(suchasflecainide,encainide,

carbamazepineandtricyclicantidepressants),shouldbeinitiatedatoradjustedtothelowendoftheirdoserange.This

willalsoapplyiffluoxetinehasbeentakenintheprevious5weeks.

Oralanticoagulants:alteredanti-coagulanteffects(laboratoryvaluesand/orclinicalsignsandsymptoms),withno

consistentpattern,butincludingincreasedbleeding,havebeenreporteduncommonlywhenfluoxetineisco-

administeredwithoralanticoagulants.PatientsreceivingWarfarintherapyshouldreceivecarefulcoagulation

monitoringwhenfluoxetineisinitiatedorstopped.(SeeSection4.4).

ElectroconvulsiveTherapy(ECT):Therehavebeenrarereportsofprolongedseizuresinpatientsonfluoxetine

receivingECTtreatment,thereforecautionisadvisable.

Alcohol:Informaltesting,fluoxetinedidnotraisealcohollevelsorenhancetheeffectsofalcohol.However,the

combinationofSSRItreatmentandalcoholisnotadvisable.

St.John’sWort:IncommonwithotherSSRIs,pharmacodynamicinteractionsbetweenfluoxetineandtheherbal

remedySt.John’sWort(Hypericumperforatum)mayoccur,whichmayresultinanincreaseofundesirableeffects.

4.6Fertility,pregnancyandlactation

Pregnancy:Fluoxetinecanbeusedduringpregnancy,butcautionshouldbeexercised,especiallyduringlatepregnancy

orjustpriortotheonsetoflaboursincethefollowingeffectshavebeenreportedinneonates:irritability,tremor,

hypotonia,persistentcrying,anddifficultyinsuckingorinsleeping.Thesesymptomsmayindicateeitherserotonergic

effectsorawithdrawalsyndrome.Thetimetooccurandthedurationofthesesymptomsmayberelatedtothelong

half-lifeoffluoxetine(4-6days)anditsactivemetabolite,norfluoxetine(4-16days)

Someepidemiologicalstudiessuggestanincreasedriskofcardiovasculardefectsassociatedwiththeuseoffluoxetine

duringthefirsttrimester.Themechanismisunknown.Overallthedatasuggestthattheriskofhavinganinfantwitha

cardiovasculardefectfollowingmaternalfluoxetineexposureisintheregionof2/100comparedwithanexpectedrate

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/02/2012 CRN 2085601 page number: 5

EpidemiologicaldatahavesuggestedthattheuseofSSRIsinpregnancy,particularinlatepregnancy,mayincreasethe

riskofpersistentpulmonaryhypertensioninthenewborn(PPHN).Theobservedriskwasapproximately5casesper

1000pregnancies.Inthegeneralpopulation1to2casesofPPHNper1000pregnanciesoccur.

Lactation:Fluoxetineanditsmetabolitenorfluoxetineareknowntobeexcretedinhumanbreastmilk.Adverseevents

havebeenreportedinbreastfeedinginfants.Iftreatmentwithfluoxetineisconsiderednecessary,discontinuationof

breastfeedingshouldbeconsidered;however,ifbreastfeedingiscontinued,thelowesteffectivedoseoffluoxetine

shouldbeprescribed.

4.7Effectsonabilitytodriveandusemachines

Althoughfluoxetinehasbeenshownnottoaffectpsychomotorperformanceinhealthyvolunteers,anypsychoactive

drugmayimpairjudgementorskills.Patientsshouldbeadvisedtoavoiddrivingacaroroperatinghazardous

machineryuntiltheyarereasonablycertainthattheirperformanceisnotaffected.

4.8Undesirableeffects

Undesirableeffectsmaydecreaseinintensityandfrequencywithcontinuedtreatmentanddonotgenerallyleadto

cessationoftherapy.

IncommonwithotherSSRIsthefollowingundesirableeffectshavebeenseen:

Bodyasawhole:Hypersensitivity(e.g.pruritus,rash,urticaria,anaphylactoidreaction,vasculitis,serumsickness-like

reaction,angioedema)(see‘Contraindications’and‘Warnings’),chills,serotoninsyndrome,photosensitivity,very

rarelyToxicEpidermalNecrolysis(Lyellsyndrome).

Digestivesystem:Gastrointestinaldisorders(e.g.diarrhoea,nausea,vomiting,dyspepsia,dysphagia,tasteperversion),

drymouth.Abnormalliverfunctiontestshavebeenreportedrarely,veryrarecasesofidiosyncratichepatitis.

Nervoussystem:Headache,sleepabnormalities(e.g.abnormaldreams,insomnia),dizziness,anorexia,fatigue(e.g.

somnolence,drowsiness),euphoria,transientabnormalmovement(e.g.,twitching,ataxia,tremor,myoclonus),seizures

andpsychomotorrestlessness.Hallucinations,manicreaction,confusion,agitation,anxietyandassociatedsymptoms

(e.g.nervousness),impairedconcentrationandthoughtprocess(e.g.depersonalisation),panicattacks(thesesymptoms

maybeduetotheunderlyingdisease),veryrarelyserotoninsyndrome.

Urogenitalsystem:Urinaryretention,urinaryfrequency

Reproductivedisorders:Sexualdysfunction(delayedorabsentejaculation,anorgasmia),priapism,galactorrhoea.

Miscellaneous:Alopecia,yawn,abnormalvision(e.g.,blurredvision,mydriasis),sweating,vasodilatation,arthralgia,

myalgia,posturalhypotension,ecchymosis.Otherhaemorrhagicmanifestations(e.g.,gynaecologicalhaemorrhages,

gastrointestinalbleedingsandothercutaneousormucousbleedings)havebeenreportedrarely(see‘Precautions’

Haemorrhage).

Hyponatraemia:Hyponatraemia(includingserumsodiumbelow110mmol/l)hasbeenrarelyreportedandappearedto

bereversiblewhenfluoxetinewasdiscontinued.Somecaseswerepossiblyduetothesyndromeofinappropriate

antidiuretichormonesecretion.Themajorityofreportswereassociatedwitholderpatients,andpatientstaking

diureticsorotherwisevolumedepleted.

Respiratorysystem:Pharyngitis,dyspnoea.Pulmonaryevents(includinginflammatoryprocessesofvarying

histopathologyand/orfibrosis)havebeenreportedrarely.Dyspnoeamaybetheonlyprecedingsymptom.

Musculoskeletaldisorders:

Classeffects

Epidemiologicalstudies,mainlyconductedinpatients50yearsofageandolder,showanincreasedriskofbone

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/02/2012 CRN 2085601 page number: 6

Withdrawalsymptoms:

Whenstoppingtreatment,withdrawalsymptomshavebeenreportedinassociationwithSSRIs,althoughtheavailable

evidencedoesnotsuggestthisisduetodependence.Commonsymptomsincludedizziness,paraesthesia,headache,

anxietyandnausea,themajorityofwhicharemildandself-limiting.Fluoxetinehasbeenonlyrarelyassociatedwith

suchsymptoms.Plasmafluoxetineandnorfluoxetineconcentrationsdecreasegraduallyattheconclusionoftherapy,

whichmakesdosagetaperingunnecessaryinmostpatients.

4.9Overdose

Casesofoverdoseoffluoxetinealoneusuallyhaveamildcourse.Symptomsofoverdosehaveincludednausea,

vomiting,seizures,cardiovasculardysfunctionrangingfromasymptomaticarrhythmiastocardiacarrest,pulmonary

dysfunction,andsignsofalteredCNSstatusrangingfromexcitationtocoma.Fatalityattributedtooverdoseof

fluoxetinealonehasbeenextremelyrare.Cardiacandvitalsignsmonitoringarerecommended,alongwithgeneral

symptomaticandsupportivemeasures.Nospecificantidoteisknown.

Forceddiuresis,dialysis,haemoperfusion,andexchangetransfusionareunlikelytobeofbenefit.Activatedcharcoal,

whichmaybeusedwithsorbitol,maybeasormoreeffectivethanemesisorlavage.Inmanagingoverdosage,consider

thepossibilityofmultipledruginvolvement.Anextendedtimeforclosemedicalobservationmaybeneededinpatients

whohavetakenexcessivequantitiesofatricyclicantidepressantiftheyarealsotaking,orhaverecentlytaken,

fluoxetine.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:SelectiveSerotoninreuptakeInhibitors

ATCcode:N06AB03

Fluoxetineisaselectiveinhibitorofserotoninreuptake,andthisprobablyaccountsforthemechanismofaction.

Fluoxetinehaspracticallynoaffinitytootherreceptorssuchas1-,2-,and-adrenergic,serotonergic;dopaminergic;

histaminergic1muscarinic;andGABAreceptors.

Majordepressiveepisodes:Clinicaltrialsinpatientswithmajordepressiveepisodeshavebeenconductedversus

placeboandactivecontrols.Fluoxetinehasbeenshowntobesignificantlymoreeffectivethanplaceboasmeasuredby

theHamiltonDepressionRatingScale(HAM-D).Inthesestudies,fluoxetineproducedasignificantlyhigherrateof

response(definedbya50%decreaseintheHAM-Dscore)andremission,comparedtoplacebo.

Doseresponse:Inthefixeddosestudiesofpatientswithmajordepressionthereisaflatdoseresponsecurve,providing

nosuggestionofadvantageintermsofefficacyforusinghigherthantherecommendeddoses.However,itisclinical

experiencethatuptitratingmightbebeneficialforsomepatients.

Obsessive-compulsivedisorder:Inshort-termtrials(under24weeks),fluoxetinewasshowntobesignificantlymore

effectivethanplacebo.Therewasatherapeuticeffectat20mg/day,buthigherdoses(40or60mg/day)showeda

higherresponserate.Inlongtermstudies(threeshorttermstudiesextensionphaseandarelapsepreventionstudy)

efficacyhasnotbeenshown.

Bulimianervosa:Inshorttermtrials(under16weeks),inout-patientsfulfillingDSM-III-R-criteriaforbulimia

nervosa,fluoxetine60mg/daywasshowntobesignificantlymoreeffectivethanplaceboforthereductionofbingeing

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/02/2012 CRN 2085601 page number: 7

Majordepressiveepisodes(childrenandadolescents):Fluoxetine60mgcapsulesarenotlicensedforuseinthe

treatmentofchildrenandadolescentsundertheageof18years.Clinicaltrialsinchildrenandadolescentsaged8

yearsandabovehavebeenconductedversusplacebo.Fluoxetine,atadoseof20mg,hasbeenshowntobesignificantly

moreeffectivethanplacebointwoshort-termpivotalstudies,asmeasuredbythereductionofChildhoodDepression

RatingScale-Revised(CDRS-R)totalscoresandClinicalGlobalImpressionofImprovement(CGI-I)scores.Inboth

studies,patientsmetcriteriaformoderatetosevereMDD(DSM-IIIorDSM-IV)atthreedifferentevaluationsby

practisingchildpsychiatrists.Efficacyinthefluoxetinetrialsmaydependontheinclusionofaselectivepatient

population(onethathasnotspontaneouslyrecoveredwithinaperiodof3-5weeksandwhosedepressionpersistedin

thefaceofconsiderableattention).Thereisonlylimiteddataonsafetyandefficacybeyond9weeks.Ingeneral,

efficacyoffluoxetinewasmodest.Responserates(theprimaryendpoint,definedasa30%decreaseintheCDRS-R

score)demonstratedastatisticallysignificantdifferenceinoneofthetwopivotalstudies(58%forfluoxetineversus

32%forplacebo,P=0.013and65%forfluoxetineversus54%forplacebo,P=0.093).Inthesetwostudiesthemean

absolutechangesinCDRS-Rfrombaselinetoendpointwere20forfluoxetineversus11forplacebo,P=0.002and22

forfluoxetineversus15forplacebo,P<0.001.

5.2Pharmacokineticproperties

Absorption

Fluoxetineiswellabsorbedfromthegastrointestinaltractafteroraladministration.Thebioavailabilityisnotaffected

byfoodintake.

Distribution

Fluoxetineisextensivelyboundtoplasmaproteins(about95%)anditiswidelydistributed(VolumeofDistribution:20

-401/kg).Steady-stateplasmaconcentrationsareachievedafterdosingforseveralweeks.Steady-stateconcentrations

afterprolongeddosingaresimilartoconcentrationsseenat4to5weeks.

Metabolism

Fluoxetinehasanon-linearpharmacokineticprofilewithfirstpasslivereffect.Maximumplasmaconcentrationis

generallyachieved6to8hoursafteradministration.Fluoxetineisextensivelymetabolisedbythepolymorphicenzyme

CYP2D6.Fluoxetineisprimarilymetabolisedbythelivertotheactivemetabolitenorfluoxetine(desmethylfluoxetine),

bydesmethylation.

Elimination

Theeliminationhalf-lifeoffluoxetineis4to6daysandfornorfluoxetine4tol6days.Theselonghalf-livesare

responsibleforpersistenceofthedrugfor5-6weeksafterdiscontinuation.Excretionismainly(about60%)viathe

kidney.Fluoxetineissecretedintobreastmilk.

At-riskpopulations

Elderly:Kineticparametersarenotalteredinhealthyelderlywhencomparedtoyoungersubjects

Hepaticinsufficiency:Incaseofhepaticinsufficiency(alcoholiccirrhosis),fluoxetineandnorfluoxetinehalf-livesare

increasedto7and12days,respectively.Alowerorlessfrequentdoseshouldbeconsidered.

Renalinsufficiency:Aftersingle-doseadministrationoffluoxetineinpatientswithmild,moderateorcomplete(anuria)

renalinsufficiency,kineticparametershavenotbeenalteredwhencomparedtohealthyvolunteers.However,after

repeatedadministration,anincreaseinsteady-stateplateauofplasmaconcentrationsmaybeobserved.

Childrenandadolescents:Themeanfluoxetineconcentrationinchildrenisapproximately2-foldhigherthanthat

observedinadolescentsandthemeannorfluoxetineconcentration1.5-foldhigher.Steadystateplasmaconcentrations

aredependentonbodyweightandarehigherinlowerweightchildren.Asinadults,fluoxetineandnorfluoxetine

accumulatedextensivelyfollowingmultipleoraldosing;steady-stateconcentrationswereachievedwithin3to4weeks

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/02/2012 CRN 2085601 page number: 8

5.3Preclinicalsafetydata

Thereisnoevidenceofcarcinogenicityormutagenicityfrominvitrooranimalstudies.

InajuveniletoxicologystudyinCDrats,administrationof30mg/kg/dayoffluoxetinehydrochlorideonpostnataldays

21to90resultedinirreversibletesticulardegenerationandnecrosis,epididymalepithelialvacuolation,immaturityand

inactivityofthefemalereproductivetractanddecreasedfertility.Delaysinsexualmaturationoccurredinmales(10

and30mg/kg/day)andfemales(30mg/kg/day).Thesignificanceofthesefindingsinhumansisunknown.Rats

administered30mg/kgalsohaddecreasedfemurlengthscomparedwithcontrolsandskeletalmuscledegeneration,

necrosisandregeneration.At10mg/kg/day,plasmalevelsachievedinanimalswereapproximately0.8to8.8fold

(fluoxetine)and3.6to23.2fold(norfluoxetine)thoseusuallyobservedinpaediatricpatients.At3mg/kg/day,plasma

levelsachievedinanimalswereapproximately0.04to0.5fold(fluoxetine)and0.3to2.1fold(norfluoxetine)those

usuallyachievedinpaediatricpatients.

Astudyinjuvenilemicehasindicatedthatinhibitionoftheserotonintransporterpreventstheaccrualofbone

formation.Thisfindingwouldappeartobesupportedbyclinicalfindings.Thereversibilityofthiseffecthasnotbeen

established.

Anotherstudyinjuvenilemice(treatedonpostnataldays4to21)hasdemonstratedthatinhibitionoftheserotonin

transporterhadlonglastingeffectsonthebehaviourofthemice.Thereisnoinformationonwhethertheeffectwas

reversible.Theclinicalrelevanceofthisfindinghasnotbeenestablished.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

6.2Incompatibilities

NotApplicable

6.3Shelflife

3years.

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

PVC-Aclar/AluminiumBlisterstrips

Packsizes:Cartonscontaining5,7,10,14,28,30,42,56or60capsules.

CapsuleContents: Pre-gelatinised(maize)starch

CapsuleShell: FD&CYellow#5(Tartrazine–E102)FD&CYellow#6(SunsetYellow

FCF–E110)

TitaniumDioxide(E171)

Sorbitanmonolaurate

Sodiumlaurilsulfate

Gelatin

PrintingInk: BlackIronOxide(E172)

Shellac

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/02/2012 CRN 2085601 page number: 9

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

DrReddy’sLaboratories(UK)Ltd

6RiverviewRoad

Beverley

EastYorkshire

HU170LD

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA1364/001/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:03/10/2008

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/02/2012 CRN 2085601 page number: 10