FLUOXETINE AUROBINDO

Main information

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

Documents

Localization

  • Available in:
  • FLUOXETINE AUROBINDO
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1050/006/001
  • Authorization date:
  • 21-01-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

FluoxetineAurobindo20mg/5mloralsolution

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each5mloforalsolutioncontains20mgoffluoxetine(ashydrochloride).

Excipients:Contains3gofsucroseper5mldose.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Oralsolution.

Aclear,colorless,peppermintflavoredliquid.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Adults:

Majordepressiveepisodes.

Obsessive-compulsivedisorder.

Bulimianervosa:Fluoxetineisindicatedasacomplementofpsychotherapyforthereductionofbinge-eating

andpurgingactivity.

ChildrenandAdolescentsAged8YearsandAbove:

Moderatetoseveremajordepressiveepisode,ifdepressionisunresponsivetopsychologicaltherapyafter4-6sessions.

Antidepressantmedicationshouldbeofferedtoachildoryoungpersonwithmoderatetoseveredepressiononlyin

combinationwithaconcurrentpsychologicaltherapy.

4.2Posologyandmethodofadministration

Fororaladministration.

Majordepressiveepisodes:Adultsandtheelderly:Therecommendeddoseis20mgdaily.Dosageshouldbereviewed

andadjusted,ifnecessary,within3to4weeksofinitiationoftherapyandthereafterasjudgedclinicallyappropriate.

Althoughtheremaybeanincreasedpotentialforundesirableeffectsathigherdoses,insomepatients,withinsufficient

responseto20mg,thedosemaybeincreasedgraduallyuptoamaximumof60mg(seesection5.1).Dosage

adjustmentsshouldbemadecarefully,onanindividualpatientbasis,tomaintainthepatientsatthelowesteffective

dose.

Patientswithdepressionshouldbetreatedforasufficientperiodofatleast6monthstoensurethattheyarefreefrom

symptoms.

Obsessive-compulsivedisorder:Adultsandtheelderly:Therecommendeddoseis20mgdaily.Althoughtheremaybe

anincreasedpotentialforundesirableeffectsathigherdoses,insomepatients,ifaftertwoweeksthereisinsufficient

responseto20mg,thedosemaybeincreasedgraduallyuptoamaximumof60mg.

Ifnoimprovementisobservedwithin10weeks,treatmentwithfluoxetineshouldbereconsidered.Ifagoodtherapeutic

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systematicstudiestoanswerthequestionofhowlongtocontinuefluoxetinetreatment,OCDisachronicconditionand

itisreasonabletoconsidercontinuationbeyond10weeksinrespondingpatients.

Dosageadjustmentsshouldbemadecarefully,onanindividualpatientbasis,tomaintainthepatientatthelowest

effectivedose.Theneedfortreatmentshouldbereassessedperiodically.Somecliniciansadvocateconcomitant

behaviouralpsychotherapyforpatientswhohavedonewellonpharmacotherapy.

Long-termefficacy(morethan24weeks)hasnotbeendemonstratedinOCD.

Bulimianervosa:Adultsandtheelderly:Adoseof60mg/dayisrecommended.Long-termefficacy(morethan3

months)hasnotbeendemonstratedinbulimianervosa.

Allindications:Adults:Therecommendeddosemaybeincreasedordecreased.Dosesabove80mg/dayhavenotbeen

systematicallyevaluated.

Fluoxetinemaybeadministeredasasingleordivideddose,duringorbetweenmeals.

Whendosingisstopped,activedrugsubstanceswillpersistinthebodyforweeks.Thisshouldbeborneinmindwhen

startingorstoppingtreatment.

Childrenandadolescentsaged8yearsandabove(moderatetoseveremajordepressiveepisode):Treatmentshouldbe

initiatedandmonitoredunderspecialistsupervision.Thestartingdoseis10mg/daygivenas2.5mloftheFluoxetine

Aurobindoliquidformulation.Doseadjustmentsshouldbemadecarefully,onanindividualbasis,tomaintainthe

patientatthelowesteffectivedose.

Afteronetotwoweeks,thedosemaybeincreasedto20mg/day.Clinicaltrialexperiencewithdailydosesgreaterthan

20mgisminimal.Thereisonlylimiteddataontreatmentbeyond9weeks.

Lowerweightchildren:Duetohigherplasmalevelsinlowerweightchildren,thetherapeuticeffectmaybeachieved

withlowerdoses(seesection5.2).

Forpaediatricpatientswhorespondtotreatment,theneedforcontinuedtreatmentafter6monthsshouldbereviewed.

Ifnoclinicalbenefitisachievedwithin9weeks,treatmentshouldbereconsidered.

Elderly:Cautionisrecommendedwhenincreasingthedose,andthedailydoseshouldgenerallynotexceed40mg.

Maximumrecommendeddoseis60mg/day.

Alowerorlessfrequentdose(eg,20mgeverysecondday)shouldbeconsideredinpatientswithhepaticimpairment

(seesection5.2),orinpatientswhereconcomitantmedicationhasthepotentialforinteractionwithFluoxetine

Aurobindo(seesection4.5).

WithdrawalsymptomsseenondiscontinuationofFluoxetineAurobindo:Abruptdiscontinuationshouldbeavoided.

WhenstoppingtreatmentwithFluoxetineAurobindothedoseshouldbegraduallyreducedoveraperiodofatleastone

totwoweeksinordertoreducetheriskofwithdrawalreactions(seesection4.4andsection4.8).Ifintolerable

symptomsoccurfollowingadecreaseinthedoseorupondiscontinuationoftreatment,thenresumingthepreviously

prescribeddosemaybeconsidered.Subsequently,thephysicianmaycontinuedecreasingthedose,butatamore

gradualrate.

4.3Contraindications

Hypersensitivitytofluoxetineortoanyofitsexcipients.

Monoamineoxidaseinhibitors:Casesofseriousandsometimesfatalreactionshavebeenreportedinpatientsreceiving

anSSRIincombinationwithamonoamineoxidaseinhibitor(MAOI),andinpatientswhohaverecentlydiscontinued

anSSRIandhavebeenstartedonaMAOI.Treatmentoffluoxetineshouldonlybestarted2weeksafter

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Somecasespresentedwithfeaturesresemblingserotoninsyndrome(whichmayresembleandbediagnosedas

neurolepticmalignantsyndrome).Cyproheptadineordantrolenemaybenefitpatientsexperiencingsuchreactions.

SymptomsofadruginteractionwithaMAOIinclude:hyperthermia,rigidity,myoclonus,autonomicinstabilitywith

possiblerapidfluctuationsofvitalsigns,mentalstatuschangesthatincludeconfusion,irritabilityandextreme

agitation,progressingtodeliriumandcoma.

Therefore,fluoxetineiscontra-indicatedincombinationwithanon-selectiveMAOI.Similarly,atleast5weeksshould

elapseafterdiscontinuingfluoxetinetreatmentbeforestartingaMAOI.Iffluoxetinehasbeenprescribedchronically

and/oratahighdose,alongerintervalshouldbeconsidered.

ThecombinationoffluoxetinewithareversibleMAOI(eg,moclobemide)isnotrecommended.Treatmentwith

fluoxetinecanbeinitiatedthefollowingdayafterdiscontinuationofareversibleMAOI.

4.4Specialwarningsandprecautionsforuse

Useinchildrenandadolescentsunder18yearsofage:Suicide-relatedbehaviours(suicideattemptandsuicidal

thoughts)andhostility(predominantlyaggression,oppositionalbehaviourandanger)weremorefrequentlyobservedin

clinicaltrialsamongchildrenandadolescentstreatedwithantidepressantscomparedtothosetreatedwithplacebo.

Fluoxetineshouldonlybeusedinchildrenandadolescentsaged8to18yearsforthetreatmentofmoderatetosevere

majordepressiveepisodesanditshouldnotbeusedinotherindications.If,basedonclinicalneed,adecisiontotreatis

neverthelesstaken,thepatientshouldbecarefullymonitoredfortheappearanceofsuicidalsymptoms.Inaddition,only

limitedevidenceisavailableconcerninglong-termeffectonsafetyinchildrenandadolescents,includingeffectson

growth,sexualmaturationandcognitive,emotionalandbehaviouraldevelopments(seesection5.3).

Ina19-weekclinicaltrial,decreasedheightandweightgainwasobservedinchildrenandadolescentstreatedwith

fluoxetine(seesection4.8).Ithasnotbeenestablishedwhetherthereisaneffectonachievingnormaladultheight.The

possibilityofadelayinpubertycannotberuledout(seesections5.3and4.8).Growthandpubertaldevelopment

(height,weight,andTANNERstaging)shouldthereforebemonitoredduringandaftertreatmentwithfluoxetine.If

eitherisslowed,referraltoapaediatricianshouldbeconsidered.

Inpaediatrictrials,maniaandhypomaniawerecommonlyreported(seesection4.8).Therefore,regularmonitoringfor

theoccurrenceofmania/hypomaniaisrecommended.Fluoxetineshouldbediscontinuedinanypatiententeringa

manicphase.

Itisimportantthattheprescriberdiscussescarefullytherisksandbenefitsoftreatmentwiththechild/youngperson

and/ortheirparents.

Rashandallergicreactions:Rash,anaphylactoideventsandprogressivesystemicevents,sometimesserious

(involvingskin,kidney,liverorlung),havebeenreported.Upontheappearanceofrashorofotherallergicphenomena

forwhichanalternativeaetiologycannotbeidentified,fluoxetineshouldbediscontinued.

Seizures:Seizuresareapotentialriskwithantidepressantdrugs.Therefore,aswithotherantidepressants,fluoxetine

shouldbeintroducedcautiouslyinpatientswhohaveahistoryofseizures.Treatmentshouldbediscontinuedinany

patientwhodevelopsseizuresorwherethereisanincreaseinseizurefrequency.Fluoxetineshouldbeavoidedin

patientswithunstableseizuredisorders/epilepsyandpatientswithcontrolledepilepsyshouldbecarefullymonitored.

Mania:Antidepressantsshouldbeusedwithcautioninpatientswithahistoryofmania/hypomania.Aswithall

antidepressants,fluoxetineshouldbediscontinuedinanypatiententeringamanicphase.

Hepatic/Renalfunction:Fluoxetineisextensivelymetabolisedbytheliverandexcretedbythekidneys.Alowerdose,

eg,alternatedaydosing,isrecommendedinpatientswithsignificanthepaticdysfunction.Whengivenfluoxetine

20mg/dayfor2months,patientswithsevererenalfailure(GFR<10ml/min)requiringdialysisshowednodifferencein

plasmalevelsoffluoxetineornorfluoxetinecomparedtocontrolswithnormalrenalfunction.

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whoreceivedfluoxetineindouble-blindclinicaltrials.However,clinicalexperienceinacutecardiacdiseaseislimited;

therefore,cautionisadvisable.

Weightloss:Weightlossmayoccurinpatientstakingfluoxetinebutitisusuallyproportionaltobaselinebodyweight.

Diabetes:Inpatientswithdiabetes,treatmentwithanSSRImayalterglycaemiccontrol.Hypoglycaemiahasoccurred

duringtherapywithfluoxetineandhyperglycaemiahasdevelopedfollowingdiscontinuation.Insulinand/ororal

hypoglycaemicdosagemayneedtobeadjusted.

Suicide/suicidalthoughts:Depressionisassociatedwithanincreasedriskofsuicidalthoughts,self-harmandsuicide

(suicide-relatedevents).Thisriskpersistsuntilsignificantremissionoccurs.Asimprovementmaynotoccurduringthe

firstfewweeksormoreoftreatment,patientsshouldbecloselymonitoreduntilsuchimprovementoccurs.Itisgeneral

clinicalexperiencethattheriskofsuicidemayincreaseintheearlystagesofrecovery.

Otherpsychiatricconditionsforwhichfluoxetineisprescribedcanalsobeassociatedwithanincreasedriskofsuicide-

relatedevents.Inaddition,theseconditionsmaybeco-morbidwithmajordepressivedisorder.Thesameprecautions

observedwhentreatingpatientswithmajordepressivedisordershouldthereforebeobservedwhentreatingpatients

withotherpsychiatricdisorders.

Patientswithahistoryofsuicide-relatedeventsandthoseexhibitingasignificantdegreeofsuicidalideationpriorto

commencementoftreatmentareknowntobeatgreaterriskofsuicidalthoughtsorsuicideattempts,andshouldreceive

carefulmonitoringduringtreatment.Inaddition,thereisapossibilityofanincreasedriskofsuicidalbehaviourin

youngadults.

Patients(andcaregiversofpatients)shouldbealertedabouttheneedtomonitorfortheemergenceofsucheventsand

toseekmedicaladviceimmediatelyifthesesymptomspresent.

Akathisia/psychomotorrestlessness:Theuseoffluoxetinehasbeenassociatedwiththedevelopmentofakathisia,

characterisedbyasubjectivelyunpleasantordistressingrestlessnessandneedtomove,oftenaccompaniedbyan

inabilitytositorstandstill.Thisismostlikelytooccurwithinthefirstfewweeksoftreatment.Inpatientswho

developthesesymptoms,increasingthedosemaybedetrimental.

WithdrawalsymptomsseenondiscontinuationofSSRItreatment:Withdrawalsymptomswhentreatmentis

discontinuedarecommon,particularlyifdiscontinuationisabrupt(seesection4.8).Inclinicaltrials,adverseevents

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(see'Withdrawalsymptomsseenon

discontinuationoffluoxetine',section4.2).

Haemorrhage:Therehavebeenreportsofcutaneousbleedingabnormalities,suchasecchymosisandpurpurawith

SSRIs.Ecchymosishasbeenreportedasaninfrequenteventduringtreatmentwithfluoxetine.

Otherhaemorrhagicmanifestations(eg,gynaecologicalhaemorrhages,gastro-intestinalbleedingsandothercutaneous

ormucousbleedings)havebeenreportedrarely.CautionisadvisedinpatientstakingSSRIs,particularlyin

concomitantusewithoralanticoagulants,drugsknowntoaffectplateletfunction(eg,atypicalantipsychotics,suchas

clozapine,phenothiazines,mostTCAs,aspirin,NSAIDs),orotherdrugsthatmayincreaseriskofbleeding,aswellas

inpatientswithahistoryofbleedingdisorders.

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receivingECTtreatment;therefore,cautionisadvisable.

StJohn'sWort:Anincreaseinserotonergiceffects,suchasserotoninsyndrome,mayoccurwhenselectiveserotonin

reuptakeinhibitorsandherbalpreparationscontainingStJohn'sWort(Hypericumperforatum)areusedtogether.

Onrareoccasions,developmentofaserotoninsyndromeorneurolepticmalignantsyndrome-likeeventshavebeen

reportedinassociationwithtreatmentoffluoxetine,particularlywhengivenincombinationwithotherserotonergic

(amongothers,L-tryptophan)and/orneurolepticdrugs.Asthesesyndromesmayresultinpotentiallylife-threatening

conditions,treatmentwithfluoxetineshouldbediscontinuedifsuchevents(characterisedbyclustersofsymptoms,

suchashyperthermia,rigidity,myoclonus,autonomicinstabilitywithpossiblerapidfluctuationsofvitalsigns,mental

statuschanges,includingconfusion,irritability,extremeagitation,progressingtodeliriumandcoma)occurand

supportivesymptomatictreatmentshouldbeinitiated.

FluoxetineAurobindooralsolutioncontainssucrose:Patientswithrarehereditaryproblemsoffructoseintolerance,

glucose-galactosemalabsorptionorsucrase-isomaltaseinsufficiencyshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Interactionstudieshaveonlybeenperformedinadults.

Half-life:Thelongeliminationhalf-livesofbothfluoxetineandnorfluoxetineshouldbeborneinmind(seesection

5.2)whenconsideringpharmacodynamicorpharmacokineticdruginteractions(eg,whenswitchingfromfluoxetineto

otherantidepressants).

Monoamineoxidaseinhibitors:Seesection4.3.

Notrecommendedcombinations:MAOI-A(seesection4.3).

Combinationsrequiringprecautionsforuse:MAOI-B(selegeline):Riskofserotoninsyndrome.Clinicalmonitoring

isrecommended.

Phenytoin:Changesinbloodlevelshavebeenobservedwhencombinedwithfluoxetine.Insomecasesmanifestations

oftoxicityhaveoccurred.Considerationshouldbegiventousingconservativetitrationschedulesoftheconcomitant

drugandtomonitoringclinicalstatus.

Serotonergicdrugs:Co-administrationwithserotonergicdrugs(eg,tramadol,triptans)mayincreasetheriskof

serotoninsyndrome.Usewithtriptanscarriestheadditionalriskofcoronaryvasoconstrictionandhypertension.

Lithiumandtryptophan:TherehavebeenreportsofserotoninsyndromewhenSSRIshavebeengivenwithlithiumor

tryptophanand,therefore,theconcomitantuseoffluoxetinewiththesedrugsshouldbeundertakenwithcaution.When

fluoxetineisusedincombinationwithlithium,closerandmorefrequentclinicalmonitoringisrequired.

CYP2D6isoenzyme:Becausefluoxetine'smetabolism(liketricyclicantidepressantsandotherselectiveserotonin

antidepressants)involvesthehepaticcytochromeCYP2D6isoenzymesystem,concomitanttherapywithdrugsalso

metabolisedbythisenzymesystemmayleadtodruginteractions.Concomitanttherapywithdrugspredominantly

metabolisedbythisisoenzyme,andwhichhaveanarrowtherapeuticindex(suchasflecainide,encainide,

carbamazepineandtricyclicantidepressants),shouldbeinitiatedatoradjustedtothelowendoftheirdoserange.This

willalsoapplyiffluoxetinehasbeentakenintheprevious5weeks.

Oralanticoagulants:Alteredanticoagulanteffects(laboratoryvaluesand/orclinicalsignsandsymptoms),withno

consistentpattern,butincludingincreasedbleeding,havebeenreporteduncommonlywhenfluoxetineisco-

administeredwithoralanticoagulants.Patientsreceivingwarfarintherapyshouldreceivecarefulcoagulation

monitoringwhenfluoxetineisinitiatedorstopped(seesection4.4,'Haemorrhage').

Electroconvulsivetherapy(ECT):Therehavebeenrarereportsofprolongedseizuresinpatientsonfluoxetine

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Alcohol:Informaltesting,fluoxetinedidnotraisebloodalcohollevelsorenhancetheeffectsofalcohol.However,the

combinationofSSRItreatmentandalcoholisnotadvisable.

StJohn'sWort:IncommonwithotherSSRIs,pharmacodynamicinteractionsbetweenfluoxetineandtheherbal

remedyStJohn'sWort(Hypericumperforatum)mayoccur,whichmayresultinanincreaseofundesirableeffects.

4.6Fertility,pregnancyandlactation

Pregnancy:Someepidemiologicalstudiessuggestanincreasedriskofcardiovasculardefectsassociatedwiththeuse

offluoxetineduringthefirsttrimester.Themechanismisunknown.Overallthedatasuggestthattheriskofhavingan

infantwithacardiovasculardefectfollowingmaternalfluoxetineexposureisintheregionof2/100comparedwithan

expectedrateforsuchdefectsofapproximately1/100inthegeneralpopulation.

Fluoxetinecanbeusedduringpregnancy,butcautionshouldbeexercised,especiallyduringlatepregnancyorjust

priortotheonsetoflabour,sincethefollowingeffectshavebeenreportedinneonates:irritability,tremor,hypotonia,

persistentcrying,difficultyinsuckingorinsleeping.Thesesymptomsmayindicateeitherserotonergiceffectsora

withdrawalsyndrome.Thetimetooccurandthedurationofthesesymptomsmayberelatedtothelonghalf-lifeof

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

EpidemiologicaldatahavesuggestedthattheuseofSSRIsinpregnancy,particularinlatepregnancy,mayincreasethe

riskofpersistentpulmonaryhypertensioninthenewborn(PPHN).Theobservedriskwasapproximately5casesper

1000pregnancies.Inthegeneralpopulation1to2casesofPPHNper1000pregnanciesoccur.

Lactation:Fluoxetineanditsmetabolite,norfluoxetine,areknowntobeexcretedinhumanbreastmilk.Adverseevents

havebeenreportedinbreast-feedinginfants.Iftreatmentwithfluoxetineisconsiderednecessary,discontinuationof

breast-feedingshouldbeconsidered;however,ifbreast-feedingiscontinued,thelowesteffectivedoseoffluoxetine

shouldbeprescribed.

4.7Effectsonabilitytodriveandusemachines

Althoughfluoxetinehasbeenshownnottoaffectpsychomotorperformanceinhealthyvolunteers,anypsychoactive

drugmayimpairjudgementorskills.Patientsshouldbeadvisedtoavoiddrivingacaroroperatinghazardous

machineryuntiltheyarereasonablycertainthattheirperformanceisnotaffected.

4.8Undesirableeffects

Undesirableeffectsmaydecreaseinintensityandfrequencywithcontinuedtreatmentanddonotgenerallyleadto

cessationoftherapy.

IncommonwithotherSSRIs,thefollowingundesirableeffectshavebeenseen:

Bodyasawhole:Hypersensitivity(eg,pruritus,rash,urticaria,anaphylactoidreaction,vasculitis,serumsickness-like

reaction,angioedema)(seesections4.3and4.4),chills,serotoninsyndrome,photosensitivityandveryrarely,erythema

multiformethatcouldprogresstoStevens-Johnsonsyndromeortoxicepidermalnecrolysis(Lyellsyndrome).

Digestivesystem:Gastro-intestinaldisorders(eg,diarrhoea,nausea,vomiting,dyspepsia,dysphagia,tasteperversion),

drymouth.Abnormalliverfunctiontestshavebeenreportedrarely.Veryrarecasesofidiosyncratichepatitis.

Nervoussystem:Headache,sleepabnormalities(eg,abnormaldreams,insomnia),dizziness,anorexia,fatigue(eg,

somnolence,drowsiness),euphoria,transientabnormalmovement(eg,twitching,ataxia,tremor,myoclonus),seizures

andrarely,psychomotorrestlessness/akathisia(seesection4.4).Hallucinations,manicreaction,confusion,agitation,

anxietyandassociatedsymptoms(eg,nervousness),impairedconcentrationandthoughtprocess(eg,

depersonalisation),panicattacks,suicidalthoughtsandbehaviour(thesesymptomsmaybeduetotheunderlying

disease),and,veryrarely,serotoninsyndrome.

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

Miscellaneous:Alopecia,yawn,abnormalvision(eg,blurredvision,mydriasis),sweating,vasodilatation,arthralgia,

myalgia,posturalhypotension,ecchymosis.Otherhaemorrhagicmanifestations(eg,gynaecologicalhaemorrhages,

gastro-intestinalbleedingsandothercutaneousormucousbleedings)havebeenreportedrarely(seesection4.4,

'Haemorrhage').

Hyponatraemia:Hyponatraemia(includingserumsodiumbelow110mmol/l)hasbeenrarelyreportedandappearedto

bereversiblewhenfluoxetinewasdiscontinued.Somecaseswerepossiblyduetothesyndromeofinappropriate

antidiuretichormonesecretion.Themajorityofreportswereassociatedwitholderpatients,andpatientstaking

diureticsorotherwisevolumedepleted.

Respiratorysystem:Pharyngitis,dyspnoea.Pulmonaryevents(includinginflammatoryprocessesofvarying

histopathologyand/orfibrosis)havebeenreportedrarely.Dyspnoeamaybetheonlyprecedingsymptom.

Withdrawalsymptomsseenondiscontinuationoffluoxetinetreatments:Discontinuationoffluoxetinecommonly

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

insomniaandintensedreams),asthenia,agitationoranxiety,nauseaand/orvomiting,tremorandheadachearethemost

commonlyreportedreactions.Generally,theseeventsaremildtomoderateandareself-limiting;however,insome

patientstheymaybesevereand/orprolonged(seesection4.4).Itisthereforeadvisedthatwhenfluoxetinetreatmentis

nolongerrequired,gradualdiscontinuationbydosetaperingshouldbecarriedout(seesection4.2andsection4.4).

Childrenandadolescents(seesection4.4):Inpaediatricclinicaltrials,suicide-relatedbehaviours(suicideattemptand

suicidalthoughts)andhostilityweremorefrequentlyobservedamongchildrenandadolescentstreatedwith

antidepressantscomparedtothosetreatedwithplacebo.

Thesafetyoffluoxetinehasnotbeensystematicallyassessedforchronictreatmentlongerthan19weeks.

Inpaediatricclinicaltrials,manicreactions,includingmaniaandhypomania,werereported(2.6%offluoxetine-treated

patientsversus0%inplacebo-controls),leadingtodiscontinuationinthemajorityofcases.Thesepatientshadnoprior

episodesofhypomania/mania.

After19weeksoftreatment,paediatricsubjectstreatedwithfluoxetineinaclinicaltrialgainedanaverageof1.1cm

lessinheight(P=0.004)and1.1kglessinweight(P=0.008)thansubjectstreatedwithplacebo.Isolatedcasesof

growthretardationhavealsobeenreportedfromclinicaluse.

Isolatedcasesofadverseeventspotentiallyindicatingdelayedsexualmaturationorsexualdysfunctionhavebeen

reportedfrompaediatricclinicaluse(seealsosection5.3).

Inpaediatricclinicaltrials,fluoxetinetreatmentwasassociatedwithadecreaseinalkalinephosphataselevels.

4.9Overdose

Casesofoverdoseoffluoxetinealoneusuallyhaveamildcourse.Symptomsofoverdosehaveincludednausea,

vomiting,seizures,cardiovasculardysfunctionrangingfromasymptomaticarrhythmiastocardiacarrest,pulmonary

dysfunction,andsignsofalteredCNSstatusrangingfromexcitationtocoma.Fatalityattributedtooverdoseof

fluoxetinealonehasbeenextremelyrare.

Cardiacandvitalsignsmonitoringarerecommended,alongwithgeneralsymptomaticandsupportivemeasures.No

specificantidoteisknown.

Forceddiuresis,dialysis,haemoperfusion,andexchangetransfusionareunlikelytobeofbenefit.Activatedcharcoal,

whichmaybeusedwithsorbitol,maybeasormoreeffectivethanemesisorlavage.Inmanagingoverdosage,consider

thepossibilityofmultipledruginvolvement.Anextendedtimeforclosemedicalobservationmaybeneededinpatients

whohavetakenexcessivequantitiesofatricyclicantidepressantiftheyarealsotaking,orhaverecentlytaken,

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Selectiveserotoninreuptakeinhibitors.ATCcode:N06AB03.

Fluoxetineisaselectiveinhibitorofserotoninreuptake,andthisprobablyaccountsforthemechanismofaction.

Fluoxetinehaspracticallynoaffinitytootherreceptorssuchas

-,and-adrenergic;serotonergic;dopaminergic;

histaminergic

;muscarinic;andGABAreceptors.

Majordepressiveepisodes:Clinicaltrialsinpatientswithmajordepressiveepisodeshavebeenconductedversus

placeboandactivecontrols.Fluoxetinehasbeenshowntobesignificantlymoreeffectivethanplacebo,asmeasuredby

theHamiltonDepressionRatingScale(HAM-D).Inthesestudies,Fluoxetineproducedasignificantlyhigherrateof

response(definedbya50%decreaseintheHAM-Dscore)andremissioncomparedtoplacebo.

Doseresponse:Inthefixeddosestudiesofpatientswithmajordepressionthereisaflatdoseresponsecurve,providing

nosuggestionofadvantageintermsofefficacyforusinghigherthantherecommendeddoses.However,itisclinical

experiencethatuptitratingmightbebeneficialforsomepatients.

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

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

responserate.Inlong-termstudies(threeshort-termstudiesextensionphaseandarelapsepreventionstudy),efficacy

hasnotbeenshown.

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

nervosa,fluoxetine60mg/daywasshowntobesignificantlymoreeffectivethanplaceboforthereductionofbingeing

andpurgingactivities.However,forlong-termefficacynoconclusioncanbedrawn.

Twoplacebo-controlledstudieswereconductedinpatientsmeetingpre-menstrualdysphoricdisorder(PMDD)

diagnosticcriteriaaccordingtoDSM-IV.Patientswereincludediftheyhadsymptomsofsufficientseveritytoimpair

socialandoccupationalfunctionandrelationshipswithothers.Patientsusingoralcontraceptiveswereexcluded.Inthe

firststudyofcontinuous20mgdailydosingfor6cycles,improvementwasobservedintheprimaryefficacyparameter

(irritability,anxietyanddysphoria).Inthesecondstudy,withintermittentlutealphasedosing(20mgdailyfor14days)

for3cycles,improvementwasobservedintheprimaryefficacyparameter(DailyRecordofSeverityofProblems

score).However,definitiveconclusionsonefficacyanddurationoftreatmentcannotbedrawnfromthesestudies.

Majordepressiveepisodes(childrenandadolescents):Clinicaltrialsinchildrenandadolescentsaged8yearsand

abovehavebeenconductedversusplacebo.Fluoxetine,atadoseof20mg,hasbeenshowntobesignificantlymore

effectivethanplacebointwoshort-termpivotalstudies,asmeasuredbythereductionofChildhoodDepressionRating

Scale-Revised(CDRS-R)totalscoresandClinicalGlobalImpressionofImprovement(CGI-I)scores.Inbothstudies,

patientsmetcriteriaformoderatetosevereMDD(DSM-IIIorDSM-IV)atthreedifferentevaluationsbypractising

childpsychiatrists.Efficacyinthefluoxetinetrialsmaydependontheinclusionofaselectivepatientpopulation(one

thathasnotspontaneouslyrecoveredwithinaperiodof3-5weeksandwhosedepressionpersistedinthefaceof

considerableattention).Thereisonlylimiteddataonsafetyandefficacybeyond9weeks.Ingeneral,efficacyof

fluoxetinewasmodest.Responserates(theprimaryendpoint,definedasa30%decreaseintheCDRS-Rscore)

demonstratedastatisticallysignificantdifferenceinoneofthetwopivotalstudies(58%forfluoxetineversus32%for

placebo,P=0.013;and65%forfluoxetineversus54%forplacebo,P=0.093).

Inthesetwostudies,themeanabsolutechangesinCDRS-Rfrombaselinetoendpointwere20forfluoxetineversus11

forplacebo,P=0.002;and22forfluoxetineversus15forplacebo,P<0.001.

5.2Pharmacokineticproperties

Absorption:Fluoxetineiswellabsorbedfromthegastro-intestinaltractafteroraladministration.Thebioavailabilityis

notaffectedbyfoodintake.

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distribution:20-40l/kg).Steady-stateplasmaconcentrationsareachievedafterdosingforseveralweeks.Steady-state

concentrationsafterprolongeddosingaresimilartoconcentrationsseenat4to5weeks.

Metabolism:Fluoxetinehasanon-linearpharmacokineticprofilewithfirstpasslivereffect.Maximumplasma

concentrationisgenerallyachieved6to8hoursafteradministration.Fluoxetineisextensivelymetabolisedbythe

polymorphicenzymeCYP2D6.Fluoxetineisprimarilymetabolisedbythelivertotheactivemetabolitenorfluoxetine

(desmethylfluoxetine),bydesmethylation.

Elimination:Theeliminationhalf-lifeoffluoxetineis4to6daysandfornorfluoxetine4to16days.Theselonghalf-

livesareresponsibleforpersistenceofthedrugfor5-6weeksafterdiscontinuation.Excretionismainly(about60%)

viathekidney.Fluoxetineissecretedintobreastmilk.

At-RiskPopulations

Elderly:Kineticparametersarenotalteredinhealthyelderlywhencomparedtoyoungersubjects.

Childrenandadolescents:Themeanfluoxetineconcentrationinchildrenisapproximately2-foldhigherthanthat

observedinadolescentsandthemeannorfluoxetineconcentration1.5-foldhigher.Steady-stateplasmaconcentrations

aredependentonbodyweightandarehigherinlowerweightchildren(seesection4.2).Asinadults,fluoxetineand

norfluoxetineaccumulatedextensivelyfollowingmultipleoraldosing;steady-stateconcentrationswereachieved

within3to4weeksofdailydosing.

Hepaticinsufficiency:Incaseofhepaticinsufficiency(alcoholiccirrhosis),fluoxetineandnorfluoxetinehalf-livesare

increasedto7and12days,respectively.Alowerorlessfrequentdoseshouldbeconsidered.

Renalinsufficiency:Aftersingle-doseadministrationoffluoxetineinpatientswithmild,moderate,orcomplete

(anuria)renalinsufficiency,kineticparametershavenotbeenalteredwhencomparedtohealthyvolunteers.However,

afterrepeatedadministration,anincreaseinsteady-stateplateauofplasmaconcentrationsmaybeobserved.

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,plasmalevelsachievedinanimalswereapproximately0.8to8.8-fold

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

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

usuallyachievedinpaediatricpatients.

Astudyinjuvenilemicehasindicatedthatinhibitionoftheserotonintransporterpreventstheaccrualofbone

formation.Thisfindingwouldappeartobesupportedbyclinicalfindings.Thereversibilityofthiseffecthasnotbeen

established.

Anotherstudyinjuvenilemice(treatedonpostnataldays4to21)hasdemonstratedthatinhibitionoftheserotonin

transporterhadlonglastingeffectsonthebehaviourofthemice.Thereisnoinformationonwhethertheeffectwas

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Benzoicacid

Sucrose

Glycerol

Ethanol

Naturalpeppermintflavour(Naturalflavoringingredients,Propyleneglycol&Benzylalcohol)

Purifiedwater

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Unopened:2years

Afterfirstopening:28dayswhenstoredbelow25ºC

6.4Specialprecautionsforstorage

Unopened:Thismedicinalproductdoesnotrequireanyspecialstoragecondition.

Forstorageconditionsafterfirstopeningofthemedicinalproduct,seesection6.3.

6.5Natureandcontentsofcontainer

FluoxetineAurobindoisavailableinambercolouredtypeIIIglassbottlescontaining70mloforalsolutionandclosed

withwhiteopaquepolypropylenechildresistantclosure.Thepackcontainsa5mlplasticmeasuringspoon,with

graduationsof2.5mland5mltomeasuretheliquid.

6.6Specialprecautionsfordisposal

Nospecialrequirements

7MARKETINGAUTHORISATIONHOLDER

MilpharmLimited

Ares

OdysseyBusinessPark

WestEndRoad

SouthRuislipHA46QD

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA1050/6/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

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10DATEOFREVISIONOFTHETEXT

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