BIOZAC

Main information

  • Trade name:
  • BIOZAC Capsules Hard 20 Milligram
  • Dosage:
  • 20 Milligram
  • Pharmaceutical form:
  • Capsules Hard
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BIOZAC Capsules Hard 20 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1063/011/001
  • Authorization date:
  • 04-05-2001
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Biozac20mgHardCapsules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachcapsulecontains22.36mgfluoxetinehydrochlorideequivalentto20mgfluoxetine.

Excipient:58mgoflactosemonohydratepercapsule.

Forfulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Capsuleshard.

Olive/greencapsulesmarkedFLE20.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Adults:

Majordepressiveepisodes.

Obsessive-compulsivedisorder.

Bulimianervosa:Fluoxetineisindicatedasacomplementofpsychotherapyforthereductionofbinge-eatingand

purgingactivity.

ChildrenandAdolescentsAged8YearsandAbove:

Moderatetoseveremajordepressiveepisode,ifdepressionisunresponsivetopsychologicaltherapyafter4-6sessions.

Antidepressantmedicationshouldbeofferedtoachildoryoungpersonwithmoderatetoseveredepressiononlyin

combinationwithaconcurrentpsychologicaltherapy.

4.2Posologyandmethodofadministration

Fororaladministration.

Majordepressiveepisodes

Adultsandtheelderly:Therecommendeddoseis20mgdaily.Dosageshouldbereviewedandadjustedifnecessary

within3to4weeksofinitiationoftherapyandthereafterasjudgedclinicallyappropriate.Althoughtheremaybean

increasedpotentialforundesirableeffectsathigherdoses,insomepatients,withinsufficientresponseto20mg,the

dosemaybeincreasedgraduallyuptoamaximumof60mg(seesection5.1).Dosageadjustmentsshouldbemade

carefullyonanindividualpatientbasis,tomaintainthepatientsatthelowesteffectivedose.

Patientswithdepressionshouldbetreatedforasufficientperiodofatleast6monthstoensurethattheyarefreefrom

symptoms.

Obsessive-compulsivedisorder

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undesirableeffectsathigherdoses,insomepatients,ifaftertwoweeksthereisinsufficientresponseto20mg,thedose

maybeincreasedgraduallyuptoamaximumof60mg.

Ifnoimprovementisobservedwithin10weeks,treatmentwithfluoxetineshouldbereconsidered.Ifagoodtherapeutic

responsehasbeenobtained,treatmentcanbecontinuedatadosageadjustedonanindividualbasis.Whilethereareno

systematicstudiestoanswerthequestionofhowlongtocontinuefluoxetinetreatment,OCDisachronicconditionand

itisreasonabletoconsidercontinuationbeyond10weeksinrespondingpatients.Dosageadjustmentsshouldbemade

carefully,onanindividualpatientbasis,tomaintainthepatientatthelowesteffectivedose.

Theneedfortreatmentshouldbereassessedperiodically.Somecliniciansadvocateconcomitantbehavioural

psychotherapyforpatientswhohavedonewellonpharmacotherapy.

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):

Treatmentshouldbeinitiatedandmonitoredunderspecialistsupervision.Thestartingdoseis10mg/day.Dose

adjustmentsshouldbemadecarefully,onanindividualbasis,tomaintainthepatientatthelowesteffectivedose.

Afteronetotwoweeks,thedosemaybeincreasedto20mg/day.Clinicaltrialexperiencewithdailydosesgreaterthan

20mgisminimal.Thereisonlylimiteddataontreatmentbeyond9weeks.

Lowerweightchildren:Duetohigherplasmalevelsinlower-weightchildren,thetherapeuticeffectmaybeachieved

withlowerdoses(seesection5.2).

Forpaediatricpatientswhorespondtotreatment,theneedforcontinuedtreatmentafter6monthsshouldbereviewed.

Ifnoclinicalbenefitisachievedwithin9weeks,treatmentshouldbereconsidered.

Elderly:Cautionisrecommendedwhenincreasingthedose,andthedailydoseshouldgenerallynotexceed40mg.

Maximumrecommendeddoseis60mg/day.

Alowerorlessfrequentdose(e.g.,20mgeverysecondday)shouldbeconsideredinpatientswithhepaticimpairment

(seesection5.2),orinpatientswhereconcomitantmedicationhasthepotentialforinteractionwithFluoxetine(see

section4.5).

Withdrawalsymptomsseenondiscontinuationoffluoxetine:Abruptdiscontinuationshouldbeavoided.Whenstopping

treatmentwithfluoxetinethedoseshouldbegraduallyreducedoveraperiodofatleastonetotwoweeksinorderto

reducetheriskofwithdrawalreactions(seesection4.4andsection4.8).Ifintolerablesymptomsoccurfollowinga

decreaseinthedoseorupondiscontinuationoftreatment,thenresumingthepreviouslyprescribeddosemaybe

considered.Subsequently,thephysicianmaycontinuedecreasingthedose,butatamoregradualrate.

4.3Contraindications

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Monoamineoxidaseinhibitors:Casesofseriousandsometimesfatalreactionshavebeenreportedinpatientsreceiving

anSSRIincombinationwithamonoamineoxidaseinhibitor(MAOI),andinpatientswhohaverecentlydiscontinued

anSSRIandhavebeenstartedonaMAOI.Treatmentoffluoxetineshouldonlybestarted2weeksafter

discontinuationofanirreversibleMAOIandthefollowingdayafterdiscontinuationofareversibleMAOI-A.

Somecasespresentedwithfeaturesresemblingserotoninsyndrome(whichmayresemble,andbediagnosedas

neurolepticmalignantsyndrome).Cyproheptadineordantrolenemaybenefitpatientsexperiencingsuchreactions

SymptomsofadruginteractionwithaMAOIinclude:hyperthermia,rigidity,myoclonus,autonomicinstabilitywith

possiblerapidfluctuationsofvitalsigns,mentalstatuschangesthatincludeconfusion,irritability,andextreme

agitation,progressingtodeliriumandcoma.

Therefore,fluoxetineiscontra-indicatedincombinationwithanon-selectiveMAOI.Similarly,atleast5weeksshould

elapseafterdiscontinuingfluoxetinetreatmentbeforestartingaMAOI.Iffluoxetinehasbeenprescribedchronically

and/oratahighdose,alongerintervalshouldbeconsidered.

ThecombinationoffluoxetinewithareversibleMAOI(e.g.moclobemide)isnotrecommended.Howevertreatment

withfluoxetinecanbeinitiatedthefollowingdayafterdiscontinuationofareversibleMAOI.

4.4Specialwarningsandprecautionsforuse

UseinChildrenandadolescentsunder18yearsofage

Suicide-relatedbehaviours(suicideattemptandsuicidalthoughts)andhostility(predominantlyaggression,

oppositionalbehaviourandanger)weremorefrequentlyobservedinclinicaltrialsamongchildrenandadolescents

treatedwithantidepressantscomparedtothosetreatedwithplacebo.Fluoxetineshouldonlybeusedinchildrenand

adolescentsaged8-18yearsforthetreatmentofmoderatetoseveremajordepressiveepisodesanditshouldnotbeused

inotherindications.If,basedonclinicalneed,adecisiontotreatisneverthelesstaken;thepatientshouldbecarefully

monitoredfortheappearanceofsuicidalsymptoms.Inaddition,longtermsafetydatainchildrenandadolescents

concerninggrowth,maturationandcognitiveandbehaviouraldevelopmentarelacking.Inaddition,onlylimited

evidenceisavailableconcerninglong-termeffectonsafetyinchildrenandadolescents,includingeffectsongrowth,

sexualmaturationandcognitive,emotionalandbehaviouraldevelopments.(seesection5.3)

Ina19weekclinicaltrial,decreasedheightandweightgainwasobservedinchildrenandadolescentstreatedwith

fluoxetine(seesection4.8).Ithasnotbeenestablishedwhetherthereisaneffectonachievingnormaladultheight.The

possibilityofadelayinpubertycannotberuledout(seesection5.3and4.8).Growthandpubertaldevelopment

(height,weight,andTANNERstaging)shouldthereforebemonitoredduringandaftertreatmentwithFluoxetine.If

eitherisslowed,referraltoapaediatricianshouldbeconsidered.

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

theoccurrenceofmania/hypomaniaisrecommended.Fluoxetineshouldbediscontinuedinanypatiententeringa

manicphase.

Itisimportantthattheprescriberdiscussescarefullytherisksandbenefitsoftreatmentwiththechild/youngperson

and/ortheirparents.

Rashandallergicreactions:Rash,anaphylactoidevents,andprogressivesystemicevents,sometimesserious

(involvingskin,kidney,liver,orlung),havebeenreported.Upontheappearanceofrashorofotherallergicphenomena

forwhichanalternativeaetiologycannotbeidentified,fluoxetineshouldbediscontinued.

Seizures:Seizuresareapotentialriskwithantidepressantdrugs.Therefore,aswithotherantidepressants,fluoxetine

shouldbeintroducedcautiouslyinpatientswhohaveahistoryofseizures.Treatmentshouldbediscontinuedinany

patientwhodevelopsseizuresorwherethereisanincreaseinseizurefrequency.Fluoxetineshouldbeavoidedin

patientswithunstableseizuredisorders/epilepsy,andpatientswithcontrolledepilepsyshouldbecarefullymonitored.

Mania:Antidepressantsshouldbeusedwithcautioninpatientswithahistoryofmania/hypomania.Aswithall

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Hepatic/renalfunction:Fluoxetineisextensivelymetabolisedbytheliverandexcretedbythekidneys.Alowerdose,

eg,alternatedaydosing,isrecommendedinpatientswithsignificanthepaticdysfunction.Whengivenfluoxetine20

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

plasmalevelsoffluoxetineornorfluoxetinecomparedtocontrolswithnormalrenalfunction.

Cardiacdisease:NoconductionabnormalitiesthatresultedinheartblockwereobservedintheECGof312patients

whoreceivedfluoxetineindouble-blindclinicaltrials.However,clinicalexperienceinacutecardiacdiseaseislimited,

thereforecautionisadvisable.

Weightloss:Weightlossmayoccurinpatientstakingfluoxetinebutitisusuallyproportionaltobaselinebodyweight.

Diabetes:Inpatientswithdiabetes,treatmentwithanSSRImayalterglycaemiccontrol.Hypoglycaemiahasoccurred

duringtherapywithfluoxetine,andhyperglycaemiahasdevelopedfollowingdiscontinuation.Insulinand/ororal

hypoglycaemicdosagemayneedtobeadjusted.

Suicide/suicidalthoughtsorclinicalworsening:Depressionisassociatedwithanincreasedriskofsuicidalthoughts,

selfharmandsuicide(suicide-relatedevents).Thisriskpersistsuntilsignificantremissionoccurs.Asimprovement

maynotoccurduringthefirstfewweeksormoreoftreatment,patientsshouldbecloselymonitoreduntilsuch

improvementoccurs.Itisgeneralclinicalexperiencethattheriskofsuicidemayincreaseintheearlystagesof

recovery.

OtherpsychiatricconditionsforwhichFluoxetineisprescribedcanalsobeassociatedwithanincreasedriskofsuicide-

relatedevents.Inaddition,theseconditionsmaybeco-morbidwithmajordepressivedisorder.Thesameprecautions

observedwhentreatingpatientswithmajordepressivedisordershouldthereforebeobservedwhentreatingpatients

withotherpsychiatricdisorders.

Patientswithahistoryofsuicide-relatedevents,orthoseexhibitingasignificantdegreeofsuicidalideationpriorto

commencementoftreatmentareknowntobeatgreaterriskofsuicidalthoughtsorsuicideattempts,andshouldreceive

carefulmonitoringduringtreatment.Ameta–analysisofplacebo-controlledclinicaltrialsofantidepressantdrugsin

adultpatientswithpsychiatricdisordersshowedanincreasedriskofsuicidalbehaviourwithantidepressantscompared

toplaceboinpatientslessthan25yearsold.Closesupervisionofpatientsandinparticularthoseathighriskshould

accompanydrugtherapyespeciallyinearlytreatmentandfollowingdosechanges.Patients(andcaregiversofpatients)

shouldbealertedabouttheneedtomonitorforanyclinicalworsening,suicidalbehaviourorthoughtsandunusual

changesinbehaviourandtoseekmedicaladviceimmediatelyifthesesymptomspresent.

Akathisia/psychomotorrestlessness:Theuseoffluoxetinehasbeenassociatedwiththedevelopmentofakathisia,

characterisedbyasubjectivelyunpleasantordistressingrestlessnessandneedtomoveoftenaccompaniedbyan

inabilitytositorstandstill.Thisismostlikelytooccurwithinthefirstfewweeksoftreatment.Inpatientswho

developthesesymptoms,increasingthedosemaybedetrimental.

WithdrawalsymptomsseenondiscontinuationofSSRItreatment:Withdrawalsymptomswhentreatmentis

discontinuedarecommon,particularlyifdiscontinuationisabrupt(seesection4.8).Inclinicaltrialsadverseevents

seenontreatmentdiscontinuationoccurredinapproximately60%ofpatientsinboththefluoxetineandplacebogroups.

Oftheseadverseevents,17%inthefluoxetinegroupand12%intheplacebogroupweresevereinnature.

Theriskofwithdrawalsymptomsmaybedependentonseveralfactorsincludingthedurationanddoseoftherapyand

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

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

commonlyreportedreactions.Generallythesesymptomsaremildtomoderatehowever,insomepatientstheymaybe

severeinintensity.Theyusuallyoccurwithinthefirstfewdaysofdiscontinuingtreatment.Generallythesesymptoms

areself-limitingandusuallyresolvewithin2weeks,thoughinsomeindividualstheymaybeprolonged(2-3monthsor

more).ItisthereforeadvisedthatFluoxetineshouldbegraduallytaperedwhendiscontinuingtreatmentoveraperiodof

atleastonetotwoweeks,accordingtothepatient’sneeds(see"WithdrawalSymptomsSeenonDiscontinuationof

Fluoxetine",Section4.2).

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SSRIs.Ecchymosishasbeenreportedasaninfrequenteventduringtreatmentwithfluoxetine.Otherhaemorrhagic

manifestations(e.g.,gynaecologicalhaemorrhages,gastro-intestinalbleedings,andothercutaneousormucous

bleedings)havebeenreportedrarely.CautionisadvisedinpatientstakingSSRIs,particularlyinconcomitantusewith

oralanticoagulants,drugsknowntoaffectplateletfunction(e.g.,atypicalantipsychotics,suchasclozapine,

phenothiazines,mostTCAs,aspirin,NSAIDs),orotherdrugsthatmayincreaseriskofbleeding,aswellasinpatients

withahistoryofbleedingdisorders.

Electroconvulsivetherapy(ECT):Therehavebeenrarereportsofprolongedseizuresinpatientsonfluoxetine

receivingECTtreatment,thereforecautionisadvisable.

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)occur,and

supportivesymptomatictreatmentshouldbeinitiated.

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Interactionstudieshaveonlybeenperformedinadults

Half-life:Thelongeliminationhalf-livesofbothfluoxetineandnorfluoxetineshouldbeborneinmind(seesection5.2)

whenconsideringpharmacodynamicorpharmacokineticdruginteractions(e.g.,whenswitchingfromfluoxetineto

otherantidepressants).

Monoamineoxidaseinhibitors:(seesection4.3).

Notrecommendedcombinations:MAOI-A(seesection4.3)

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

recommended.

Phenytoin:Changesinbloodlevelshavebeenobservedwhencombinedwithfluoxetine.Insomecasesmanifestations

oftoxicityhaveoccurred.Considerationshouldbegiventousingconservativetitrationschedulesoftheconcomitant

drugandtomonitoringclinicalstatus.

Serotonergicdrugs:Co-administrationwithserotonergicdrugs(e.g.,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,

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willalsoapplyiffluoxetinehasbeentakenintheprevious5weeks.

Oralanticoagulants:Alteredanticoagulanteffects(laboratoryvaluesand/orclinicalsignsandsymptoms),withno

consistentpattern,butincludingincreasedbleeding,havebeenreporteduncommonlywhenfluoxetineisco-

administeredwithoralanticoagulants.Patientsreceivingwarfarintherapyshouldreceivecarefulcoagulation

monitoringwhenfluoxetineisinitiatedorstopped(seesection4.4).

Electroconvulsivetherapy(ECT):Therehavebeenrarereportsofprolongedseizuresinpatientsonfluoxetine

receivingECTtreatment,thereforecautionisadvisable.

Alcohol:Informaltesting,fluoxetinedidnotraisebloodalcohollevelsorenhancetheeffectsofalcohol.However,the

combinationofSSRItreatmentandalcoholisnotadvisable.

StJohn'sWort:IncommonwithotherSSRIs,pharmacodynamicinteractionsbetweenfluoxetineandtheherbalremedy

StJohn'sWort(Hypericumperforatum)mayoccur,whichmayresultinanincreaseofundesirableeffects.

4.6Fertility,pregnancyandlactation

Pregnancy:EpidemiologicaldatahavesuggestedthattheuseofSSRIsinpregnancy,particularlyinlatepregnancy,

mayincreasetheriskofpersistentpulmonaryhypertensioninthenewborn(PPHN)>Theobservedriskwas

approximately5casesper1000pregnancies.Ingeneralpopulation1to2casesofPPHNper1000pregnanciesoccur.

AlthoughFluoxetinecanbeusedduringpregnancy,butcautionshouldbeexercised,especiallyduringlatepregnancy

orjustpriortotheonsetoflabour,sincethefollowingeffectshavebeenreportedinneonates:irritability,tremor,

hypotonia,persistentcrying,difficultyinsuckingorinsleeping.Thesesymptomsmayindicateeitherserotonergic

effectsorawithdrawalsyndrome.Thetimetooccurandthedurationofthesesymptomsmayberelatedtothelong

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

Someepidemiologicalstudiessuggestanincreasedriskofcardiovasculardefectsassociatedwiththeuseoffluoxetine

duringthefirsttrimester.Themechanismisunknown.Overallthedatasuggestthattheriskofhavinganinfantwitha

cardiovasculardefectfollowingmaternalfluoxetineexposureisintheregionof2/100comparedwithanexpectedrate

forsuchdefectsofapproximately1/100inthegeneralpopulation.

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

reaction,angioedema)(seesection4.3andsection4.4)chills,serotoninsyndrome,photosensitivity,and,veryrarely,

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Digestivesystem:Gastro-intestinaldisorders(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,andrarelypsychomotorrestlessness/akathisia(seesection4.4).Hallucinations,manicreaction,confusion,

agitation,anxietyandassociatedsymptoms(e.g.,nervousness),impairedconcentrationandthoughtprocess(e.g.,

depersonalisation),panicattacks,suicidalthoughtsandbehaviour*(thesesymptomsmaybeduetotheunderlying

disease),andveryrarelyserotoninsyndrome.

Casesofsuicidalideationandsuicidalbehaviourshavebeenreportedduringfluoxetinetherapyorearlyaftertreatment

discontinuation(seesection4.4).

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,

gastro-intestinalbleedings,andothercutaneousormucousbleedings)havebeenreportedrarely(seesection4.4).

Hyponatraemia:Hyponatraemia(includingserumsodiumbelow110mmol/l)hasbeenrarelyreportedandappearedto

bereversiblewhenfluoxetinewasdiscontinued.Somecaseswerepossiblyduetothesyndromeofinappropriate

antidiuretichormonesecretion.Themajorityofreportswereassociatedwitholderpatients,andpatientstaking

diureticsorotherwisevolumedepleted.

Respiratorysystem:Pharyngitis,dyspnoea.Pulmonaryevents(includinginflammatoryprocessesofvarying

histopathologyand/orfibrosis)havebeenreportedrarely.Dyspnoeamaybetheonlyprecedingsymptom.

Bonefractures:Epidemiologicalstudies,mainlyconductedinpatients50yearsofageandolder,showanincreasedrisk

ofbonefracturesinpatientsreceivingSSRIsandTCAs.Themechanismleadingtothisriskisunknown.

Withdrawalsymptomsseenondiscontinuationoffluoxetinetreatments:Discontinuationoffluoxetinecommonlyleads

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

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

commonlyreportedreactions.Generallytheseeventsaremildtomoderateandareself-limiting,however,insome

patientstheymaybesevereand/orprolonged(seesection4.4).ItisthereforeadvisedthatwhenFluoxetinetreatmentis

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

Childrenandadolescents(seesection4.4):Inpaediatricclinicaltrials,suiciderelatedbehaviours(suicideattemptand

suicidalthoughts)andhostilityweremorefrequentlyobservedamongchildrenandadolescentstreatedwith

antidepressantscomparedtothosetreatedwithplacebo.

Thesafetyoffluoxetinehasnotbeensystematicallyassessedforchronictreatmentlongerthan19weeks.

Inpaediatricclinicaltrials,manicreactions,includingmaniaandhypomania,werereported(2.6%offluoxetinetreated

patientsversus0%inplacebocontrols),leadingtodiscontinuationinthemajorityofcases.Thesepatientshadnoprior

episodesofhypomania/mania.

After19weeksoftreatment,paediatricsubjectstreatedwithfluoxetineinaclinicaltrialgainedanaverageof1.1cm

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

retardationhavealsobeenreportedfromclinicaluse.

Isolatedcasesofadverseeventspotentiallyindicatingdelayedsexualmaturationorsexualdysfunctionhavebeen

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Inpaediatricclinicaltrials,fluoxetinetreatmentwasassociatedwithadecreaseinalkalinephosphatelevels.

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:selectiveserotoninre-uptakeinhibitors(SSRIs)

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)andremission,comparedtoplacebo.Doseresponse:Inthe

fixeddosestudiesofpatientswithmajordepressionthereisaflatdoseresponsecurve,providingnosuggestionof

advantageintermsofefficacyforusinghigherthantherecommendeddoses.However,itisclinicalexperiencethatup

titratingmightbebeneficialforsomepatients

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

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

higherresponserate.Inlong-termstudies(threeshort-termstudiesextensionphaseandarelapsepreventionstudy)

efficacyhasnotbeenshown.

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

fluoxetine60mg/daywasshowntobesignificantlymoreeffectivethanplaceboforthereductionofbingeingand

purgingactivities.However,forlong-termefficacynoconclusioncanbedrawn.Twoplacebo-controlledstudieswere

conductedinpatientsmeetingPre-MenstrualDysphoricDisorder(PMDD)diagnosticcriteriaaccordingtoDSM-IV.

Patientswereincludediftheyhadsymptomsofsufficientseveritytoimpairsocialandoccupationalfunctionand

relationshipswithothers.Patientsusingoralcontraceptiveswereexcluded.Inthefirststudyofcontinuous20mgdaily

dosingfor6cycles,improvementwasobservedintheprimaryefficacyparameter(irritability,anxiety,anddysphoria).

Inthesecondstudy,withintermittentlutealphasedosing(20mgdailyfor14days)for3cycles,improvementwas

observedintheprimaryefficacyparameter(DailyRecordofSeverityofProblemsscore).However,definitive

conclusionsonefficacyanddurationoftreatmentcannotbedrawnfromthesestudies.

Majordepressiveepisodes(childrenandadolescents):Clinicaltrialsinchildrenandadolescentsaged8yearsandabove

havebeenconductedversusplacebo.Fluoxetineatadoseof20mg,hasbeenshowntobesignificantlymoreeffective

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

patientsmetcriteriaformoderatetosevereMDD(DSM-IIIorDSMIV)atthreedifferentevaluationsbypractising

childpsychiatrists.Efficacyinthefluoxetinetrialsmaydependontheinclusionofaselectivepatientpopulation(one

thathasnotspontaneouslyrecoveredwithinaperiodof3-5weeksandwhosedepressionpersistedinthefaceof

considerableattention.Thereisonlylimiteddataonsafetyandefficacybeyond9weeks.Ingeneral,efficacyof

fluoxetinewasmodest.Responserates(theprimaryendpoint,definedas30%decreaseintheCDRS-Rscore)

demonstratedastatisticallysignificantdifferenceinoneofthetwopivotalstudies(58%forfluoxetineversus32%for

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

changesinCDRS-Rfrombaselinetoendpointwere20forfluoxetineversus11forplacebo,P=0.002;and22for

fluoxetineversus15forplacebo,P<0.001.

5.2Pharmacokineticproperties

Absorption:Fluoxetineiswellabsorbedfromthegastro-intestinaltractafteroraladministration.Thebioavailabilityis

notaffectedbyfoodintake.

Distribution:Fluoxetineisextensivelyboundtoplasmaproteins(about95%)anditiswidelydistributed(volumeof

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:Themeanfluoxetineconcentrationinchildrenisapproximately2foldhigherthanthat

observedinadolescentsandthemeannorfluoxetineconcentration1.5foldhigher.Steadystateplasmaconcentrations

aredependantonbodyweightandarehigherinlowerweightchildren(seesection4.2).Asinadults,fluoxetineand

norfluoxetineaccumulatedextensivelyfollowingmultipleoraldosing:steadystateconcentrationswereachievedwithin

3-4weeksofdailydosing.

Hepaticinsufficiency:Incaseofhepaticinsufficiency(alcoholiccirrhosis),fluoxetineandnorfluoxetinehalf-livesare

increasedto7and12days,respectively.Alowerorlessfrequentdoseshouldbeconsidered.

Renalinsufficiency:Aftersingle-doseadministrationoffluoxetineinpatientswithmild,moderate,orcomplete

(anuria)renalinsufficiency,kineticparametershavenotbeenalteredwhencomparedtohealthyvolunteers.However,

afterrepeatedadministration,anincreaseinsteady-stateplateauofplasmaconcentrationsmaybeobserved.

5.3Preclinicalsafetydata

Thereisnoevidenceofcarcinogenicity,mutagenicity,orimpairmentoffertilityfrominvitrooranimalstudies.

InajuveniletoxicologystudyinCDrats,administrationof30mg/kg/dayoffluoxetinehydrochlorideonpostnataldays

21to90resultedinirreversibletesticulardegenerationandnecrosis,epididymalepithelialvacuolation,immaturityand

inactivityofthefemalereproductivetractanddecreasedfertility.Delaysinsexualmaturationoccurredinmales(10

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

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

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

levelsachievedinanimalswereapproximately0.04to0.05-fold(fluoxetine)and0.3to2.1-fold(norfluoxetine)those

usuallyachievedinpaediatricpatients.

Astudyinjuvenilemicehasindicatedthatinhibitionoftheserotonintransporterpreventstheaccrualofbone

formation.Thisfindingwouldappeartobesupportedbyclinicalfindings.Thereversibilityofthiseffecthasnotbeen

established.

Anotherstudyinjuvenilemice(treatedonpostnataldays4to21)hasdemonstratedthatinhibitionoftheserotonin

transporterhadlong-lastingeffectsonthebehaviourofthemice.Thereisnoinformationonwhethertheeffectwas

reversible.Theclinicalrelevanceofthisfindinghasnotbeenestablished.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Microcrystallinecellulose

Crospovidone

Magnesiumstearate

PrintingInk–OpacodeS-1-27794

Shellac E904

BlackIronOxide E172

PropyleneGlycol E1520

CapsuleShell:

Body:

Indigocarmine E132

YellowIronoxide E172

BlackIronoxide E172

Titaniumdioxide E171

Gelatin

Cap:

Blackironoxide E172

Indigocarmine E132

Yellowironoxide E172

Titaniumdioxide E171

Gelatin

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

4years.

6.4Specialprecautionsforstorage

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6.5Natureandcontentsofcontainer

BiozacHardCapsulesarepackedin:

Al/PVC/PVdCblisterinacartonbox.Aboxmaycontain10,14,20,28,30,50,60,100,200,250,500or1000

capsules.Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

NicheGenericsLimited

1TheCamCentre,

WilburyWay,

Hitchin,

HertfordshireSG40TW,

UnitedKingdom.

8MARKETINGAUTHORISATIONNUMBER

PA1063/11/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:04May2001

Dateoflastrenewal:08September2009

10DATEOFREVISIONOFTHETEXT

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