BELLZAC

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0408/055/001
  • Authorization date:
  • 03-12-2001
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Bellzac20mgCapsules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachcapsulecontains22.5mgfluoxetinehydrochlorideequivalentto20mgflouxetine.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Capsule,Hard.

Green/Off-whitehardgelatinselflockedcapsulesofsize‘2’imprintedwith‘R/FXT20’oncap/bodyinblackedible

inkcontainingwhitepowder.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Majordepressiveepisodes.

Obessive-compulsivedisorder.

Bulimianervosaisindicatedasacomplementofpsychotherapyforthereductionofbinge-eatingandpurgingactivity.

4.2Posologyandmethodofadministration

Fororaladministrationtoadultsonly.

Majordepressiveepisode

Adultsandtheelderly;20mg/dayto60mg/day.Adoseof20mg/dayisrecommendedastheinitialdose.Dosage

shouldbereviewedandadjustedifnecessarywithin3to4weeksofinitiationoftherapyandthereafterasjudged

clinicallyappropriate.Althoughtheremaybeanincreasedpotentialforundesirable-effectsathigherdoses,insome

patientswithinsufficientresponseto20mg,agradualdoseincreaseuptoamaximumof60mg/day(seesection5.1)

maybeconsidered. Dosageadjustmentsshouldbemadecarefullyonanindividualpatientbasis,tomaintainthe

patientsatthelowesteffectivedose.

InagreementwiththeconsensusstatementoftheWHO,antidepressantmedicationshouldbecontinuedforatleast6

months.

Obsessive-compulsivedisorder–Adultsandtheelderly;20mg/dayto60mg/day.Adoseof20mg/dayis

recommendedastheinitialdose.Althoughtheremaybeanincreasedpotentialforside-effectsathigherdoses,adose

increasemaybeconsideredaftertwoweeksifthereisnoresponse,uptoamaximumof60mg/day(seesection5.1).If

noimprovementisobservedwithin10weeks,treatmentwithfluoxetineshouldbereconsidered.Ifagoodtherapeutic

responsehasbeenobtained,treatmentcanbecontinuedatadosageadjustedonanindividualbasis.Whilethereareno

systematicstudiestoanswerthequestionofhowlongtocontinuefluoxetinetreatment,OCDisachronicconditionand

itisreasonabletoconsidercontinuationbeyond10weeksinrespondingpatients.Dosageadjustmentsshouldbemade

carefullyonanindividualpatientbasis,tomaintainthepatientatthelowesteffectivedose.Theneedfortreatment

shouldbereassessedperiodically.Somecliniciansadvocateconcomitantbehaviouralpsychotherapyforpatientswho

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Long-termefficacy(morethan24weeks)hasnotbeendemonstratedinOCD.

Bulimianervosa–Adultsandtheelderly:Adoseof60mg/dayisrecommended.

Long-termefficacy(morethan3months)hasnotbeendemonstratedinbulimianervosa.

Allindications:Therecommendeddosemaybeincreasedordecreased.Dosesabove80mg/dayhavenotbeen

systematicallyevaluated.

Fluoxetinemaybeadministeredasasingleordivideddose,duringorbetweenmeals.

Whendosingisstopped,activedrugsubstanceswillpersistinthebodyforweeks.Thisshouldbeborneinmindwhen

startingorstoppingtreatment.

WithdrawalsymptomsseenondiscontinuationofFluoxetine

Abruptdiscontinuationshouldbeavoided.WhenstoppingtreatmentwithFluoxetinethedoseshouldbegradually

reducedoveraperiodofatleastoneortwoweeksinordertoreducetheriskofwithdrawalreactions(seesection4.4

Specialandsection4.8).Ifintolerablesymptomsoccurfollowingadecreaseinthedoseorupondiscontinuationof

treatment,thenresumingthepreviouslyprescribeddosemaybeconsidered.Subsequently,thephysicianmaycontinue

decreasingthedose,butatamoregradualrate.

Children:Fluoxetineshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years(see

section4.4).

Elderly:Cautionisrecommendedwhenincreasingthedoseandthedailydoseshouldgenerallynotexceed40mg.

Maximumrecommendeddoseis60mg/day.

Alowerorlessfrequentdose(e.g.20mgeverysecondday)shouldbeconsideredinpatientswithhepaticimpairment

(seesection5.2),orinpatientswhereconcomitantmedicationhasthepotentialforinteractionwithBellzac20mg

Capsules(seesection4.5).

4.3Contraindications

Hypersensitivitytofluoxetineortoanyofitsexcipients.

MonoamineOxidaseInhibitors:Casesofseriousandsometimesfatalreactionshavebeenreportedinpatientsreceiving

anSSRIincombinationwithamonoamineoxidaseinhibitor(MAOI),andinpatientswhohaverecentlydiscontinued

anSSRIandhavebeenstartedonaMAOI.Treatmentoffluoxetineshouldonlybestarted2weeksafter

discontinuationofanirreversibleMAOIandthefollowingdayafterdiscontinuationofareversibleMAOI-A.

Somecasespresentedwithfeaturesresemblingserotoninsyndrome(whichmayresembleandbediagnosedas

neurolepticmalignantsyndrome).Cyproheptadineordantrolenemaybenefitpatientsexperiencingsuchreactions.

SymptomsofadruginteractionwithaMAOIinclude:hyperthermia,rigidity,myoclonus,autonomicinstabilitywith

possiblerapidfluctuationsofvitalsigns,mentalstatuschangesthatincludeconfusion,irritabilityandextremeagitation

progressingtodeliriumandcoma.

Therefore,fluoxetineiscontra-indicatedincombinationwithanon-selectiveMAOI.Similarly,atleast5weeksshould

elapseafterdiscontinuingfluoxetinetreatmentbeforestartingaMAOI.Iffluoxetinehasbeenprescribedchronically

and/oratahighdose,alongerintervalshouldbeconsidered.

ThecombinationfluoxetinewithareversibleMAOI(e.g.moclobemide)isnotrecommended.Treatmentwith

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4.4Specialwarningsandprecautionsforuse

Warnings

Rashandallergicreactions:Rash,anaphylactoideventsandprogressivesystemicevents,sometimesserious(involving

skin,kidney,liverorlung)havebeenreported.Upontheappearanceofrashorofotherallergicphenomenaforwhich

analternativeaetiologycannotbeidentified,fluoxetineshouldbediscontinued.

Precautions

Seizures:Seizuresareapotentialriskwithantidepressantdrugs.Therefore,aswithotherantidepressants,fluoxetine

shouldbeintroducedcautiouslyinpatientswhohaveahistoryofseizures.Treatmentshouldbediscontinuedinany

patientwhodevelopsseizuresorwherethereisanincreaseinseizurefrequency.Fluoxetineshouldbeavoidedin

patientswithunstableseizuredisorders/epilepsyandpatientswithcontrolledepilepsyshouldbecarefullymonitored.

Mania:Antidepressantsshouldbeusedwithcautioninpatientswithahistoryofmania/hypomania.Aswithall

antidepressants,fluoxetineshouldbediscontinuedinanypatiententeringamanicphase.

Hepatic/RenalFunction:Fluoxetineisextensivelymetabolizedbytheliverandexcretedbythekidneys.Alowerdose,

e.g.,alternatedaydosing,isrecommendedinpatientswithsignificanthepaticdysfunction.WhengivenBellzac20

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).

Thisriskpersistsuntilsignificantremissionoccurs.Asimprovementmaynotoccurduringthefirstfewweeksormore

oftreatment,patientsshouldbecloselymonitoreduntilsuchimprovementoccurs.Itisgeneralclinicalexperiencethat

theriskofsuicidemayincreaseintheearlystagesofrecovery.

OtherpsychiatricconditionsforwhichFluoxetineisprescribedcanalsobeassociatedwithanincreasedriskofsuicide-

relatedevents.Inaddition,theseconditionsmaybeco-morbidwithmajordepressivedisorder.Thesameprecautions

observedwhentreatingpatientswithmajordepressivedisordershouldthereforebeobservedwhentreatingpatients

withotherpsychiatricdisorders.

Patientswithahistoryofsuicide-relatedevents,orthoseexhibitingasignificantdegreeofsuicideideationpriorto

commencementoftreatmentareknowntobeatagreaterriskofsuicidalthoughtsorsuicidalattempts,andshould

receivecarefulmonitoringduringtreatment.Ameta-analysisofplacebo-controlledclinicaltrialsofantidepressants

drugsinadultpatientswithpsychiatricdisordersshowedanincreasedriskofsuicidalbehaviourwithantidepressants

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Closesupervisionofpatientsandinparticularthoseathighriskshouldaccompanydrugtherapyespeciallyinearly

treatmentandfollowingdosechanges.Patients(andcaregiversofpatients)shouldbealertedabouttheneedof

monitoringforanyclinicalworsening,suicidalbehaviourorthoughtsandunusualchangesinbehaviourandtoseek

medicaladviceimmediatelyifthesesymptomspresent.

Akathisia/psychomotorrestlessness

TheuseofFluoxetinehasbeenassociatedwiththedevelopmentofakathisia,characterisedbyasubjectivelyunpleasant

ordistressingrestlessnessandneedtomoveoftenaccompaniedbyaninabilitytositorstandstill.Thisisthemost

likelytooccurwithinthefirstfewweeksoftreatment.Inpatientswhodevelopthesesymptoms,increasingthedose

maybedetrimentalanditmaybenecessarytoreviewtheuseofFluoxetine.

Haemorrhage:Therehavebeenreportsofcutaneousbleedingabnormalitiessuchasecchymosisandpurpurawith

SSRI’s.Ecchymosishasbeenreportedasaninfrequenteventduringtreatmentwithfluoxetine.Otherhemorrhagic

manifestations(e.g.,gynaecologicalhaemorrhages,gastrointestinalbleedingsandothercutaneousormucous

bleedings)havebeenreportedrarely.CautionisadvisedinpatientstakingSSRI’s,particularlyinconcomitantusewith

oralanticoagulants,drugsknowntoaffectplateletfunctions(e.g.,atypicalanitpsychoticssuchasclozapine,

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

withahistoryofbleedingdisorders.

ElectroconvulsiveTherapy(ECT):Therehavebeenrarereportsofprolongedseizureinpatientsonfluoxetinereceiving

ECTtreatment,thereforecautionisadvisable.

StJohn’sWort:Anincreaseinserotonergiceffects,suchasserotoninsyndrome,mayoccurwhenselectiveserotonin

reuptakeinhibitorsandherbalpreparationscontainingStJohn’sWort(Hypericumperforatum)areusedtogether.

Onrareoccasionsdevelopmentofaserotoninsyndromeorneurolepticmalignantsyndrome-likeeventshavebeen

reportedinassociationwithtreatmentoffluoxetine,particularlywhengivenincombinationwithotherserotonergic

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

conditions,treatmentwithfluoxetineshouldbediscontinuedifsuchevents(characterizedbyclustersofsymptoms

suchashyperthermia,rigidity,myoclonus,autonomicinstabilitywithpossiblerapidfluctuationsofvitalsigns,mental

statuschangesincludingconfusion,irritability,extremeagitationprogressingtodeliriumandcoma)occurand

supportivesymptomatictreatmentshouldbeinitiated.

WithdrawalsymptomsseenondiscontinuationofFluoxetinetreatment

Withdrawalsymptomswhentreatmentisdiscontinuedarecommon,particularlyifdiscontinuationisabrupt(see

section4.8).Inclinicaltrialsadverseeventsseenontreatmentdiscontinuationoccurredinapproximately60%of

patientsinboththefluoxetineandplacebogroups.Oftheseadverseevents,17%inthefluoxetinegroupand12%in

theplacebogroupweresevereinnature.

Theriskofwithdrawalsymptomsmaybedependentonseveralfactorsincludingthedurationanddoseoftherapyand

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

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

commonlyreportedreactions.Generallythesesymptomsaremildtomoderate;however,insomepatientstheymaybe

severeinintensity.Theyusuallyoccurwithinthefirstfewdaysofdiscontinuingtreatment,buttherehavebeenvery

rarereportsofsuchsymptomsinpatientswhohaveinadvertentlymissedadose.Generallythesesymptomsareself-

limitingandusuallyresolvewithin2weeks,thoughinsomeindividualstheymaybeprolonged(2-3monthsormore).

ItisthereforeadvisedthatFluoxetineshouldbegraduallytaperedwhendiscontinuingtreatmentoveraperiodofat

leastonetotwoweeks,accordingtothepatient’sneeds(see“WithdrawalSymptomsSeenonDiscontinuationof

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Useinchildrenandadolescentsunder18yearsofage

Bellzac20mgCapsulesshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years.

Suicide-relatedbehaviours(suicideattemptsandsuicidalthoughts),andhostility(predominantlyaggression,

oppositionalbehaviourandanger)weremorefrequentlyobservedinclinicaltrialsamongchildrenandadolescents

treatedwithantidepressantscomparedtothosetreatedwithplacebo.If,basedonclinicalneed,adecisiontotreatis

neverthelesstaken,thepatientshouldbecarefullymonitoredfortheappearanceofsuicidalsymptoms.Inaddition,

long-termsafetydatainchildrenandadolescentsincludingeffectsongrowth,sexualmaturationandcognitive

behaviouraldevelopmentarelacking(seesection5.3).

Ina19-weekclinicaltrialdecreasedheightandweightgainwasobservedinchildrenandadolescentstreatedwith

fluoxetine(seesection4.8).Ithasnotbeenestablishedwhetherthereisaneffectonachievingnormaladultheight.

Thepossibilityofadelayinpubertycannotberuledout(seesections5.3and4.8).

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

theoccurrenceofmania/hypomaniaisrecommended.Fluoxetineshouldbediscontinuedinanypatiententeringa

manicphase.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Half-life:Thelongeliminationhalf-livesofbothfluoxetineandnorfluoxetineshouldbeborneinmind(see

‘PharmacokineticProperties’)whenconsideringpharmacodynamicorpharmacokineticdruginteractions(e.g.,when

switchingfromfluoxetinetootherantidepressants).

Monoamineoxidaseinhibitors:(see‘Contraindications’)

Notrecommendedcombinations:

MAOI-A(seesection4.3)

Combinationsrequiringprecautionsforuse:

MAOI-B(selegeline);riskofserotoninsyndrome.Clinicalmonitoringisrecommended.

Phenytoin:Changesinbloodlevelshavebeenobservedwhencombinedwithfluoxetine.Insomecasesmanifestations

oftoxicityhaveoccurred.Considerationshouldbegiventousingconservativetitrationschedulesoftheconcomitant

drugandtomonitoringclinicalstatus.

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

serotoninsyndrome.Usewithtriptanscarriestheadditionalriskofcoronaryvasoconstrictionsandhypertension.

Lithiumandtryptophan:TherehavebeenreportsofserotoninsyndromewhenSSRI’shavebeengivenwithlithiumor

tryptophanand,therefore,theconcomitantuseoffluoxetinewiththesedrugsshouldbeundertakenwithcaution.

Whenfluoxetineisusedincombinationwithlithium,closerandmorefrequentclinicalmonitoringisrequired.

CYP2D6isoenzyme:Becausefluoxetine’smetabolism(liketricyclicantidepressantsandotherselectiveserotonin

antidepressants)involvesthehepaticcytochromeCYP2D6isoenzymesystem,concomitanttherapywithdrugsalso

metabolizedbythisenzymesystemmayleadtodruginteractions.

Concomitanttherapywithdrugspredominantlymetabolizedbythisisoenzyme,andwhichhaveanarrowtherapeutic

index(suchasflecainide,encainide,carbamezepineandtricyclicantidepressants),shouldbeinitiatedatoradjustedto

thelowendoftheirdoserange.Thiswillalsoapplyiffluoxetinehasbeentakenintheprevious5weeks.

Oralanticoagulants:Alteredanti-coagulanteffects(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.

St.John’sWort:IncommonwithotherSSRIs,pharmacodynamicinteractionsbetweenfluoxetineandtheherbal

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

4.6Fertility,pregnancyandlactation

Pregnancy:EpidemiologicaldatahavesuggestedthattheuseofSSRIsinpregnancy,particularinlatepregnancy,may

increasetheriskofpersistentpulmonaryhypertensioninthenewborn(PPHN).Theobservedriskwasapproximately5

casesper1000pregnancies.Inthegeneralpopulation1to2casesofPPHNper1000pregnanciesoccur.

Fluoxetinecanbeusedduringpregnancy,butcautionshouldbeexercised,especiallyduringlatepregnancyorjust

priortotheonsetoflaboursincethefollowingeffectshavebeenreportedinneonates:irritability,tremor,hypotonia,

persistentcrying,difficultyinsuckingorinsleeping.Thesesymptomsmayindicateeitherserotonergiceffectsora

withdrawalsyndrome.Thetimetooccurandthedurationofthesesymptomsmayberelatedtothelonghalf-lifeof

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

Someepidemiologicalstudiessuggestanincreasedriskofcardiovasculardefectsassociatedwiththeuseoffluoxetine

duringthefirsttrimester.Themechanismisunknown.Overallthedatasuggestthattheriskofhavinganinfantwitha

cardiovasculardefectfollowingmaternalfluoxetineexposureisintheregionof2/100comparedwithanexpectedrate

forsuchdefectsofapproximately1/100inthegeneralpopulation.

Breastfeeding:Fluoxetineanditsmetabolitenorfluoxetine,areknowntobeexcretedinhumanbreastmilk.Adverse

eventshavebeenreportedinbreast-feedinginfants.Iftreatmentwithfluoxetineisconsiderednecessary,

discontinuationofbreastfeedingshouldbeconsidered;however,ifbreastfeedingiscontinued,thelowesteffectivedose

offluoxetineshouldbeprescribed.

4.7Effectsonabilitytodriveandusemachines

Althoughfluoxetinehasbeenshownnottoaffectpsychomotorperformanceinhealthyvolunteers,anypsychoactive

drugmayimpairjudgementorskills.Patientsshouldbeadvisedtoavoiddrivingacaroroperatinghazardous

machineryuntiltheyarereasonablycertainthattheirperformanceisnotaffected.

4.8Undesirableeffects

Undesirableeffectsmaydecreaseinintensityandfrequencywithcontinuedtreatmentanddonotgenerallyleadto

cessationoftherapy.

Inthissectionfrequenciesofundesirableeffectsaredefinedasfollows:Verycommon( ≥1/10);common(≥1/100to

<1/10);uncommon( ≥1/1,000to<1/100);rare(≥1/10,000to<1/1,000);veryrare(<1/10,000),notknown(cannotbe

estimatedfromtheavailabledata).

IncommonwithotherSSRIsthefollowingundesirableeffectshavebeenseen:

Bloodandlymphaticsystemdisorders

Rare:Otherhaemorrhagicmanifestations(e.g.,gynaecologicalhaemorrhages,gastrointestinalbleedingsandother

cutaneousormucousbleedings)havebeenreportedrarely(seesection4.4.‘Haemorrhage’)

Notknown:Ecchymosis,

Immunesystemdisorders

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

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Metabolismandnutritiondisorders

Rare:Hyponatraemia(includingserumsodiumbelow110mmol/l)appearedtobereversiblewhenfluoxetinewas

discontinued.Somecaseswerepossiblyduetothesyndromeofinappropriateanti-diuretichormonesecretion.The

majorityofreportswereassociatedwitholderpatients,andpatientstakingdiureticsorotherwisevolumedepleted.

Notknown:Anorexia.

Psychiatricdisorders

Notknown:suicidalthoughtsandbehavior(thesesymptomsmaybeduetotheunderlyingdisease).Casesofsuicidal

ideationandsuicidalbehaviorhavebeenreportedduringfluoxetinetherapyorearlyaftertreatmentdiscontinuation.

Sleepabnormalities(e.g.,abnormaldreams,insomnia),euphoria,hallucinations,manicreaction,confusion,agitation,

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

depersonalization),panicattacks(thesesymptomsmaybeduetotheunderlyingdisease)

Nervoussystem

Rare:psychomotorrestlessness/akathisia(seesection4.4)

Veryrare:serotoninsyndrome

Notknown:Headache,,dizziness,transientabnormalmovement(e.g.,twitching,ataxia,tremor,myoclonus),seizures,

hypoaesthesia.

Eyedisorders

Notknown:Abnormalvision(e.g.,blurredvision,mydriasis)

Vasculardisorders

Notknown:Posturalhypotension,vasodilatation

Respiratory,thoracicandmediastinaldisorders

Rare:.Pulmonaryevents(includinginflammatoryprocessesofvaryinghistopathologyand/orfibrosis).Dyspnoea

maybetheonlyprecedingsymptom.

Notknown:Pharyngitis,dyspnoea,yawn,dysphonia.

Gastrointestinaldisorders

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

mouth,glossodynia.

Hepatobiliarydisorders

Rare:Abnormalliverfunctiontests

Veryrare:idiosyncratichepatitis.

Skinandsubcutaneoustissuedisorders

Veryrare:ErythemaMultiformethatcouldprogresstoStevens-JohnsonsyndromeorToxicEpidermalNecrolysis

(Lyellsyndrome).

Notknown:photosensitivity,alopecia,sweating,erythromelalgia.

Musculoskeletalandconnectivetissuedisorders

Notknown:Arthralgia,myalgia

Bonefracture:Epidemiologicalstudies,mainlyconductedinpatients50yearsofageandolder,showanincreasedrisk

ofbonefracturesinpatientsreceivingSSRIsandTCAs.Themechanismleadingtothisriskisunknown.

Renalandurinarydisorders

Notknown:Urinaryretention,urinaryfrequency

Reproductivesystemandbreastdisorders:

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Generaldisordersandadministrationsiteconditions

Notknown:Chills,fatigue(e.g.somnolence,drowsiness).

Withdrawalsymptomsseenondiscontinuationoffluoxetinetreatments:

Discontinuationoffluoxetinecommonlyleadstowithdrawalsymptoms.Dizziness,sensorydisturbances(including

paraesthesia),sleepdisturbances(includinginsomniaandintensedreams),asthenia,agitationoranxiety,nauseaand/or

vomiting,tremorandheadachearethemostcommonlyreportedreactions.Generallytheseeventsaremildtomoderate

andareself-limiting,however,insomepatientstheymaybesevereand/orprolonged(seesection4.4).Itistherefore

advisedthatwhenBellzac20mgtreatmentisnolongerrequired,gradualdiscontinuationbydosetaperingshouldbe

carriedout(seesection4.2andsection4.4)

4.9Overdose

Casesofoverdoseoffluoxetinealoneusuallyhaveamildcourse.Symptomsofoverdosehaveincludednausea,

vomiting,seizures,cardiovasculardysfunctionrangingfromasymptomaticarrhythmiastocardiacarrest,pulmonary

dysfunction,andsignsofalteredCNSstatusrangingfromexcitationtocoma.Fatalityattributedtooverdoseof

fluoxetinealonehasbeenextremelyrare.Cardiacandvitalsignsmonitoringarerecommended,alongwithgeneral

symptomaticandsupportivemeasures.Nospecificantidoteisknown.

Forceddiuresis,dialysis,haemoperfusion,andexchangetransfusionareunlikelytobeofbenefit.Activatedcharcoal,

whichmaybeusedwithsorbitol,maybeasormoreeffectivethanemesisorlavage.Inmanagingoverdosage,

considerthepossibilityofmultipledruginvolvement.Anextendedtimeforclosemedicalobservationmaybeneeded

inpatientswhohavetakenexcessivequantitiesofatricyclicantidepressantiftheyarealsotaking,orhaverecently

taken,fluoxetine.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Selectiveserotoninreuptakeinhibitors

ATCcode:N06AB03.

Fluoxetineisaselectiveinhibitorofserotoninreuptake,andthisprobablyaccountsforthemechanismofaction.

Fluoxetinehaspracticallynoaffinitytootherreceptorssuchasa

-,a

-,andB-adrenergicserotonergic;dopaminergic;

histaminergic

;muscarinic;andGABAreceptors.

Majordepressiveepisodes:Clinicaltrialsinpatientswithmajordepressiveepisodeshavebeenconductedversus

placeboandactivecontrols.Bellzac20mgCapsuleshasbeenshowntobesignificantlymoreeffectivethanplaceboas

measuredbytheHamiltonDepressionRatingScale(HAM-D).Inthesestudies,Bellzac20mgCapsulesproduceda

significantlyhigherrateofresponse(definedbya50%decreaseintheHAM-Dscore)andremission,comparedto

placebo.

Doseresponse:Inthefixeddosestudiesofpatientswithmajordepressionthereisaflatdoseresponsecurve,providing

nosuggestionofadvantageintermsofefficacyforusinghigherthantherecommendeddoses.However,itisclinical

experiencethatuptitratingmightbebeneficialforsomepatients.

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

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

higherresponserate.Inlongtermstudies(threeshorttermstudiesextensionphaseandarelapsepreventionstudy)

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

nervosa,fluoxetine60mg/daywasshowntobesignificantlymoreeffectivethanplaceboforthereductionofbingeing

andpurgingactivities.However,forlong-termefficacynoconclusioncanbedrawn.

Twoplacebo-controlledstudieswereconductedinpatientsmeetingPre-MenstrualDysphoricDisorder(PMDD)

diagnosticcriteriaaccordingtoDSM-IV.Patientswereincludediftheyhadsymptomsofsufficientseveritytoimpair

socialandoccupationalfunctionandrelationshipswithothers.Patientsusingoralcontraceptiveswereexcluded.

Inthefirststudyofcontinuous20mgdailydosingfor6cycles,improvementwasobservedintheprimaryefficacy

parameter(irritability,anxietyanddysphoria).Inthesecondstudy,withintermittentlutealphasedosing(20mgdaily

for14days)for3cycles,improvementwasobservedintheprimaryefficacyparameter(DailyRecordofSeverityof

Problemsscore).However,definitiveconclusionsonefficacyanddurationoftreatmentcannotbedrawnfromthese

studies.

5.2Pharmacokineticproperties

Absorption

Fluoxetineiswellabsorbedfromthegastrointestinaltractafteroraladministration.Thebioavailabilityisnotaffected

byfoodintake.

Distribution

Fluoxetineisextensivelyboundtoplasmaproteins(about95%)anditiswidelydistributed(VolumeofDistribution:20

–40l/kg).Steady-stateplasmaconcentrationsareachievedafterdosingforseveralweeks.Steady-stateconcentrations

afterprolongeddosingaresimilartoconcentrationsseenat4to5weeks.

Metabolism

Fluoxetinehasanon-linearpharmacokineticprofilewithfirstpasslivereffect.Maximumplasmaconcentrationis

generallyachieved6to8hoursafteradministration.Fluoxetineisextensivelymetabolizedbythepolymorphicenzyme

CYP2D6.Fluoxetineisprimarilymetabolizedbythelivertotheactivemetabolitenorfluoxetine(demethylfluoxetine),

bydemethylation.

Elimination

Theeliminationhalf-lifeoffluoxetineis4to6daysandfornorfluoxetine4to16days.Theselonghalf-livesare

responsibleforpersistenceofthedrugfor5-6weeksafterdiscontinuation.Excretionismainly(about60%)viathe

kidney.Fluoxetineissecretedintobreastmilk.

At-riskpopulations

Elderly:Kineticparametersarenotalteredinhealthyelderlywhencomparedto

youngersubjects

Hepaticinsufficiency:

Incaseofhepaticinsufficiency(alcoholiccirrhosis),fluoxetineandnorfluoxetinehalf-livesareincreasedto7and

12days,respectively.Alowerorlessfrequentdoseshouldbeconsidered.

Renalinsufficiency:

Aftersingle-doseadministrationoffluoxetineinpatientswithmild,moderateorcomplete(anuria)renal

insufficiency,kineticparametershavenotbeenalteredwhencomparedtohealthyvolunteers.However,after

repeatedadministration,anincreaseinsteady-stateplateauofplasmaconcentrationsmaybeobserved.

5.3Preclinicalsafetydata

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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

Capsulecontent:

Pregelatinisedmaizestarch

Capsuleshellcomponents:

Gelatin

Yellowironoxide(E172)

Titaniumdioxide(E171)

Brilliantblue(E133)

PrintingInkcomponents:

Activatedcharcoal

Shellac(E904)

6.2Incompatibilities

Notapplicable

6.3Shelflife

3years.

6.4Specialprecautionsforstorage

Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

BlisterpackcontainingPVdCcoatedPVCfilmwithabackingofaluminiumfoil(coatedwithheatseallacquer)

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6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

RanbaxyIrelandLtd

Spafield,CorkRoad,

Cashel,Co.Tipperary

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA0408/055/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:03December2001

Dateoflastrenewal:30November2004

10DATEOFREVISIONOFTHETEXT

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Date Printed 30/05/2011 CRN 2003679 page number: 11