FAVERIN

Main information

  • Trade name:
  • FAVERIN Film Coated Tablet 50 Milligram
  • Dosage:
  • 50 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FAVERIN Film Coated Tablet 50 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0108/016/001
  • Authorization date:
  • 11-10-1989
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Faverin50mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains50mgfluvoxaminemaleate.

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Film-coatedtablet

Round,biconvex,scored,whitetooff-whitefilmcoatedtabletsimprinted'291'onbothsidesofthescore.

Thetabletcanbedividedintoequaldoses.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Majordepressiveepisode

ObsessiveCompulsiveDisorder(OCD)

4.2Posologyandmethodofadministration

Depression

Adults

Therecommendeddoseis100mgdaily.Patientsshouldstarton50or100mg,givenasasingledoseintheevening.

Dosageshouldbereviewedandadjustedifnecessarywithin3to4weeksofinitiationoftherapyandthereafteras

judgedclinicallyappropriate.Althoughtheremaybeanincreasedpotentialforundesirableeffectsathigherdoses,if

aftersomeweeksontherecommendeddoseinsufficientresponseisseensomepatientsmaybenefitfromhavingtheir

doseincreasedgraduallyuptoamaximumof300mgaday(seesection5.1).Dosesupto150mgcanbegivenasa

singledose,preferablyintheevening.Itisadvisablethatatotaldailydoseofmorethan150mgisgivenin2or3

divideddoses.Dosageadjustmentsshouldbemadecarefullyonanindividualpatientbasis,tomaintainthepatientsat

thelowesteffectivedose.

Patientswithdepressionshouldbetreatedforasufficientperiodofatleast6monthstoensurethattheyarefreefrom

symptoms.

Children/adolescents

Faverinshouldnotbeusedinchildrenandadolescentsundertheageof18yearsforthetreatmentofmajordepressive

episode.TheefficacyandsafetyofFaverinhavenotbeenestablishedinthetreatmentofpaediatricmajordepressive

episode(seesection4.4).

ObsessiveCompulsiveDisorder

Adults

Therecommendeddoseisbetween100-300mgdaily.Patientsshouldstartat50mgperday.Althoughtheremaybean

increasedpotentialforundesirableeffectsathigherdoses,ifaftersomeweeksontherecommendeddoseinsufficient

responseisseensomepatientsmaybenefitfromhavingtheirdoseincreasedgraduallyuptoamaximumof300mga

day(seesection5.1).Dosesupto150mgcanbegivenasasingledose,preferablyintheevening.Itisadvisablethata

totaldailydoseofmorethan150mgisgivenin2or3divideddoses.Ifagoodtherapeuticresponsehasbeenobtained,

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Whiletherearenosystematicstudiestoanswerthequestionofhowlongtocontinuefluvoxaminetreatment,OCDisa

chronicconditionanditisreasonabletoconsidercontinuationbeyond10weeksinrespondingpatients.Dosage

adjustmentsshouldbemadecarefullyonanindividualpatientbasis,tomaintainthepatientsatthelowesteffective

dose.Theneedfortreatmentshouldbereassessedperiodically.Somecliniciansadvocateconcomitantbehavioural

psychotherapyforpatientswhohavedonewellonpharmacotherapy.Long-termefficacy(morethan24weeks)hasnot

beendemonstratedinOCD.

Children/adolescents

Inchildrenover8yearsandadolescentsthereislimiteddataonadoseofupto100mgb.i.dfor10weeks.Thestarting

doseis25mgperday.Increaseevery4-7daysin25mgincrementsastolerateduntilaneffectivedoseisachieved.The

maximumdoseinchildrenshouldnotexceed200mg/day.(Forfurtherdetailsseesection5.1and5.2).Itisadvisable

thatatotaldailydoseofmorethan50mgshouldbegivenintwodivideddoses.Ifthetwodivideddosesarenotequal,

thelargerdoseshouldbegivenatbedtime.

Withdrawalsymptomsseenondiscontinuationoffluvoxamine

Abruptdiscontinuationshouldbeavoided.Whenstoppingtreatmentwithfluvoxaminethedoseshouldbegradually

reducedoveraperiodofatleastoneortwoweeksinordertoreducetheriskofwithdrawalreactions(seesection4.4

Specialwarningsandspecialprecautionsforuseandsection4.8Undesirableeffects).Ifintolerablesymptomsoccur

followingadecreaseinthedoseorupondiscontinuationoftreatment,thenresumingthepreviouslyprescribeddose

maybeconsidered.Subsequently,thephysicianmaycontinuedecreasingthedose,butatamoregradualrate.

Hepaticorrenalinsufficiency

Patientssufferingfromhepaticorrenalinsufficiencyshouldstartonalowdoseandbecarefullymonitored.

Methodofadministration

Fluvoxaminetabletsshouldbeswallowedwithwaterandwithoutchewing.

4.3Contraindications

Faverintabletsarecontraindicatedincombinationwithtizanidineandmonoamineoxidaseinhibitors(MAOIs)(see

section4.5).

Treatmentwithfluvoxaminecanbeinitiated:

-twoweeksafterdiscontinuationofanirreversibleMAOI,or

-thefollowingdayafterdiscontinuationofareversibleMAOI(e.g.moclobemide).

AtleastoneweekshouldelapsebetweendiscontinuationoffluvoxamineandinitiationoftherapywithanyMAOI.

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

4.4Specialwarningsandprecautionsforuse

Suicide/suicidalthoughtsorclinicalworsening

Depressionisassociatedwithanincreasedriskofsuicidalthoughts,selfharmandsuicide(suicide-relatedevents).This

riskpersistsuntilsignificantremissionoccurs.Asimprovementmaynotoccurduringthefirstfewweeksormoreof

treatment,patientsshouldbecloselymonitoreduntilsuchimprovementoccurs.Itisgeneralclinicalexperiencethatthe

riskofsuicidemayincreaseintheearlystagesofrecovery.

OtherpsychiatricconditionsforwhichFaverinisprescribedcanalsobeassociatedwithanincreasedriskofsuicide-

relatedevents.Inaddition,theseconditionsmaybeco-morbidwithmajordepressivedisorder.Thesameprecautions

observedwhentreatingpatientswithmajordepressivedisordershouldthereforebeobservedwhentreatingpatients

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Patientswithahistoryofsuicide-relatedevents,orthoseexhibitingasignificantdegreeofsuicidalideationpriorto

commencementoftreatmentareknowntobeatgreaterriskofsuicidalthoughtsorsuicideattempts,andshouldreceive

carefulmonitoringduringtreatment.Ameta-analysisofplacebo-controlledclinicaltrialsofantidepressantdrugsin

adultpatientswithpsychiatricdisordersshowedanincreasedriskofsuicidalbehaviourwithantidepressantscompared

toplaceboinpatientslessthan25yearsold.

Closesupervisionofpatientsandinparticularthoseathighriskshouldaccompanydrugtherapyespeciallyinearly

treatmentandfollowingdosechanges.

Patients(andcaregiversofpatients)shouldbealertedabouttheneedtomonitorforanyclinicalworsening,suicidal

behaviourorthoughtsandunusualchangesinbehaviourandtoseekmedicaladviceimmediatelyifthesesymptoms

present.

Paediatricpopulation

Fluvoxamineshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years,exceptfor

patientswithObsessiveCompulsiveDisorder.Suicide-relatedbehaviours(suicideattemptandsuicidalthoughts),and

hostility(predominantlyaggression,oppositionalbehaviourandanger)weremorefrequentlyobservedinclinicaltrials

amongchildrenandadolescentstreatedwithantidepressantscomparedtothosetreatedwithplacebo.If,basedon

clinicalneed,adecisiontotreatisneverthelesstaken,thepatientshouldbecarefullymonitoredfortheappearanceof

suicidalsymptoms.

Inaddition,long-termsafetydatainchildrenandadolescentsconcerninggrowth,maturationandcognitiveand

behaviouraldevelopmentarelacking.

Geriatricpopulation

Datainelderlysubjectsgivenoindicationofclinicallysignificantdifferencesinnormaldailydosagescomparedto

youngersubjects.However,upwarddosetitrationshouldbedoneslowerintheelderly,anddosingshouldalwaysbe

donewithcaution.

Renalandhepaticimpairment

Patientssufferingfromhepaticorrenalinsufficiencyshouldstartonalowdoseandbecarefullymonitored.

Treatmentwithfluvoxaminehasrarelybeenassociatedwithanincreaseinhepaticenzymes,generallyaccompaniedby

clinicalsymptoms.Insuchcasestreatmentshouldbediscontinued.

Withdrawalsymptomsseenondiscontinuationoffluvoxaminetreatment

Withdrawalsymptomswhentreatmentisdiscontinuedarecommon,particularlyifdiscontinuationisabrupt(see

section4.8Undesirableeffects).Inclinicaltrials,adverseeventsseenontreatmentdiscontinuationoccurredin

approximately12%ofpatientstreatedwithfluvoxamine,whichissimilartotheincidenceseeninpatientstaking

placebo.Theriskofwithdrawalsymptomsmaybedependentonseveralfactorsincludingthedurationanddoseof

therapyandtherateofdosereduction.

Dizziness,sensorydisturbance(includingparaesthesia,visualdisturbancesandelectricshocksensations),sleep

disturbances(includinginsomniaandintensedreams),agitationandanxiety,irritability,confusion,emotional

instability,nauseaand/orvomitinganddiarrhoea,sweatingandpalpitations,headacheandtremorarethemost

commonlyreportedreactions.Generallythesesymptomsaremildtomoderate;however,insomepatientstheymaybe

severeinintensity.Theyusuallyoccurwithinthefirstfewdaysofdiscontinuingtreatment,buttherehavebeenvery

rarereportsofsuchsymptomsinpatientswhohaveinadvertentlymissedadose.

Generallythesesymptomsareself-limitingandusuallyresolvewithin2weeks,thoughinsomeindividualstheymay

beprolonged(2-3monthsormore).Itisthereforeadvisedthatfluvoxamineshouldbegraduallytaperedwhen

discontinuingtreatmentoveraperiodofseveralweeksormonths,accordingtothepatient’sneeds(see"Withdrawal

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PsychiatricDisorders

Fluvoxamineshouldbeusedwithcautioninpatientswithahistoryofmania/hypomania.Fluvoxamineshouldbe

discontinuedinanypatiententeringamanicphase.

Akathisia/psychomotorrestlessness

Theuseoffluvoxaminehasbeenassociatedwiththedevelopmentofakathisia,characterisedbyasubjectively

unpleasantordistressingrestlessnessandneedtomoveoftenaccompaniedbyaninabilitytositorstandstill.Thisis

mostlikelytooccurwithinthefirstfewweeksoftreatment.Inpatientswhodevelopthesesymptoms,increasingthe

dosemaybedetrimental.

Nervoussystemdisorders

Althoughinanimalstudiesfluvoxaminehasnopro-convulsiveproperties,cautionisrecommendedwhenthedrugis

administeredtopatientswithahistoryofconvulsivedisorders.Fluvoxamineshouldbeavoidedinpatientswith

unstableepilepsyandpatientswithcontrolledepilepsyshouldbecarefullymonitored.Treatmentwithfluvoxamine

shouldbediscontinuedifseizuresoccurorifseizurefrequencyincreases.

Onrareoccasions,developmentofaserotoninsyndromeorneurolepticmalignantsyndrome-likeeventshavebeen

reportedinassociationwithtreatmentoffluvoxamine,particularlywhengivenincombinationwithotherserotonergic

and/orneurolepticdrugs.Asthesesyndromesmayresultinpotentiallylife-threateningconditions,treatmentwith

fluvoxamineshouldbediscontinuedifsuchevents(characterisedbyclustersofsymptomssuchashyperthermia,

rigidity,myoclonus,autonomicinstabilitywithpossiblerapidfluctuationsofvitalsigns,mentalstatuschanges

includingconfusion,irritability,extremeagitationprogressingtodeliriumandcoma)occurandsupportive

symptomatictreatmentshouldbeinitiated.

Metabolismandnutritiondisorders

AswithotherSSRIs,hyponatremiahasbeenrarelyreported,andappearstobereversiblewhenfluvoxamineis

discontinued.Somecaseswerepossiblyduetothesyndromeofinappropriateantidiuretichormonesecretion.The

majorityofreportswereassociatedwitholderpatients.

Glycaemiccontrolmaybedisturbed(i.e.,hyperglycemia,hypoglycemia,decreasedglucosetolerance),especiallyinthe

earlystagesoftreatment.Whenfluvoxamineisgiventopatientswithaknownhistoryofdiabetesmellitus,thedosage

ofanti-diabeticdrugsmayneedtobeadjusted.

Nausea,sometimesaccompaniedbyvomitingisthemostfrequentlyobservedsymptomassociatedwithfluvoxamine

treatment.Thissideeffectusuallydiminisheswithinthefirsttwoweeksoftreatment.

Haematologicaldisorders

Therehavebeenreportsofthefollowinghaemorrhagicdisorders:gastrointestinalbleeding,gynaecological

haemorrhage,andothercutaneousormucousbleedingwithSSRIs.CautionisadvisedinpatientstakingSSRIs

particularlyinelderlypatientsandinpatientswhoconcomitantlyusedrugsknowntoaffectplateletfunction(e.g.

atypicalantipsychoticsandphenothiazines,mostTCAs,acetylsalicylicacid,NSAIDs)ordrugsthatincreaseriskof

bleeding,aswellasinpatientswithahistoryofbleedingandinthosewithpredisposingconditions(e.g.

thrombocytopeniaorcoagulationdisorders).

Cardiacdisorders

Fluvoxamineshouldnotbeco-administeredwithterfenadine,astemizoleorcisaprideasplasmaconcentrationsmaybe

increasedresultinginahigherriskforQT-prolongation/TorsadedePointes.

Duetolackofclinicalexperience,specialattentionisadvisedinthesituationofpost-acutemyocardialinfarction.

Electroconvulsivetherapy(ECT)

ThereislimitedclinicalexperienceofconcomitantadministrationoffluvoxamineandECTthereforecautionis

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

FluvoxamineshouldnotbeusedincombinationwithMAOIs(seealsosection4.3Contraindications).

FluvoxamineisapotentinhibitorofCYP1A2,andtoalesserextentofCYP2CandCYP3A4.Drugswhicharelargely

metabolisedviatheseisoenzymesareeliminatedslowerandmayhavehigherplasmaconcentrationswhenco-

administeredwithfluvoxamine.Thisisparticularlyrelevantfordrugswithanarrowtherapeuticindex.Patientsshouldbe

carefullymonitoredand,ifnecessary,doseadjustmentofthesedrugsisrecommended.

FluvoxaminehasmarginalinhibitoryeffectsonCYP2D6andseemsnottoaffectnon-oxidativemetabolismorrenal

excretion.

CYP1A2

Anincreaseinpreviouslystableplasmalevelsofthosetricyclicantidepressants(e.g.clomipramine,imipramine,

amitriptyline)andneuroleptics(e.g.clozapineandolanzapine)whicharelargelymetabolisedthroughcytochromeP450

1A2whengiventogetherwithfluvoxamine,hasbeenreported.Adecreaseinthedoseoftheseproductsshouldbe

considerediftreatmentwithfluvoxamineisinitiated.

Patientsco-administeredfluvoxamineandCYP1A2metaboliseddrugswithanarrowtherapeuticindex(suchas

tacrine,theophylline,methadone,mexiletine)shouldbecarefullymonitoredand,ifnecessary,doseadjustmentofthese

drugsisrecommended.

Isolatedcasesofcardiactoxicityhavebeenreportedwhenfluvoxaminewascombinedwiththioridazine.

Asplasmaconcentrationsofpropranololareincreasedincombinationwithfluvoxamine,thepropranololdosemay

needtobelowered.

Caffeineplasmalevelsarelikelytobeincreasedduringco-administrationwithfluvoxamine.Thus,patientswho

consumehighquantitiesofcaffeine-containingbeveragesshouldlowertheirintakewhenfluvoxamineisadministered

andadversecaffeineeffects(liketremor,palpitations,nausea,restlessness,insomnia)areobserved.

Asplasmaconcentrationsofropinirolemaybeincreasedincombinationwithfluvoxaminethusincreasingtheriskof

overdose,surveillanceandreductioninthedosageofropiniroleduringfluvoxaminetreatmentandafteritswithdrawal

mayberequired.

CYP2C

Patientsco-administeredfluvoxamineandCYP2Cmetaboliseddrugswithanarrowtherapeuticindex(suchasphenytoin)

shouldbecarefullymonitoredand,ifnecessary,doseadjustmentofthesedrugsisrecommended.

Warfarin:

Whengivenwithfluvoxamine,warfarinplasmaconcentrationsweresignificantlyincreasedandprothrombintimes

prolonged.

ThecytochromeP-450isozymesinvolvedinthemetabolismofwarfarininclude2C9,2C19,2C8,2C18,1A2,and

3A4.2C9islikelytobetheprincipalformofhumanliverP-450whichmodulatestheinvivoanticoagulantactivityof

warfarin.

CYP3A4

Terfenadine,astemizole,cisapride(seealsosection4.4SpecialWarningsandPrecautionsforUse).

Patientsco-administeredfluvoxamineandCYP3A4metaboliseddrugswithanarrowtherapeuticindex(suchas

carbamazepineandciclosporin)shouldbecarefullymonitoredand,ifnecessary,doseadjustmentofthesedrugsis

recommended.

Theplasmalevelsofoxidativelymetabolisedbenzodiazepines(e.g.triazolam,midazolam,alprazolam,anddiazepam)

arelikelytobeincreasedwhenco-administeredwithfluvoxamine.Thedosageofthesebenzodiazepinesshouldbe

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Glucuronidation

Fluvoxaminedoesnotinfluenceplasmaconcentrationsofdigoxin.

Renalexcretion

Fluvoxaminedoesnotinfluenceplasmaconcentrationsofatenolol.

Pharmacodynamicinteractions

Theserotonergiceffectsoffluvoxaminemaybeenhancedwhenusedincombinationwithotherserotonergicagents

(includingtriptans,SSRIsandSt.John´sWortpreparations).(Seealsosection4.4SpecialWarningsandPrecautionsfor

Use).

Fluvoxaminehasbeenusedincombinationwithlithiuminthetreatmentofseverelyill,drug-resistantpatients.However,

lithium(andpossiblyalsotryptophan)enhancestheserotonergiceffectsoffluvoxamine.Thecombinationshouldbeused

withcautioninpatientswithsevere,drug-resistantdepression.

Inpatientsonoralanticoagulantsandfluvoxamine,theriskforhaemorrhagemayincreaseandthesepatientsshould

thereforebecloselymonitored.

Aswithotherpsychotropicdrugs,patientsshouldbeadvisedtoavoidalcoholusewhiletakingfluvoxamine.

4.6Fertility,pregnancyandlactation

Pregnancy

EpidemiologicaldatahavesuggestedthattheuseofSelectiveSerotoninReuptakeInhibitors(SSRIs)inpregnancy,

particularinlatepregnancy,mayincreasetheriskofpersistentpulmonaryhypertensioninthenewborn(PPHN).The

observedriskwasapproximately5casesper1000pregnancies.Inthegeneralpopulation1to2casesofPPHNper

1000pregnanciesoccur.

Reproductiontoxicitystudiesinanimalsrevealedtreatmentrelatedincreasesinembryotoxicity(embryofetaldeath,

fetaleyeabnormalities).Therelevancetohumansisunknown.Thesafetymarginforreproductivetoxicityisunknown

(seesection5.3).

Faverinshouldnotbeusedduringpregnancyunlesstheclinicalconditionofthewomanrequirestreatmentwith

fluvoxamine.

Isolatedcasesofwithdrawalsymptomsinthenewbornchildhavebeendescribedaftertheuseoffluvoxamineatthe

endofpregnancy.

Somenewbornsexperiencefeedingand/orrespiratorydifficulties,seizures,temperatureinstability,hypoglycaemia,

tremor,abnormalmuscletone,jitteriness,cyanosis,irritability,lethargy,somnolence,vomiting,difficultyinsleeping

andconstantcryingafterthirdtrimesterexposuretoSSRIsandmayrequireprolongedhospitalization

Breastfeeding

Fluvoxamineisexcretedviahumanmilkinsmallquantities.Therefore,thedrugshouldnotbeusedbywomenwho

breastfeed.

Fertility

ReproductivetoxicitystudiesinanimalshaveshownthatFaverinimpairsmaleandfemalefertility.Thesafetymargin

forthiseffectwasnotidentified.Therelevanceofthesefindingstohumansisunknown(seesection5.3).

Faverinshouldnotbeusedinpatientsattemptingtoconceiveunlesstheclinicalconditionofthepatientrequires

treatmentwithfluvoxamine.

4.7Effectsonabilitytodriveandusemachines

Fluvoxamineupto150mghasnoornegligibleinfluenceontheabilitytodriveandusemachines.Itshowednoeffect

onpsychomotorskillsassociatedwithdrivingandoperatingmachineryinhealthyvolunteers.However,somnolence

hasbeenreportedduringtreatmentwithfluvoxamine.Therefore,cautionisrecommendeduntiltheindividualresponse

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4.8Undesirableeffects

Adverseevents,observedinclinicalstudiesatfrequencieslistedbelow,areoftenassociatedwiththeillnessandarenot

necessarilyrelatedtotreatment.

Inadditiontothoseadverseeventsreportedduringclinicaltrials,thefollowingsideeffectshavebeenreported

spontaneouslyduringpostmarketinguseoffluvoxamine.Aprecisefrequencycannotbeprovidedandistherefore

classifiedas‘notknown’.

MedDrasystem

organclass Common1/100,

<1/10 Uncommon

1/1,000,<1/100 Rare1/10,000,

<1/1,000 Veryrare

<1/10,000

incl.isolated

reports

Metabolismand

nutritiondisorders Anorexia

Psychiatric

disorders Hallucination,

confusionalstage Mania

Nervoussystem

disorders Agitation,

nervousness,

anxiety,insomnia,

somnolence,tremor,

headache,dizziness Extrapyramidal

disorder,ataxia Convulsion

Cardiacdisorders Palpitations/

tachycardia

Vasculardisorders (Orthostatic)

hypotension

Gastrointestinal

disorders Abdominalpain,

constipation,

diarrhoea,dry

mouth,dyspepsia,

nausea,vomiting

Hepatobiliary

disorders Hepaticfunction

abnormal

Skinand

subcutaneous

tissuedisorders Hyperhydrosis

Sweating Cutaneous

hypersensitivity

reactions(incl.

angioneurotic

oedema,rash,

pruritis) Photosensitivity

reaction

Musculoskeletal,

connectivetissue

andbonedisorders Arthralgia,myalgia

Reproductive

systemandbreast

disorders Abnormal(delayed)

ejaculation Galactorrhoea

Generaldisorders

andadministration

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Endocrinedisorders:Hyperprolactinemia,Inappropriateantidiuretichormonesecretion.

Metabolismandnutritiondisorders:Hyponatraemia,weightincreased,weightdecreased.

Nervoussystemdisorders:Serotoninsyndrome,neurolepticmalignantsyndrome-likeevents,paresthesia,dysgeusia,

andSIADHhavebeenreported(seealsosection4.4Specialwarningsandspecialprecautionsforuse).

Renalandurinarydisorders:micturitiondisorder(includingurinaryretention,urinaryincontinence,pollakiura,nocturia

andenuresis)

Reproductivesystemandbreastdisorders:Anorgasmia,menstrualdisorders(suchasamenorrhea,hypomenorrhea,

metrorrhagia,menorrhagia).

Generaldisordersandadministrationsiteconditions:drugwithdrawalsyndromeincludingdrugwithdrawalsyndrome

neonatal (seesection4.6Fertility,PregnancyandLactation).

Psychomotorrestlessness/akathisia(seesection4.4Specialwarningsandprecautionsforuse).

Casesofsuicidalideationandsuicidalbehaviourshavebeenreportedduringfluvoxaminetherapyorearlyafter

treatmentdiscontinuation(seesection4.4Specialwarningsandprecautionsforuse).

Inone10-weekplacebo-controlledtrialinchildrenandadolescentswithOCD,frequentlyreportedadverseeventswith

ahigherincidencethanplacebo,were:insomnia,asthenia,agitation,hyperkinesia,somnolenceanddyspepsia.Serious

adverseeventsinthisstudyincluded:agitationandhypomania.Convulsionsinchildrenandadolescentshavebeen

reportedduringuseoutsideclinicaltrials.

Withdrawalsymptomsseenondiscontinuationoffluvoxaminetreatment

Discontinuationoffluvoxamine(particularlywhenabrupt)commonlyleadstowithdrawalsymptoms.Dizziness,

sensorydisturbance(includingparaesthesia,visualdisturbanceandelectricshocksensations),sleepdisturbances

(includinginsomniaandintensedreams),agitationandanxiety,irritability,confusion,emotionalinstability,nausea

and/orvomiting,diarrhoea,sweating,palpitations,headacheandtremorarethemostcommonlyreportedreactions.

Generallytheseeventsaremildtomoderateandareself-limiting,however,insomepatientstheymaybesevereand/or

prolonged.Itisthereforeadvisedthatwhenfluvoxaminetreatmentisnolongerrequired,gradualdiscontinuationby

dosetaperingshouldbecarriedout(seesection4.2Posologyandmethodofadministrationandsection4.4Special

warningsandprecautionsforuse).

Classeffects:Epidemiologicalstudies,mainlyconductedinpatients50yearsofageandolder,showanincreasedrisk

ofbonefracturesinpatientsreceivingSelectiveSerotoninReuptakeInhibitors(SSRIs)andTricyclicAntidepressants

(TCAs).Themechanismleadingtothisriskisunknown.

4.9Overdose

Symptoms

Symptomsincludegastro-intestinalcomplaints(nausea,vomitinganddiarrhoea),somnolenceanddizziness.Cardiac

events(tachycardia,bradycardia,hypotension),liverfunctiondisturbances,convulsionsandcomahavealsobeen

reported.

Fluvoxaminehasawidemarginofsafetyinoverdose.Sincemarketintroduction,reportsofdeathsattributedto

overdoseoffluvoxaminealonehavebeenextremelyrare.Thehighestdocumenteddoseoffluvoxamineingestedbya

patientis12grams.Thispatientrecoveredcompletely.Occasionally,moreseriouscomplicationswereobservedin

casesofdeliberateoverdoseoffluvoxamineincombinationwithotherdrugs.

Treatment

Thereisnospecificantidotetofluvoxamine.Incaseofoverdosethestomachshouldbeemptiedassoonaspossible

aftertabletingestionandsymptomatictreatmentshouldbegiven.Therepeateduseofmedicinalcharcoal,ifnecessary

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antidepressants,Selectiveserotoninreuptakeinhibitors,ATCcode:N06AB08.

Themechanismofactionoffluvoxamineisthoughttoberelatedtoselectiveserotoninre-uptakeinhibitioninbrain

neurones.Thereisminimuminterferencewithnoradrenergicprocesses.Receptorbindingstudieshavedemonstratedthat

fluvoxaminehasnegligiblebindingcapacitytoalphaadrenergic,betaadrenergic,histaminergic,muscarinecholinergic,

dopaminergicorserotonergicreceptors.

Inaplacebocontrolledtrialin120patientswithOCD,agedbetween8and17years,astatisticallysignificantimprovement

wasseeninthetotalpopulationinfavouroffluvoxamineat10weeks.Afurthersubgroupanalysisshowedimprovement

ontheC-YBOCSratingscaleinchildrenwhereasnoeffectwasseeninadolescents.Themeandosewasrespectively158

mgand168mg/day.

Doseresponse

Noformalclinicaltrialswereconductedinvestigatingthedoseresponseoffluvoxamine.However,itisclinical

experiencethatup-titratingthedosemightbebeneficialforsomepatients.

5.2Pharmacokineticproperties

Absorption

Fluvoxamineiscompletelyabsorbedfollowingoraladministration.Maximumplasmaconcentrationsoccurwithin3-8

hoursofdosing.Themeanabsolutebioavailabilityis53%duetofirst-passmetabolism.

ThepharmacokineticsofFaverinisnotinfluencedbyconcomitantfoodintake.

Distribution

Invitroplasmaproteinbindingoffluvoxamineis80%.Volumeofdistributioninhumansis25l/kg.

Metabolism

Fluvoxamineundergoesextensivemetabolismintheliver.AlthoughCYP2D6isinvitrothemainisoenzymeinvolved

influvoxamine’smetabolism,plasmaconcentrationsinpoormetabolisersforCYP2D6arenotmuchhigherthanthose

inextensivemetabolisers.

Themeanplasmahalf-lifeisapproximately13-15hoursafterasingledoseandslightlylonger(17-22hours)during

repeateddosing,whensteady-stateplasmalevelsareusuallyachievedwithin10-14days.

Fluvoxamineundergoesextensivehepatictransformation,mainlyviaoxidativedemethylation,intoatleastnine

metabolites,whichareexcretedbythekidneys.Thetwomajormetabolitesshowednegligiblepharmacologicalactivity.

Theothermetabolitesarenotexpectedtobepharmacologicallyactive.FluvoxamineisapotentinhibitorofCYP1A2

andamoderateinhibitorofCYP2CandCYP3A4,withonlymarginalinhibitoryeffectsonCYP2D6.

Fluvoxaminedisplayslinearsingle-dosepharmacokinetics.Steady-stateconcentrationsarehigherthancalculatedfrom

single-dosedata,andaredisproportionatelyhigherathigherdailydoses.

SpecialPatientsgroups

Thepharmacokineticsoffluvoxamineissimilarinhealthyadults,elderlypatients,andpatientswithrenalinsufficiency.

Themetabolismoffluvoxamineisimpairedinpatientswithliverdisease.

Steady-stateplasmaconcentrationsoffluvoxamineweretwiceashighinchildren(aged6-11)asinadolescents(aged

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5.3Preclinicalsafetydata

Thereisnoevidenceofcarcinogenicityormutagenicitywithfluvoxamine.

Reproductivetoxicitystudiesinratshaveshownthatfluvoxamineimpairsmaleandfemalefertility(reducedsperm

counts,increasedovaryweightsandreducedfertility),andisembryotoxic(increasedembryofetaldeath[resorptions],

increasedfetaleyeabnormalities[foldedretina],reducedfetalweightsanddelayedossification).Theeffectsonfetal

weightsandossificationarelikelytobesecondarytomaternaltoxicity(reducedmaternalbodyweightandbodyweight

gain).Thesafetymarginforreproductivetoxicityisunknown.

Thepotentialforabuse,toleranceandphysicaldependencehasbeenstudiedinanon-humanprimatemodel.No

evidenceofdependencyphenomenawasfound.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcores:

Mannitol

Maizestarch

Pregelatinisedstarch

Sodiumstearylfumarate

Colloidalanhydroussilica

Film-coat:

Hypromellose

Macrogol6000

Talc

TitaniumDioxideE171

6.2Incompatibilities

Notapplicable.

6.3Shelflife

3years.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

6.5Natureandcontentsofcontainer

PVC/PVdC/Aluminiumpress-throughblister.

Packscontain:5,10,20,30,50,60,90,100and250tablets.

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6.6Specialprecautionsfordisposal

Nospecialrecommendation.

7MARKETINGAUTHORISATIONHOLDER

AbbottHealthcareProductsLtd

MansbridgeRoad

WestEnd

Southampton

SO183JD

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA108/16/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:11October1989

Dateoflastrenewal:21June2009

10DATEOFREVISIONOFTHETEXT

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