FAVERIN

Main information

  • Trade name:
  • FAVERIN Film Coated Tablet 100 Milligram
  • Dosage:
  • 100 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FAVERIN Film Coated Tablet 100 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0108/016/003
  • Authorization date:
  • 11-10-1989
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Faverin100mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains100mgfluvoxaminemaleate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Oval,biconvex,scored,whitetooff-whitefilm-coatedtabletsimprinted'313'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

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ObsessiveCompulsiveDisorder

Adults

Therecommendeddoseisbetween100-300mgdaily.Patientsshouldstartat50mgperday.Althoughtheremaybean

increasedpotentialforundesirableeffectsathigherdoses,ifaftersomeweeksontherecommendeddoseinsufficient

responseisseensomepatientsmaybenefitfromhavingtheirdoseincreasedgraduallyuptoamaximumof300mga

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

totaldailydoseofmorethan150mgisgivenin2or3divideddoses.Ifagoodtherapeuticresponsehasbeenobtained,

treatmentcanbecontinuedatadosageadjustedonanindividualbasis.

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.

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4.4Specialwarningsandprecautionsforuse

Suicide/suicidalthoughtsorclinicalworsening

Depressionisassociatedwithanincreasedriskofsuicidalthoughts,selfharmandsuicide(suicide-relatedevents).This

riskpersistsuntilsignificantremissionoccurs.Asimprovementmaynotoccurduringthefirstfewweeksormoreof

treatment,patientsshouldbecloselymonitoreduntilsuchimprovementoccurs.Itisgeneralclinicalexperiencethatthe

riskofsuicidemayincreaseintheearlystagesofrecovery.

OtherpsychiatricconditionsforwhichFaverinisprescribedcanalsobeassociatedwithanincreasedriskofsuicide-

relatedevents.Inaddition,theseconditionsmaybeco-morbidwithmajordepressivedisorder.Thesameprecautions

observedwhentreatingpatientswithmajordepressivedisordershouldthereforebeobservedwhentreatingpatients

withotherpsychiatricdisorders.

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.

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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

SymptomsSeenonDiscontinuationofFluvoxamine",Section4.2Posologyandmethodofadministration).

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.

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Cardiacdisorders

Fluvoxamineshouldnotbeco-administeredwithterfenadine,astemizoleorcisaprideasplasmaconcentrationsmaybe

increasedresultinginahigherriskforQT-prolongation/TorsadedePointes.

Duetolackofclinicalexperience,specialattentionisadvisedinthesituationofpost-acutemyocardialinfarction.

Electroconvulsivetherapy(ECT)

ThereislimitedclinicalexperienceofconcomitantadministrationoffluvoxamineandECTthereforecautionis

advisable.

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)

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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

reducedduringco-administrationwithfluvoxamine.

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.

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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

tothedrughasbeendetermined.

4.8Undesirableeffects

Adverseevents,observedinclinicalstudiesatfrequencieslistedbelow,areoftenassociatedwiththeillnessandarenot

necessarilyrelatedtotreatment.

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, Photosensitivity

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Inadditiontothoseadverseeventsreportedduringclinicaltrials,thefollowingsideeffectshavebeenreported

spontaneouslyduringpostmarketinguseoffluvoxamine.Aprecisefrequencycannotbeprovidedandistherefore

classifiedas‘notknown’.

Bloodandlymphaticsystemdisorders:Haemorrhage(e.g.gastrointestinalhaemorrhage,ecchymosis,purpura).

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

pruritis)

Musculoskeletal,

connectivetissue

andbonedisorders Arthralgia,myalgia

Reproductive

systemandbreast

disorders Abnormal(delayed)

ejaculation Galactorrhoea

Generaldisorders

andadministration

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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

accompaniedbyanosmoticlaxative,isalsorecommended.Forceddiuresisordialysisisunlikelytobeofbenefit.

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

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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

12-17).Plasmaconcentrationsinadolescentsaresimilartothoseinadults.

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

Irish Medicines Board

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Date Printed 04/04/2012 CRN 2109737 page number: 10

6.3Shelflife

3years.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.Keepblisterintheoutercarton

6.5Natureandcontentsofcontainer

PVC/PVdC/Aluminiumpress-throughblisters.

Packssizes:15,20,30,50,60,90,100,120or250tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialrecommendation.

7MARKETINGAUTHORISATIONHOLDER

AbbottHealthcareProductsLtd

MansbridgeRoad

WestEnd

Southampton

SO183JD

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA108/16/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:11October1989

Dateoflastrenewal:21June2009

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 04/04/2012 CRN 2109737 page number: 11