BELLSERT

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0408/091/001
  • Authorization date:
  • 07-10-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

BELLSERT50mgfilm–coatedTablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains50mgofsertralineassertralinehydrochloride.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Whitefilm-coatedcapletshapedtabletembossedwith“50”ononesideandbreak-lineontheotherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Sertralineisindicatedforthetreatmentof:

Majordepressiveepisodes.Preventionofrecurrenceofmajordepressiveepisodes.

Panicdisorder,withorwithoutagoraphobia.

Obsessivecompulsivedisorder(OCD)inadultsandpaediatricpatientsaged6-17years.

Socialanxietydisorder.

Posttraumaticstressdisorder(PTSD)

4.2Posologyandmethodofadministration

Sertralineshouldbeadministeredoncedaily,eitherinthemorningorevening.

Sertralinetabletcanbeadministeredwithorwithoutfood.

Initialtreatment

DepressionandOCD

Sertralinetreatmentshouldbestartedatadoseof50mg/day.

PanicDisorder,PTSD,andSocialAnxietyDisorder

Therapyshouldbeinitiatedat25mg/day.Afteroneweek,thedoseshouldbeincreasedto50mgoncedaily.This

dosageregimenhasbeenshowntoreducethefrequencyofearlytreatmentemergentsideeffectscharacteristicofpanic

disorder.

Titration

Depression,OCD,PanicDisorder,SocialAnxietyDisorderandPTSD

Patientsnotrespondingtoa50mgdosemaybenefitfromdoseincreases.Dosechangesshouldbemadeinstepsof50

mgatintervalsofatleastoneweek,uptoamaximumof

200mg/day.Changesindoseshouldnotbemademorefrequentlythanonceperweekgiventhe24-hourelimination

halflifeofsertraline.

Theonsetoftherapeuticeffectmaybeseenwithin7days.However,longerperiodsareusuallynecessaryto

demonstratetherapeuticresponse,especiallyinOCD.

Maintenance

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therapeuticresponse.

Depression

Longer-termtreatmentmayalsobeappropriateforpreventionofrecurrenceofmajordepressiveepisodes(MDE).In

mostofthecases,therecommendeddoseinpreventionofrecurrenceofMDEisthesameastheoneusedduring

currentepisode.Patientswithdepressionshouldbetreatedforasufficientperiodoftimeofatleast6monthstoensure

theyarefreefromsymptoms.

PanicdisorderandOCD

ContinuedtreatmentinpanicdisorderandOCDshouldbeevaluatedregularly,asrelapsepreventionhasnotbeen

shownforthesedisorders.

Paediatricpatients

Childrenandadolescentswithobsessivecompulsivedisorder

Age13-17years:Initially50mgoncedaily.

Age6-12years:Initially25mgoncedaily.Thedosagemaybeincreasedto50mgoncedailyafteroneweek.

Subsequentdosesmaybeincreasedincaseoflessthandesiredresponsein50mgincrementsoveraperiodof

someweeks,asneeded.Themaximumdosageis200mgdaily.However,thegenerallylowerbodyweightsof

childrencomparedtothoseofadultsshouldbetakenintoconsiderationwhenincreasingthedosefrom50mg.

Dosechangesshouldnotoccuratintervalsoflessthanoneweek.

Efficacyisnotshowninpaediatricmajordepressivedisorder.

Nodataisavailableforchildrenunder6yearsofage(seealsosection4.4).

Useinelderly

Elderlyshouldbedosedcarefully,aselderlymaybemoreatriskforhyponatraemia(seesection4.4).

Useinhepaticinsufficiency

Theuseofsertralineinpatientswithhepaticdiseaseshouldbeapproachedwithcaution.Alowerorlessfrequentdose

shouldbeusedinpatientswithhepaticimpairment(seesection4.4).Sertralineshouldnotbeusedincaseofsevere

hepaticimpairmentasnoclinicaldataareavailable(seesection4.4).

Useinrenalinsufficiency

Nodosageadjustmentisnecessaryinpatientswithrenalinsufficiency(seesection4.4).

Withdrawalsymptomsseenondiscontinuationofsertraline

Abruptdiscontinuationshouldbeavoided.Whenstoppingtreatmentwithsertralinethedoseshouldbegradually

reducedoveraperiodofatleastonetotwoweeksinordertoreducetheriskofwithdrawalreactions(seesections4.4

and4.8).Ifintolerablesymptomsoccurfollowingadecreaseinthedoseorupondiscontinuationoftreatment,then

resumingthepreviouslyprescribeddosemaybeconsidered.Subsequently,thephysicianmaycontinuedecreasingthe

dose,butatamoregradualrate.

4.3Contraindications

Hypersensitivitytotheactivesubstanceoranyoftheexcipients.

Concomitanttreatmentwithirreversiblemonoamineoxidaseinhibitors(MAOIs)iscontraindicatedduetotheriskof

serotoninsyndromewithsymptomssuchasagitation,tremorandhyperthermia.

Sertralinemustnotbeinitiatedforatleast14daysafterdiscontinuationoftreatmentwithanirreversibleMAOI.

Sertralinemustbediscontinuedforatleast7daysbeforestartingtreatmentwithanirreversibleMAOI(seesection4.5).

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4.4Specialwarningsandprecautionsforuse

SerotoninSyndrome(SS)orNeurolepticMalignantSyndrome(NMS):

Thedevelopmentofpotentiallylife-threateningsyndromeslikeserotoninsyndrome(SS)orNeurolepticMalignant

Syndrome(NMS)hasbeenreportedwithSSRIs,includingtreatmentwithsertraline.TheriskofSSorNMSwith

SSRIsisincreasedwithconcomitantuseofserotonergicdrugs(includingtriptans),withdrugswhichimpair

metabolismofserotonin(includingMAOIs),antipsychoticsandotherdopamineantagonists.Patientsshouldbe

monitoredfortheemergenceofsignsandsymptomsofSSorNMSsyndrome(seesection4.3).

SwitchingfromSelectiveSerotoninReuptakeInhibitors(SSRIs),antidepressantsorantiobsessionaldrugs

ThereislimitedcontrolledexperienceregardingtheoptimaltimingofswitchingfromSSRIs,antidepressantsor

antiobsessionaldrugstosertraline.Careandprudentmedicaljudgmentshouldbeexercisedwhenswitching,

particularlyfromlong-actingagentssuchasfluoxetine.

Otherserotonergicdrugse.g.tryptophan,fenfluramineand5-HTagonists

Co-administrationofsertralinewithotherdrugswhichenhancetheeffectsofserotonergicneurotransmissionsuchas

tryptophanorfenfluramineor5-HTagonists,ortheherbalmedicine,StJohn’sWort(Hypericumperforatum),should

beundertakenwithcautionandavoidedwheneverpossibleduetothepotentialforapharmacodynamicinteraction.

Activationofhypomaniaormania

Manic/hypomanicsymptomshavebeenreportedtoemergeinasmallproportionofpatientstreatedwithmarketed

antidepressantandantiobsessionaldrugs,includingsertraline.Thereforesertralineshouldbeusedwithcautionin

patientswithahistoryofmania/hypomania.Closesurveillancebythephysicianisrequired.Sertralineshouldbe

discontinuedinanypatiententeringamanicphase.

Schizophrenia

Psychoticsymptomsmightbecomeaggravatedinschizophrenicpatients.

Seizures

Seizuresmayoccurwithsertralinetherapy:Sertralineshouldbeavoidedinpatientswithunstableepilepsyandpatients

withcontrolledepilepsyshouldbecarefullymonitored.Sertralineshouldbediscontinuedinanypatientwhodevelops

seizures.

Suicide/suicidalthoughts/suicideattemptsorclinicalworsening

Depressionisassociatedwithanincreasedriskofsuicidalthoughts,selfharmandsuicide(suicide-relatedevents).This

riskpersistsuntilsignificantremissionoccurs.Asimprovementmaynotoccurduringthefirstfewweeksormoreof

treatment,patientsshouldbecloselymonitoreduntilsuchimprovementoccurs.Itisgeneralclinicalexperiencethatthe

riskofsuicidemayincreaseintheearlystagesofrecovery.

Otherpsychiatricconditions,forwhichsertralineisprescribed,canalsobeassociatedwithanincreasedriskofsuicide-

relatedevents.Inaddition,theseconditionsmaybeco-morbidwithmajordepressivedisorder.Thesameprecautions

observedwhentreatingpatientswithmajordepressivedisordershouldthereforebeobservedwhentreatingpatients

withotherpsychiatricdisorders.

Patientswithahistoryofsuicide-relatedevents,orthoseexhibitingasignificantdegreeofsuicidalideationpriorto

commencementoftreatmentareknowntobeatgreaterriskofsuicidalthoughtsorsuicideattempts,andshouldreceive

carefulmonitoringduringtreatment.Ameta-analysisofplacebo-controlledclinicaltrialsofantidepressantdrugsin

adultpatientswithpsychiatricdisordersshowedanincreasedriskofsuicidalbehaviourwithantidepressantscompared

toplaceboinpatientslessthan25yearsold.

Closesupervisionofpatientsandinparticularthoseathighriskshouldaccompanydrugtherapyespeciallyinearly

treatmentandfollowingdosechanges.Patients(andcaregiversofpatients)shouldbealertedabouttheneedtomonitor

foranyclinicalworsening,suicidalbehaviourorthoughtsandunusualchangesinbehaviourandtoseekmedicaladvice

immediatelyifthesesymptomspresent.

Useinchildrenandadolescentsunder18yearsofage

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withobsessivecompulsivedisorderaged6-17yearsold.Suicide-relatedbehaviours(suicideattemptandsuicidal

thoughts),andhostility(predominantlyaggression,oppositionalbehaviourandanger)weremorefrequentlyobserved

inclinicaltrialsamongchildrenandadolescentstreatedwithantidepressantscomparedtothosetreatedwithplacebo.If,

basedonclinicalneed,adecisiontotreatisneverthelesstaken;thepatientshouldbecarefullymonitoredforthe

appearanceofsuicidalsymptoms.Inaddition,long-termsafetydatainchildrenandadolescentsconcerninggrowth,

maturationandcognitiveandbehaviouraldevelopmentarelacking.Physiciansmustmonitorpaediatricpatientsonlong

termtreatmentforabnormalitiesinthesebodysystems

Abnormalbleeding/Haemorrhage

Therehavebeenreportsofcutaneousbleedingabnormalitiessuchasecchymosesandpurpuraandotherhemorrhagic

eventssuchasgastrointestinalorgynaecologicalbleeding,withSSRIs.CautionisadvisedinpatientstakingSSRIs,

particularlyinconcomitantusewithdrugsknowntoaffectplateletfunction(e.g.anticoagulants,atypicalantipsychotics

andphenothiazines,mosttricyclicantidepressants,acetylsalicylicacidandnon-steroidalanti-inflammatorydrugs

(NSAIDs))aswellasinpatientswithahistoryofbleedingdisorders(seesection4.5.)

Hyponatraemia

HyponatraemiamayoccurasaresultoftreatmentwithSSRIsorSNRIsincludingsertraline.Inmanycases,

hyponatraemiaappearstobetheresultofasyndromeofinappropriateantidiuretichormonesecretion(SIADH).Cases

ofserumsodiumlevelslowerthan110mmol/lhavebeenreported.

ElderlypatientsmaybeatgreaterriskofdevelopinghyponatraemiawithSSRIsandSNRIs.Alsopatientstaking

diureticsorwhoareotherwisevolume-depletedmaybeatgreaterrisk(seeUseinelderly).Discontinuationofsertraline

shouldbeconsideredinpatientswithsymptomatichyponatraemiaandappropriatemedicalinterventionshouldbe

instituted.Signsandsymptomsofhyponatraemiaincludeheadache,difficultyconcentrating,memoryimpairment,

confusion,weaknessandunsteadinesswhichmayleadtofalls.Signsandsymptomsassociatedwithmoresevereand/or

acutecaseshaveincludedhallucination,syncope,seizure,coma,respiratoryarrest,anddeath.

Withdrawalsymptomsseenondiscontinuationofsertralinetreatment

Withdrawalsymptomswhentreatmentisdiscontinuedarecommon,particularlyifdiscontinuationisabrupt(see

section4.8).Inclinicaltrials,amongpatientstreatedwithsertraline,theincidenceofreportedwithdrawalreactionswas

23%inthosediscontinuingsertralinecomparedto12%inthosewhocontinuedtoreceivesertralinetreatment.

Theriskofwithdrawalsymptomsmaybedependentonseveralfactorsincludingthedurationanddoseoftherapyand

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

insomniaandintensedreams),agitationoranxiety,nauseaand/orvomiting,tremorandheadachearethemost

commonlyreportedreactions.Generallythesesymptomsaremildtomoderate;however,insomepatientstheymaybe

severeinintensity.Theyusuallyoccurwithinthefirstfewdaysofdiscontinuingtreatment,buttherehavebeenvery

rarereportsofsuchsymptomsinpatientswhohaveinadvertentlymissedadose.Generallythesesymptomsareself-

limitingandusuallyresolvewithin2weeks,thoughinsomeindividualstheymaybeprolonged(2-3monthsormore).

Itisthereforeadvisedthatsertralineshouldbegraduallytaperedwhendiscontinuingtreatmentoveraperiodofseveral

weeksormonths,accordingtothepatient’sneeds(seesection4.2).

Akathisia/psychomotorrestlessness

Theuseofsertralinehasbeenassociatedwiththedevelopmentofakathisia,characterisedbyasubjectivelyunpleasant

ordistressingrestlessnessandneedtomoveoftenaccompaniedbyaninabilitytositorstandstill.Thisismostlikelyto

occurwithinthefirstfewweeksoftreatment.Inpatientswhodevelopthesesymptoms,increasingthedosemaybe

detrimental.

Hepaticimpairment

Sertralineisextensivelymetabolisedbytheliver.Amultipledosepharmacokineticstudyinsubjectswithmild,stable

cirrhosisdemonstratedaprolongedeliminationhalflifeandapproximatelythree-foldgreaterAUCandCmaxin

comparisontonormalsubjects.Therewerenosignificantdifferencesinplasmaproteinbindingobservedbetweenthe

twogroups.Theuseofsertralineinpatientswithhepaticdiseasemustbeapproachedwithcaution.Ifsertralineis

administeredtopatientswithhepaticimpairment,alowerorlessfrequentdoseshouldbeconsidered.Sertralineshould

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Renalimpairment

Sertralineisextensivelymetabolised,andexcretionofunchangeddruginurineisaminorrouteofelimination.In

studiesofpatientswithmildtomoderaterenalimpairment(creatinineclearance30-60ml/min)ormoderatetosevere

renalimpairment(creatinineclearance10-29ml/min),multiple-dosepharmacokineticparameters(AUC

0-24 orCmax)

werenotsignificantlydifferentcomparedwithcontrols.Sertralinedosingdoesnothavetobeadjustedbasedonthe

degreeofrenalimpairment.

Useinelderly

Over700elderlypatients(>65years)haveparticipatedinclinicalstudies.Thepatternandincidenceofadverse

reactionsintheelderlywassimilartothatinyoungerpatients.

SSRIsorSNRIsincludingsertralinehavehoweverbeenassociatedwithcasesofclinicallysignificanthyponatraemiain

elderlypatients,whomaybeatgreaterriskforthisadverseevent(seeHyponatraemiainsection4.4).

Diabetes

Inpatientswithdiabetes,treatmentwithanSSRImayalterglycaemiccontrol,possiblyduetoimprovementof

depressivesymptoms.Glycaemiccontrolshouldbecarefullymonitoredinpatientsreceivingsertralineandthedosage

ofinsulinand/orconcomitantoralhypoglycaemicmedicinalproductsmaybeneededtobeadjusted.

Electroconvulsivetherapy(ECT)

TherearenoclinicalstudiesestablishingtherisksorbenefitsofthecombineduseofECTandsertraline.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Contraindicated

MonoamineOxidaseInhibitors

Irreversible(non-selective)MAOIs(selegiline)

Sertralinemustnotbeusedincombinationwithirreversible(non-selective)MAOIssuchasselegiline.Sertralinemust

notbeinitiatedforatleast14daysafterdiscontinuationoftreatmentwithanirreversible(non-selective)MAOI.

Sertralinemustbediscontinuedforatleast7daysbeforestartingtreatmentwithanirreversible(non-selective)MAOI

(seesection4.3).

Reversible,selectiveMAO-Ainhibitor(moclobemide)

Duetotheriskofserotoninsyndrome,thecombinationofsertralinewithareversibleandselectiveMAOI,suchas

moclobemide,isnotrecommended.FollowingtreatmentwithareversibleMAO-inhibitor,ashorterwithdrawalperiod

than14daysmaybeusedbeforeinitiationofsertralinetreatment.Itisrecommendedthatsertralineshouldbe

discontinuedforatleast7daysbeforestartingtreatmentwithareversibleMAOI(seesection4.3).

Reversible,non-selectiveMAOI(linezolid)

Theantibioticlinezolidisaweakreversibleandnon-selectiveMAOIandshouldnotbegiventopatientstreatedwith

sertraline(seesection4.3).

SevereadversereactionshavebeenreportedinpatientswhohaverecentlybeendiscontinuedfromanMAOIand

startedonsertraline,orhaverecentlyhadsertralinetherapydiscontinuedpriortoinitiationofanMAOI.These

reactionshaveincludedtremor,myoclonus,diaphoresis,nausea,vomiting,flushing,dizziness,andhyperthermiawith

featuresresemblingneurolepticmalignantsyndrome,seizures,anddeath.

Pimozide

Increasedpimozidelevelsofapproximately35%havebeendemonstratedinastudyofasinglelowdosepimozide(2

mg).TheseincreasedlevelswerenotassociatedwithanychangesinEKG.Whilethemechanismofthisinteractionis

unknown,duetothenarrowtherapeuticindexofpimozide,concomitantadministrationofsertralineandpimozideis

contraindicated(seesection4.3).

Co-administrationwithsertralineisnotrecommended

CNSdepressantsandalcohol

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orphenytoinoncognitiveandpsychomotorperformanceinhealthysubjects;however,theconcomitantuseofsertraline

andalcoholisnotrecommended.

Otherserotonergicdrugs

Seesection4.4

SpecialPrecautions

Lithium

Inaplacebo-controlledtrialinnormalvolunteers,theco-administrationofsertralinewithlithiumdidnotsignificantly

alterlithiumpharmacokinetics,butdidresultinanincreaseintremorrelativetoplacebo,indicatingapossible

pharmacodynamicinteraction.Whenco-administeringsertralinewithlithium,patientsshouldbeappropriately

monitored.

Phenytoin

Aplacebo-controlledtrialinnormalvolunteerssuggeststhatchronicadministrationofsertraline200mg/daydoesnot

produceclinicallyimportantinhibitionofphenytoinmetabolism.Nonetheless,assomecasereportshaveemergedof

highphenytoinexposureinpatientsusingsertraline,itisrecommendedthatplasmaphenytoinconcentrationsbe

monitoredfollowinginitiationofsertralinetherapy,withappropriateadjustmentstothephenytoindose.Inaddition,co-

administrationofphenytoinmaycauseareductionofsertralineplasmalevels.

Triptans

Therehavebeenrarepost-marketingreportsdescribingpatientswithweakness,hyperreflexia,incoordination,

confusion,anxietyandagitationfollowingtheuseofSertralineandsumatriptan.Symptomsofserotonergicsyndrome

mayalsooccurwithotherproductsofthesameclass(triptans).Ifconcomitanttreatmentwithsertralineandtriptansis

clinicallywarranted,appropriateobservationofthepatientisadvised(seesection4.4).

Warfarin

Co-administrationofSertraline200mgdailywithwarfarinresultedinasmallbutstatisticallysignificantincreasein

prothrombintime;whichmayinsomerarecasesunbalancetheINRvalue.Accordingly,prothrombintimeshouldbe

carefullymonitoredwhensertralinetherapyisinitiatedorstopped.

Otherdruginteractions,digoxin,atenolol,cimetidine

Co-administrationwithcimetidinecausedasubstantialdecreaseinsertralineclearance.Theclinicalsignificanceof

thesechangesisunknown.Sertralinehadnoeffectonthebeta-adrenergicblockingabilityofatenolol.Nointeractionof

sertraline200mgdailywasobservedwithdigoxin.

Drugsaffectingplateletfunction

Theriskofbleedingmaybeincreasedwhenmedicinesactingonplateletfunction(e.g.NSAIDs,acetylsalicylicacid

andticlopidine)orothermedicinesthatmightincreasebleedingriskareconcomitantlyadministeredwithSSRIs,

includingsertraline(seesection4.4).

DrugsmetabolizedbyCytochromeP450

Sertralinemayactasamild-moderateinhibitorofCYP2D6.ChronicdosingwithSertraline50mgdailyshowed

moderateelevation(mean23%-37%)ofsteadystatedesipramineplasmalevels(amarkerofCYP2D6isozyme

activity).ClinicalrelevantinteractionsmayoccurwithotherCYP2D6substrateswithanarrowtherapeuticindexlike

class1Cantiarrhythmicssuchaspropafenoneandflecainide,TCAsandtypicalantipsychotics,especiallyathigher

sertralinedoselevels.

SertralinedoesnotactasaninhibitorofCYP3A4,CYP2C9,CYP2C19,andCYP1A2toaclinicallysignificant

degree.Thishasbeenconfirmedbyin-vivointeractionstudieswithCYP3A4substrates(endogenouscortisol,

carbamazepine,terfenadine,alprazolam),CYP2C19substratediazepam,andCYP2C9substratestolbutamide,

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4.6Fertility,pregnancyandlactation

Pregnancy

Therearenowellcontrolledstudiesinpregnantwomen.However,asubstantialamountofdatadidnotrevealevidence

ofinductionofcongenitalmalformationsbysertraline.Animalstudiesshowedevidenceforeffectsonreproduction

probablyduetomaternaltoxicitycausedbythepharmacodynamicactionofthecompoundand/ordirect

pharmacodynamicactionofthecompoundonthefoetus(seesection5.3).

Useofsertralineduringpregnancyhasbeenreportedtocausesymptoms,compatiblewithwithdrawalreactions,in

someneonates,whosemothershadbeenonsertraline.ThisphenomenonhasalsobeenobservedwithotherSSRI

antidepressants.Sertralineisnotrecommendedinpregnancy,unlesstheclinicalconditionofthewomanissuchthatthe

benefitofthetreatmentisexpectedtooutweighthepotentialrisk.

Neonatesshouldbeobservedifmaternaluseofsertralinecontinuesintothelaterstagesofpregnancy,particularlythe

thirdtrimester.Thefollowingsymptomsmayoccurintheneonateaftermaternalsertralineuseinlaterstagesof

pregnancy:respiratorydistress,cyanosis,apnoea,seizures,temperatureinstability,feedingdifficulty,vomiting,

hypoglycaemia,hypertonia,hypotonia,hyperreflexia,tremor,jitteriness,irritability,lethargy,constantcrying,

somnolenceanddifficultyinsleeping.Thesesymptomscouldbeduetoeitherserotonergiceffectsorwithdrawal

symptoms.Inamajorityofinstancesthecomplicationsbeginimmediatelyorsoon(<24hours)afterdelivery.

EpidemiologicaldatahavesuggestedthattheuseofSSRIsinpregnancy,particularinlatepregnancy,mayincreasethe

riskofpersistentpulmonaryhypertensioninthenewborn(PPHN).Theobservedriskwasapproximately5casesper

1000pregnancies.Inthegeneralpopulation1to2casesofPPHNper1000pregnanciesoccur.

Lactation

PublisheddataconcerningsertralinelevelsinbreastmilkshowthatsmallquantitiesofsertralineanditsmetaboliteN-

desmethylsertralineareexcretedinmilk.Generallynegligibletoundetectablelevelswerefoundininfantserum,with

oneexceptionofaninfantwithserumlevelsabout50%ofthematernallevel(butwithoutanoticeablehealtheffectin

thisinfant).Todate,noadverseeffectsonthehealthofinfantsnursedbymothersusingsertralinehavebeenreported,

butariskcannotbeexcluded.Useinnursingmothersisnotrecommendedunless,inthejudgmentofthephysician,the

benefitoutweighstherisk.

4.7Effectsonabilitytodriveandusemachines

ClinicalpharmacologystudieshaveshownthatSertralinehasnoeffectonpsychomotorperformance.However,as

psychotropicdrugsmayimpairthementalorphysicalabilitiesrequiredfortheperformanceofpotentiallyhazardous

taskssuchasdrivingacaroroperatingmachinery,thepatientshouldbecautionedaccordingly.

4.8Undesirableeffects

Nauseaisthemostcommonundesirableeffect.Inthetreatmentofsocialanxietydisorder,sexualdysfunction

(ejaculationfailure)inmenoccurredin14%forsertralinevs0%inplacebo.Theseundesirableeffectsaredose

dependentandareoftentransientinnaturewithcontinuedtreatment.

Theundesirableeffectsprofilecommonlyobservedindouble-blind,placebo-controlledstudiesinpatientswithOCD,

panicdisorder,PTSDandsocialanxietydisorderwassimilartothatobservedinclinicaltrialsinpatientswith

depression.

Table1displaysadversereactionsobservedfrompost-marketingexperience(frequencynotknown)andplacebo-

controlledclinicaltrials(comprisingatotalof2542patientsonsertralineand2145onplacebo)indepression,OCD,

panicdisorder,PTSDandsocialanxietydisorder.

SomeadversedrugreactionslistedinTable1maydecreaseinintensityandfrequencywithcontinuedtreatmentanddo

notgenerallyleadtocessationoftherapy.

Table1:AdverseReactions

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PTSDandsocialanxietydisorder.Pooledanalysisandpost-marketingexperience(frequencynotknown).

Very

Common

(1/10) Common(1/100to

<1/10) Uncommon(1/1000

to<1/100) Rare

(1/10000to<1/1000) Very.rare

(<1/10000) FrequencynotKnown

InfectionsandInfestations

Pharyngitis UpperRespiratory

TractInfection,

Rhinitis Diverticulitis,Gastroenteritis,

OtitisMedia

Neoplasmsbenign,malignant(includingcystsandpolyps)

Neoplasm†

Bloodandlymphaticsystemdisorders

Lymphadenopathy Leucopenia,Thrombocytopenia

Immunesystemdisorders

AnaphylactoidReaction,

AllergicReaction,Allergy

Endocrinedisorders

Hyperprolactinaemia

Hypothyroidismandsyndrome

ofinappropriateADHsecretion

MetabolismandNutritionDisorders

Anorexia,Increased

Appetite* Hypercholesterolaemia,

Hypoglycaemia Hyponatraemia

PsychiatricDisorders

Insomnia

(19%) Depression*,

Depersonalisation,

Nightmare,Anxiety*,

Agitation*,Nervousness,

LibidoDecreased*,

Bruxism Hallucination*,

EuphoricMood*,

Apathy,Thinking

Abnormal ConversionDisorder,Drug

Dependence,Psychotic

disorder*,Aggression*,

Paranoia,SuicidalIdeation,

SleepWalking,Premature

Ejaculation Paroniria,Suicidal

ideation/behaviour***

NervousSystemDisorders

Dizziness

(11%),

Somnolence

(13%),

Headache

(21%)* Paraesthesia*,Tremor,

Hypertonia,

Dysgeusia,Disturbancein

Attention, Convulsion*,Muscle

Contractions

Involuntary*,

Coordination

Abnormal,

Hyperkinesia,

Amnesia,

Hypoaesthesia*,

SpeechDisorder,

DizzinessPostural,

Migraine* Coma*,Choreoathetosis,

Dyskinesia,Hyperaesthesia,

Sensory

Disturbance MovementDisorders(including

extrapyramidalsymptomssuch

ashyperkinesia,hypertonia,

teethgrindingorgait

abnormalities),Syncope.

Alsoreportedweresignsand

symptomsassociatedwith

SerotoninSyndromeor

NeurolepticMalignant

Syndrome:Insomecases

associatedwithconcomitant

useofserotonergicdrugsthat

includedagitation,confusion,

diaphoresis,diarrhoea,fever,

hypertension,rigidityand

tachycardia.

Akathesiaandpyschomotor

restlessness(seesection4.4).

EyeDisorders

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Scotoma,Diplopia,

Photophobia,Hyphaema,

Mydriasis*

EarandLabyrinthDisorders

Tinnitus* EarPain

CardiacDisorders

Palpitations* Tachycardia MyocardialInfarction,

Bradycardia,CardiacDisorder

VascularDisorders

Hotflush* Hypertension*,

Flushing PeripheralIschaemia AbnormalBleeding(suchas

epistaxis,gastrointestinal

bleedingorhaematuria)

Respiratory,Thoracic,andMediastinalDisorders

Yawning* Bronchospasm*,

Dyspnoea,Epistaxis Laryngospasm,

Hyperventilation,

Hypoventilation,Stridor,

Dysphonia,Hiccups

GastrointestinalDisorders

Diarrhoea

(18%),

Nausea

(24%),Dry

Mouth

(14%) AbdominalPain*

Vomiting*,Constipation*

Dyspepsia,Flatulence Oesophagitis,

Dysphagia,

Haemorrhoids,

Salivary

Hypersecretion,

TongueDisorder,

Eructation Melaena,Haematochezia,

Stomatitis,Tongueulceration,

ToothDisorder,Glossitis,

MouthUlceration Pancreatitis

HepatobiliaryDisorders

HepaticFunctionAbnormal Seriousliverevents(including

hepatitis,jaundiceandliver

failure)

SkinandSubcutaneousTissueDisorders

Rash*,Hyperhidrosis PeriorbitalOedema*,

Purpura*,Alopecia*,

ColdSweat,Dryskin,

Urticaria* Dermatitis,DermatitisBullous,

RashFollicular,HairTexture

Abnormal,SkinOdour

Abnormal Rarereportsofsevere

cutaneousadversereactions

(SCAR):e.g.Stevens-Johnson

syndromeandepidermal

necrolysis,Angioedema,Face

Oedema,Photosensitivity,Skin

Reaction,Pruritus

MusculoskeletalandConnectiveTissueDisorders

Myalgia Osteoarthritis,

MuscularWeakness,

BackPain,Muscle

Twitching BoneDisorder Arthralgia,MuscleCramps,

Bonefractures

****

RenalandUrinaryDisorders

Nocturia,Urinary

Retention*,Polyuria,

Pollakiura,

Micturitiondisorder Oliguria,Urinary

Incontinence*,Urinary

Hesitation

ReproductiveSystemandBreastDisorders**

Ejaculation

Failure

(14%) SexualDysfunction,

ErectileDysfunction VaginalHaemorrhage,

FemaleSexual

Dysfunction Menorrhagia,Atrophic

Vulvuvaginitis,

Balanoposthitis,Genital

Discharge,Priapism*,

Galactorrhoea* Gynaecomastia,Menstrual

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Withdrawalsymptomsseenondiscontinuationofsertralinetreatment

Discontinuationofsertraline(particularlywhenabrupt)commonlyleadstowithdrawalsymptoms.Dizziness,sensory

disturbances(includingparaesthesia),sleepdisturbances(includinginsomniaandintensedreams),agitationoranxiety,

nauseaand/orvomiting,tremor,headachearethemostcommonlyreported.Generallytheseeventsaremildto

moderateandareself-limiting;however,insomepatientstheymaybesevereand/orprolonged.Itisthereforeadvised

thatwhenSertralinetreatmentisnolongerrequired,gradualdiscontinuationbydosetaperingshouldbecarriedout(see

sections4.2and4.4).

Elderlypopulation

SSRIsorSNRIsincludingsertralinehavebeenassociatedwithcasesofclinicallysignificanthyponatraemiainelderly

patients,whomaybeatgreaterriskforthisadverseevent(seesection4.4).

Paediatricpopulation

Inover600paediatricpatientstreatedwithsertraline,theoverallprofileofadversereactionswasgenerallysimilarto

thatseeninadultstudies.Thefollowingadversereactionswerereportedfromcontrolledtrials(n=281patientstreated

withsertraline):

Verycommon(1/10):Headache(22%),insomnia(21%),diarrhoea(11%)andnausea(15%).Common(1/100to

<1/10):Chestpain,mania,pyrexia,vomiting,anorexia,affectlability,aggression,agitation,nervousness,disturbance

inattention,dizziness,hyperkinesia,migraine,somnolence,tremor,visualdisturbance,drymouth,dyspepsia,

nightmare,fatigue,urinaryincontinence,rash,acne,epistaxis,flatulence.

GeneralDisordersandAdministrationSiteConditions

Fatigue

(10%)* ChestPain* Malaise*,Chills,

Pyrexia*,

Asthenia*,Thirst Hernia,InjectionSiteFibrosis,

DrugToleranceDecreased,

GaitDisturbance,Unevaluable

Event OedemaPeripheral

Investigations

WeightDecreased*,

WeightIncreased* AlanineAminotransferase

Increased*,Aspartate

AminotransferaseIncreased*,

SemenAbnormal AbnormalClinicalLaboratory

Results,AlteredPlatelet

Function,IncreasedSerum

Cholesterol

Injuryandpoisoning

Injury

Surgicalandmedicalprocedures

VasodilationProcedure

Ifadverseexperienceoccurredindepression , OCD,panicdisorder,PTSDandsocialanxietydisorder,bodytermreclassifiedby

depressionstudiesbodyterm.

Onecaseofneoplasmwasreportedinonepatientreceivingsertralinecomparedwithnocasesin

theplaceboarm.

*theseadversereactionsalsooccurredinpost-marketingexperience

**thedenominatorusesthenumberofpatientsinthatsexgroup-combined:sertraline(1118males,1424females)placebo(926males,

1219females)

ForOCD,shortterm,1-12weeksstudiesonly

***Casesofsuicidalideationandsuicidalbehaviourshavebeenreportedduringsertralinetherapyorearlyaftertreatment

discontinuation(seesection4.4).

****Classeffects:Epidemiologicalstudiesmainlyconductedinpatients50yearsofageandoldershowanincreasedriskofbone

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paraesthesia,depression,hallucination,purpura,hyperventilation,anaemia,hepaticfunctionabnormal,alanine

aminotransferaseincreased,cystitis,herpessimplex,otitisexterna,earpain,eyepain,mydriasis,malaise,haematuria,

rashpustular,rhinitis,injury,weightdecreased,muscletwitching,abnormaldreams,apathy,albuminuria,pollakiuria,

polyuria,breastpain,menstrualdisorder,alopecia,dermatitis,skindisorder,skinodourabnormal,urticaria,bruxism,

flushing.

Frequencynotknown:enuresis

4.9Overdose

Toxicity

Ontheevidenceavailable,Sertralinehasawidemarginofsafetyinoverdose.Overdosesofsertralinealoneofupto

13.5ghavebeenreported.Deathshavebeenreportedinvolvingoverdosesofsertraline,primarilyincombinationwith

othermedicationsand/oralcohol.Therefore,anyoverdosageshouldbemedicallytreatedaggressively.

Symptoms

Symptomsofoverdoseincludeserotonin-mediatedsideeffectssuchassomnolence,gastrointestinaldisturbances(such

asnauseaandvomiting),tachycardia,tremor,agitationanddizziness.Lessfrequentlyreportedwascoma.

Treatment

TherearenospecificantidotestoSertraline.Establishandmaintainanairwayandensureadequateoxygenationand

ventilation,ifnecessary.Activatedcharcoal,whichmaybeusedwithacathartic,maybeasormoreeffectivethan

lavage,andshouldbeconsideredintreatingoverdose.Inductionofemesisisnotrecommended.Cardiacandothervital

signmonitoringisrecommended,alongwithgeneralsymptomaticandsupportivemeasures.Duetothelargevolumeof

distributionofsertraline,forceddiuresis,dialysis,haemoperfusionandexchangetransfusionareunlikelytobeof

benefit.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Selectiveserotoninreuptakeinhibitors(SSRI),ATCcode:N06AB06

Sertralineisapotentandspecificinhibitorofneuronalserotonin(5HT)uptakeinvitro,whichresultsinthe

potentiationoftheeffectsof5-HTinanimals.Ithasonlyveryweakeffectsonnorepinephrineanddopamineneuronal

reuptake.Atclinicaldoses,sertralineblockstheuptakeofserotoninintohumanplatelets.Itisdevoidofstimulant,

sedativeoranticholinergicactivityorcardiotoxicityinanimals.Incontrolledstudiesinnormalvolunteers,sertraline

didnotcausesedationanddidnotinterferewithpsychomotorperformance.Inaccordwithitsselectiveinhibitionof5-

HTuptake,sertralinedoesnotenhancecatecholaminergicactivity.Sertralinehasnoaffinityformuscarinic

(cholinergic),serotonergic,dopaminergic,adrenergic,histaminergic,GABAorbenzodiazepinereceptors.Thechronic

administrationofsertralineinanimalswasassociatedwithdown-regulationofbrainnorepinephrinereceptorsas

observedwithotherclinicallyeffectiveantidepressantsandantiobsessionaldrugs.

Sertralinehasnotdemonstratedpotentialforabuse.Inaplacebo-controlled,double-blindrandomizedstudyofthe

comparativeabuseliabilityofsertraline,alprazolamandd-amphetamineinhumans,sertralinedidnotproducepositive

subjectiveeffectsindicativeofabusepotential.Incontrast,subjectsratedbothalprazolamandd-amphetamine

significantlygreaterthanplaceboonmeasuresofdrugliking,euphoriaandabusepotential.Sertralinedidnotproduce

eitherthestimulationandanxietyassociatedwithd-amphetamineorthesedationandpsychomotorimpairment

associatedwithalprazolam.Sertralinedoesnotfunctionasapositivereinforcerinrhesusmonkeystrainedtoself

administercocaine,nordoesitsubstituteasadiscriminativestimulusforeitherd-amphetamineorpentobarbitalin

rhesusmonkeys.

ClinicalTrials

MajorDepressiveDisorder

Astudywasconductedwhichinvolveddepressedoutpatientswhohadrespondedbytheendofaninitial8-weekopen

treatmentphaseonsertraline50-200mg/day.Thesepatients(n=295)wererandomizedtocontinuationfor44weekson

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patientstakingsertralinecomparedtothoseonplacebo.Themeandoseforcompleterswas70mg/day.The%of

responders(definedasthosepatientsthatdidnotrelapse)forsertralineandplaceboarmswere83.4%and60.8%,

respectively.

Posttraumaticstressdisorder(PTSD)

Combineddatafromthe3studiesofPTSDinthegeneralpopulationfoundalowerresponserateinmalescomparedto

females.Inthetwopositivegeneralpopulationtrials,themaleandfemalesertralinevs.placeboresponderrateswere

similar(females:57.2%vs34.5%;males:53.9%vs38.2%).Thenumberofmaleandfemalepatientsinthepooled

generalpopulationtrialswas184and430,respectivelyandhencetheresultsinfemalesaremorerobustandmales

wereassociatedwithotherbaselinevariables(moresubstanceabuse,longerduration,sourceoftraumaetc)whichare

correlatedwithdecreasedeffect.

PaediatricOCD

Thesafetyandefficacyofsertraline(50-200mg/day)wasexaminedinthetreatmentofnon-depressedchildren(6-12

yearsold)andadolescent(13-17yearsold)outpatientswithobsessivecompulsivedisorder(OCD).Afteraoneweek

singleblindplacebolead-in,patientswererandomlyassignedtotwelveweeksofflexibledosetreatmentwitheither

sertralineorplacebo.Children(6-12yearsold)wereinitiallystartedona25mgdose.Patientsrandomizedtosertraline

showedsignificantlygreaterimprovementthanthoserandomisedtoplaceboontheChildren’sYale-BrownObsessive

CompulsiveScaleCY-BOCS(p=0.005)theNIMHGlobalObsessiveCompulsiveScale(p=0.019),andtheCGI

Improvement(p=0.002)scales.Inaddition,atrendtowardgreaterimprovementinthesertralinegroupthanthe

placebogroupwasalsoobservedontheCGISeverityscale(p=0.089).ForCY-BOCsthemeanbaselineandchange

frombaselinescoresfortheplacebogroupwas22.25±6.15and-3.4±0.82,respectively,whileforthesertraline

group,themeanbaselineandchangefrombaselinescoreswere23.36±4.56and-6.8±0.87,respectively.Inapost-

hocanalysis,responders,definedaspatientswitha25%orgreaterdecreaseintheCY-BOCs(theprimaryefficacy

measure)frombaselinetoendpoint,were53%ofsertraline-treatedpatientscomparedto37%ofplacebo-treated

patients

(p=0.03).

Longtermsafetyandefficacydataarelackingforthispaediatricpopulation.

Nodataisavailableforchildrenunder6yearsofage.

5.2Pharmacokineticproperties

Absorption:

Sertralineexhibitsdoseproportionalpharmacokineticsintherangeof50to200mg.Inman,followinganoralonce-

dailydosageof50to200mgfor14days,peakplasmaconcentrationsofsertralineoccurat4.5to8.4hoursafterthe

dailyadministrationofthedrug.Fooddoesnotsignificantlychangethebioavailabilityofsertralinetablets.

Distribution:

Approximately98%ofthecirculatingdrugisboundtoplasmaproteins.

Biotransformation:

Sertralineundergoesextensivefirst-passhepaticmetabolism.

Elimination:

Themeanhalf-lifeofsertralineisapproximately26hours(range22-36hours).Consistentwiththeterminalelimination

half-life,thereisanapproximatelytwo-foldaccumulationuptosteadystateconcentrations,whichareachievedafter

oneweekofonce-dailydosing.Thehalf-lifeofN-desmethylsertralineisintherangeof62to104hours.Sertralineand

N-desmethylsertralinearebothextensivelymetabolizedinmanandtheresultantmetabolitesexcretedinfaecesand

urineinequalamounts.Onlyasmallamount(<0.2%)ofunchangedsertralineisexcretedintheurine.

Pharmacokineticsinspecificpatientgroups

PaediatricpatientswithOCD

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aged13-17yearsold.Patientsweregradualuptitratedtoa200mgdailydosewithin32days,eitherwith25mgstarting

doseandincrementsteps,orwith50mgstartingdoseorincrements.The25mgregimenandthe50mgregimenwere

equallytolerated.Insteadystateforthe200mgdose,thesertralineplasmalevelsinthe6-12yearoldgroupwere

approximately35%highercomparedtothe13-17yearoldgroup,and21%highercomparedtoadultreferencegroup.

Therewerenosignificantdifferencesbetweenboysandgirlsregardingclearance.Alowstartingdoseandtitration

stepsof25mgarethereforerecommendedforchildren,especiallywithlowbodyweight.Adolescentscouldbedosed

likeadults.

Adolescentsandelderly

Thepharmacokineticprofileofsertralineinelderlypatientsisnotsignificantlydifferentfromthatinadultsbetween18

and65years.

Liverfunctionimpairment:

Inpatientswithliverdamage,thehalflifeofsertralineisprolongedandAUCisincreasedthreefold(seesections4.2

and4.4).

Renalimpairment:

Inpatientswithmoderate-severerenalimpairment,therewasnosignificantaccumulationofsertraline.

5.3Preclinicalsafetydata

Preclinicaldatadoesnotindicateanyspecialhazardforhumansbasedonconventionalstudiesofsafetypharmacology,

repeateddosetoxicity,genotoxicityandcarcinogenesis.Reproductiontoxicitystudiesinanimalsshowednoevidence

ofteratogenicityoradverseeffectsonmalefertility.Observedfoetotoxicitywasprobablyrelatedtomaternaltoxicity.

Postnatalpupsurvivalandbodyweightweredecreasedonlyduringthefirstdaysafterbirth.Evidencewasfoundthat

theearlypostnatalmortalitywasduetoin-uteroexposureafterday15ofpregnancy.Postnataldevelopmentaldelays

foundinpupsfromtreateddamswereprobablyduetoeffectsonthedamsandthereforenotrelevantforhumanrisk.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Microcrystallinecellulose

Calciumhydrogenphosphatedihydrate

Sodiumstarchglycolate(typeA)

Hydroxypropylcellulose

Magnesiumstearate

Tabletcoat:

Hypromellose

TitaniumDioxide(E171)

Macrogol

Talc

6.2Incompatibilities

Notapplicable.

6.3Shelflife

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6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

BlisterpackcomprisingofwhiteopaquePVC-filmcoatedwithPVdConinnersidewithabackingofaluminiumfoil

coatedwithheatseallacquer.

Packscontaining20,28,30,50,98or100film-coatedtablets.

Hospitalpack:10packscontaining30film-coatedtablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

RanbaxyIrelandLimited

SpaField

CorkRoad

Cashel

Co.Tipperary

8MARKETINGAUTHORISATIONNUMBER

PA0408/091/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:28January2005

Dateoflastrenewal:28January2008

10DATEOFREVISIONOFTHETEXT

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