ESCITALOPRAM

Main information

  • Trade name:
  • ESCITALOPRAM Film Coated Tablet 5 Milligram
  • Dosage:
  • 5 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ESCITALOPRAM Film Coated Tablet 5 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0585/037/001
  • Authorization date:
  • 28-05-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0585/037/001

CaseNo:2044816

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

PlivaPharmaLimited

VisionHouse,BedfordRoad,Petersfield,HampshireGU323QB,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Escitalopram5mgFilm-coatedTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom28/05/2009until27/05/2014.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Escitalopram5mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains5mgescitalopram(asoxalate)

Excipients:Eachfilm-coatedtabletcontains0.26mglactosemonohydrate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

White,round,biconvexfilm-coatedtablet.OnonesideaN53markisengraved.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofmajordepressiveepisodes.

Treatmentofpanicdisorderwithorwithoutagoraphobia.

Treatmentofsocialanxietydisorder(socialphobia).

Treatmentofgeneralisedanxietydisorder.

Treatmentofobsessive-compulsivedisorder

4.2Posologyandmethodofadministration

Safetyofdailydosesabove20mg/dayhasnotbeendemonstrated.

Escitalopramisadministeredasaoncedailydoseandmaybetakenwithorwithoutfood.

Majordepressiveepisodes

Usualdosageis10mgoncedaily.Dependingonindividualpatientresponse,thedosemaybeincreasedtoamaximum

of20mgdaily.

Usually2-4weeksarenecessarytoobtainantidepressantresponse.Afterthesymptomsresolve,treatmentforatleast6

monthsisrequiredforconsolidationoftheresponse.

Panicdisorderwithorwithoutagoraphobia

Aninitialdoseof5mgisrecommendedforthefirstweekbeforeincreasingthedoseto10mgdaily.Thedosemaybe

furtherincreased,uptoamaximumof20mgdaily,dependentonindividualpatientresponse.Maximumeffectiveness

isreachedafterabout3months.Thetreatmentlastsseveralmonths.

Socialanxietydisorder

Usualdosageis10mgoncedaily.Usually2-4weeksarenecessarytoobtainsymptomrelief.Thedosemay

subsequently,dependingonindividualpatientresponse,bedecreasedto5mgorincreasedtoamaximumof20mg

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Socialanxietydisorderisadiseasewithachroniccourse,andtreatmentfor12weeksisrecommendedtoconsolidate

response.Long-termtreatmentofrespondershasbeenstudiedfor6monthsandcanbeconsideredonanindividual

basistopreventrelapse;treatmentbenefitsshouldbere-evaluatedatregularintervals.

Socialanxietydisorderisawell-defineddiagnosticterminologyofaspecificdisorder,whichshouldnotbeconfounded

withexcessiveshyness.Pharmacotherapyisonlyindicatedifthedisorderinterferessignificantlywithprofessionaland

socialactivities.

Theplaceofthistreatmentcomparedtocognitivebehaviouraltherapyhasnotbeenassessed.Pharmacotherapyispart

ofanoveralltherapeuticstrategy.

Generalisedanxietydisorder

Initialdosageis10mgoncedaily.Dependingontheindividualpatientresponse,thedosemaybeincreasedtoa

maximumof20mgdaily.

Longtermtreatmentofrespondershasbeenstudiedforatleast6monthsinpatientsreceiving20mg/day.Treatment

benefitsanddoseshouldbere-evaluatedatregularintervals.(SeeSection5.1).

Obsessive-CompulsiveDisorder

Initialdosageis10mgoncedaily.Dependingontheindividualpatientresponse,thedosemaybeincreasedtoa

maximumof20mgdaily.

AsOCDisachronicdisease,patientsshouldbetreatedforasufficientperiodtoensurethattheyaresymptomfree.

Treatmentbenefitsanddoseshouldbere-evaluatedatregularintervals(seesection5.1)

Elderlypatients(>65yearsofage)

Initialtreatmentwithhalfoftheusuallyrecommendeddoseandalowermaximumdoseshouldbeconsidered(see

section5.2).

Theefficacyofescitalopraminsocialanxietydisorderhasnotbeenstudiedinelderlypatients.

Childrenandadolescents(<18years)

Escitalopramisnotrecommendedforuseinchildrenandadolescents(<18years)duetoinsufficientdataonsafetyand

efficacy(seesection4.4)

Reducedrenalfunction

Dosageadjustmentisnotnecessaryinpatientswithmildormoderaterenalimpairment.Cautionisadvisedinpatients

withseverelyreducedrenalfunction(CL

lessthan30ml/min.)(seesection5.2).

Reducedhepaticfunction

Aninitialdoseof5mgdailyforthefirsttwoweeksoftreatmentisrecommendedinpatientswithmildtomoderate

hepaticimpairment.Dependingonindividualpatientresponse,thedosemaybeincreasedto10mgdaily.Cautionand

extracarefuldosetitrationisadvisedinpatientswithseverelyreducedhepaticfunction(seesection5.2).

PoormetabolisersofCYP2C19

ForpatientswhoareknowntobepoormetaboliserswithrespecttoCYP2C19,aninitialdoseof5mgdailyduringthe

firsttwoweeksoftreatmentisrecommended.Dependingonindividualpatientresponse,thedosemaybeincreasedto

10mgdaily(seesection5.2).

Discontinuationsymptomsseenwhenstoppingtreatment

Abruptdiscontinuationshouldbeavoided.Whenstoppingtreatmentwithescitalopramthedoseshouldbegradually

reducedoveraperiodofoneortwoweeksinordertoavoidpossiblewithdrawalreactions(seesections4.4and4.8).If

intolerablesymptomsoccurfollowingadecreaseinthedoseorupondiscontinuationoftreatment,thenresumingthe

previouslyprescribeddosemaybeconsidered.Subsequently,thephysicianmaycontinuedecreasingthedose,butata

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4.3Contraindications

Hypersensitivitytoescitalopramortoanyoftheexcipients.

Concomitanttreatmentwithnon-selective,irreversiblemonoamineoxidaseinhibitors(MAO-inhibitors)is

contraindicatedduetotheriskofserotoninesyndromewithagitation,tremor,hyperthermiaetc.(seesection4.5).

ThecombinationofescitalopramwithreversibleMAO-Ainhibitors(e.g.moclobemide)orthereversiblenon-

selectiveMAO-inhibitorlinezolidiscontraindicatedduetotheriskofonsetofaserotoninsyndrome(seesection

4.5).

4.4Specialwarningsandprecautionsforuse

ThefollowingspecialwarningsandprecautionsapplytothetherapeuticclassofSSRIs(SelectiveSerotoninRe-uptake

Inhibitors).

Useinchildrenandadolescentsunder18yearsofage

Escitalopramisnotrecommendedforuseinchildrenandadolescents(<18years)duetoinsufficientdataonsafetyand

efficacy.Suicide-relatedbehaviours(suicideattemptandsuicidalthoughts)andhostility(predominantlyaggression,

oppositionalbehaviourandanger)weremorefrequentlyobservedinclinicaltrialsamongchildrenandadolescents

treatedwithantidepressantscomparedtothosetreatedwithplacebo.If,basedonclinicalneed,adecisiontotreatis

neverthelesstaken,thepatientshouldbecarefullymonitoredfortheappearanceofsuicidalsymptoms.Inaddition,

long-termsafetydatainchildrenandadolescentsconcerninggrowth,maturationandcognitiveandbehavioural

developmentarelacking.

Paradoxicalanxiety

Somepatientswithpanicdisordermayexperienceincreasedanxietysymptomsatthebeginningoftreatmentwith

antidepressants.Thisparadoxicalreactionusuallysubsideswithintwoweeksduringcontinuedtreatment.Alow

startingdoseisadvisedtoreducethelikelihoodofananxiogeniceffect(seesection4.2).

Seizures

Themedicinalproductshouldbediscontinuedinanypatientwhodevelopsseizures.SSRIsshouldbeavoidedin

patientswithunstableepilepsyandpatientswithcontrolledepilepsyshouldbecarefullymonitored.SSRIsshouldbe

discontinuedifthereisanincreaseinseizurefrequency.

Mania

SSRIsshouldbeusedwithcautioninpatientswithahistoryofmania/hypomania.SSRIsshouldbediscontinuedinany

patiententeringamanicphase.

Diabetes

Inpatientswithdiabetes,treatmentwithanSSRImayalterglycaemiccontrol(hypoglycaemiaorhyperglycaemia).

Insulinand/ororalhypoglycaemicdosagemayneedtobeadjusted.

Suicide/suicidalideation

Depressionisassociatedwithanincreasedriskofsuicidalthoughts,selfharmandsuicide.Thisriskpersistsuntil

significantremissionoccurs.Asimprovementmaynotoccurduringthefirstfewweeksormoreoftreatment,patients

shouldbecloselymonitoreduntilsuchimprovementoccurs.Itisgeneralclinicalexperiencewithallantidepressant

therapiesthattheriskofsuicidemayincreaseintheearlystagesofrecovery.

Otherpsychiatricconditionsforwhichescitalopramisprescribedcanalsobeassociatedwithanincreasedriskof

suicidalbehaviour.Inaddition,theseconditionsmaybeco-morbidwithmajordepressivedisorder.Thesame

precautionsobservedwhentreatingpatientswithmajordepressivedisordershouldthereforebeobservedwhentreating

patientswithotherpsychiatricdisorders.

Patientswithahistoryofsuiciderelatedevents,orthoseexhibitingasignificantdegreeofsuicidalideationpriorto

commencementoftreatmentareknowntobeatgreaterriskofsuicidalthoughtsorsuicideattempts,andshouldreceive

carefulmonitoringduringtreatment.Ametaanalysisofplacebocontrolledclinicaltrialsofantidepressantdrugsin

adultpatientswithpsychiatricdisordersshowedanincreasedriskofsuicidalbehaviourwithantidepressantscompared

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Closesupervisionofpatientsandinparticularthoseathighriskshouldaccompanydrugtherapyespeciallyinearly

treatmentandfollowingdosechanges.Patients(andcaregiversofpatients)shouldbealertedabouttheneedtomonitor

foranyclinicalworsening,suicidalbehaviourorthoughtsandunusualchangesinbehaviourandtoseekmedicaladvice

immediatelyifthesesymptomspresent.

Hyponatraemia

Hyponatraemia,probablyduetoinappropriateantidiuretichormonesecretion(SIADH),hasbeenreportedrarelywith

theuseofSSRIsandgenerallyresolvesondiscontinuationoftherapy.Cautionshouldbeexercisedinpatientsatrisk,

suchaselderly,cirrhoticpatientsorpatientsconcomitantlytreatedwithmedicationsknowntocausehyponatraemia.

Haemorrhage

Therehavebeenreportsofcutaneousbleedingabnormalities,suchasecchymosesandpurpura,withSSRIs.Cautionis

advisedinpatientstakingSSRIs,particularlyinconcomitantusewithoralanticoagulants,withmedicinalproducts

knowntoaffectplateletfunction(e.g.atypicalantipsychoticsandphenothiazines,mosttricyclicantidepressants,

acetylsalicylicacidandnon-steroidalanti-inflammatorymedicinalproducts(NSAIDs),ticlopidineanddipyridamole)

andinpatientswithknownbleedingtendencies.

ECT(electroconvulsivetherapy)

ThereislimitedclinicalexperienceofconcurrentadministrationofSSRIsandECT,thereforecautionisadvisable.

Akathisia/psychomotorrestlessness

TheuseofSSRIs/SNRIshasbeenassociatedwiththedevelopmentofakathisia,characterisedbyasubjectively

unpleasantordistressingrestlessnessandneedtomoveoftenaccompaniedbyaninabilitytositorstandstill.Thisis

mostlikelytooccurwithinthefirstfewweeksoftreatment.Inpatientswhodevelopthesesymptoms,increasingthe

dosemaybedetrimental.

Serotoninsyndrome

Cautionisadvisableifescitalopramisusedconcomitantlywithmedicinalproductswithserotonergiceffectssuchas

sumatriptanorothertriptans,tramadolandtryptophan.Inrarecases,serotoninsyndromehasbeenreportedinpatients

usingSSRIsconcomitantlywithserotonergicmedicinalproducts.Acombinationofsymptoms,suchasagitation,

tremor,myoclonusandhyperthermiamayindicatethedevelopmentofthiscondition.Ifthisoccurstreatmentwiththe

SSRIandtheserotonergicmedicinalproductshouldbediscontinuedimmediatelyandsymptomatictreatmentinitiated.

Discontinuationsymptomsseenwhenstoppingtreatment

Discontinuationsymptomswhenstoppingtreatmentarecommon,particularlyifdiscontinuationisabrupt(seesection

4.8).Inclinicaltrialsadverseeventsseenontreatmentdiscontinuationoccurredinapproximately25%ofpatients

treatedwithescitalopramand15%ofpatientstakingplacebo.

Theriskofdiscontinuationsymptomsmaybedependentonseveralfactorsincludingthedurationanddoseoftherapy

andtherateofdosereduction.Dizziness,sensorydisturbances(includingparaesthesiaandelectricshocksensations),

sleepdisturbances(includinginsomniaandintensedreams),agitationoranxiety,nauseaand/orvomiting,tremor,

confusion,sweating,headache,diarrhoea,palpitations,emotionalinstability,irritability,andvisualdisturbancesarethe

mostcommonlyreportedreactions.Generallythesesymptomsaremildtomoderate,however,insomepatientsthey

maybesevereinintensity.

Theyusuallyoccurwithinthefirstfewdaysofdiscontinuingtreatment,buttherehavebeenveryrarereportsofsuch

symptomsinpatientswhohaveinadvertentlymissedadose.

Generallythesesymptomsareself-limitingandusuallyresolvewithin2weeks,thoughinsomeindividualstheymay

beprolonged(2-3monthsormore).Itisthereforeadvisedthatescitalopramshouldbegraduallytaperedwhen

discontinuingtreatmentoveraperiodofseveralweeksormonths,accordingtothepatient’sneeds(see

“Discontinuationsymptomsseenwhenstoppingtreatment”,section4.2).

Coronaryheartdisease

Duetolimitedclinicalexperience,cautionisadvisedinpatientswithcoronaryheartdisease(seesection5.3).

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Pharmacodynamicinteractions

Contra-indicatedcombinations:

Irreversiblenon-selectiveMAOIs

CasesofseriousreactionshavebeenreportedinpatientsreceivinganSSRIincombinationwithanon-selective,

irreversiblemonoamineoxidaseinhibitor(MAOI),andinpatientswhohaverecentlydiscontinuedSSRItreatmentand

havebeenstartedonsuchMAOItreatment(seesection4.3).Insomecases,thepatientdevelopedserotoninsyndrome

(seesection4.8).

Escitalopramiscontra-indicatedincombinationwithnon-selective,irreversibleMAOIs.Escitaloprammaybe

started14daysafterdiscontinuingtreatmentwithanirreversibleMAOI.Atleast7daysshouldelapseafter

discontinuingescitalopramtreatment,beforestartinganon-selective,irreversibleMAOI.

Reversible,selectiveMAO-Ainhibitor(moclobemide)

Duetotheriskofserotoninsyndrome,thecombinationofescitalopramwithaMAOAinhibitorsuchasmoclobemide

iscontraindicated(seesection4.3).Ifthecombinationprovesnecessary,itshouldbestartedattheminimum

recommendeddosageandclinicalmonitoringshouldbereinforced.

Reversible,non-selectiveMAO-inhibitor(linezolid)

Theantibioticlinezolidisareversiblenon-selectiveMAO-inhibitorandshouldnotbegiventopatientstreatedwith

escitalopram.Ifthecombinationprovesnecessary,itshouldbegivenwithminimumdosagesandundercloseclinical

monitoring(seesection4.3).

Irreversible,selectiveMAO-Binhibitor(selegiline)

Incombinationwithselegiline(irreversibleMAO-Binhibitor),cautionisrequiredduetotheriskofdeveloping

serotoninsyndrome.Selegilinedosesupto10mg/dayhavebeensafelyco-administeredwithracemiccitalopram.

Combinationsrequiringprecautionsforuse:

Serotonergicmedicinalproducts

Co-administrationwithserotonergicmedicinalproducts(e.g.tramadol,sumatriptanandothertriptans)mayleadto

serotoninsyndrome.

Medicinalproductsloweringtheseizurethreshold

SSRIscanlowertheseizurethreshold.Cautionisadvisedwhenconcomitantlyusingothermedicinalproducts

capableofloweringtheseizurethreshold(e.gantidepressants(tricyclics,SSRIs),neuroleptics(phenothiazines,

thioxanthenesandbutyrophenones),mefloquin,bupropionandtramadol).

Lithium,tryptophan

TherehavebeenreportsofenhancedeffectswhenSSRIshavebeengiventogetherwithlithiumortryptophan,

thereforeconcomitantuseofSSRIswiththesemedicinalproductsshouldbeundertakenwithcaution.

St.John’sWort

ConcomitantuseofSSRIsandherbalremediescontainingSt.John´sWort(Hypericumperforatum)mayresultin

anincreasedincidenceofadversereactions(seesection4.4).

Haemorrhage

Alteredanti-coagulanteffectsmayoccurwhenescitalopramiscombinedwithoralanticoagulants.Patients

receivingoralanticoagulanttherapyshouldreceivecarefulcoagulationmonitoringwhenescitalopramisstartedor

stopped(seesection4.4).

Alcohol

Nopharmacodynamicorpharmacokineticinteractionsareexpectedbetweenescitalopramandalcohol.However,as

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Pharmacokineticinteractions

Influenceofothermedicinalproductsonthepharmacokineticsofescitalopram

ThemetabolismofescitalopramismainlymediatedbyCYP2C19,CYP3A4andCYP2D6mayalsocontributetothe

metabolismalthoughtoasmallerextent.ThemetabolismofthemajormetaboliteS-DCT(demethylatedescitalopram)

seemstobepartlycatalysedbyCYP2D6.

Co-administrationofescitalopramwithomeprazole30mgoncedaily(aCYP2C19inhibitor)resultedinmoderate

(approximately50%)increaseintheplasmaconcentrationsofescitalopram.

Co-administrationofescitalopramwithcimetidine400mgtwicedaily(moderatelypotentgeneralenzyme-inhibitor)

resultedinamoderate(approximately70%)increaseintheplasmaconcentrationsofescitalopram.

Thus,cautionshouldbeexercisedwhenusedconcomitantlywithCYP2C19inhibitors(e.g.omeprazole,esomeprazole,

fluvoxamine,lansoprazole,ticlopidine)orcimetidine.Areductioninthedoseofescitaloprammaybenecessarybased

onmonitoringofside-effectsduringconcomitanttreatment.

Effectofescitalopramonthepharmacokineticsofothermedicinalproducts

EscitalopramisaninhibitoroftheenzymeCYP2D6.Cautionisrecommendedwhenescitalopramisco-administered

withmedicinalproductsthataremainlymetabolisedbythisenzyme,andthathaveanarrowtherapeuticindex,e.g.

flecainide,propafenoneandmetoprolol(whenusedincardiacfailure),orsomeCNSactingmedicinalproductsthatare

mainlymetabolisedbyCYP2D6,e.g.antidepressantssuchasdesipramine,clomipramineandnortriptylineor

antipsychoticslikerisperidone,thioridazineandhaloperidol.Dosageadjustmentmaybewarranted.

Co-administrationwithdesipramineormetoprololresultedinbothcasesinatwofoldincreaseintheplasmalevelsof

thesetwoCYP2D6substrates.Invitrostudieshavedemonstratedthatescitaloprammayalsocauseweakinhibitionof

CYP2C19.CautionisrecommendedwithconcomitantuseofmedicinalproductsthataremetabolisedbyCYP2C19.

4.6Pregnancyandlactation

Pregnancy

Forescitalopramonlylimitedclinicaldataareavailableregardingexposedpregnancies.Inreproductivetoxicitystudies

performedinratswithescitalopram,embryo-fetotoxiceffects,butnoincreasedincidenceofmalformations,were

observed(seesection5.3).Escitalopramshouldnotbeusedduringpregnancyunlessclearlynecessaryandonlyafter

carefulconsiderationoftherisk/benefit.

Neonatesshouldbeobservedifmaternaluseofescitalopramcontinuesintothelaterstagesofpregnancy,particularly

inthethirdtrimester.Abruptdiscontinuationshouldbeavoidedduringpregnancy.

ThefollowingsymptomsmayoccurintheneonateaftermaternalSSRI/SNRIuseinlaterstagesofpregnancy

respiratorydistress,cyanosis,apnoea,seizures,temperatureinstability,feedingdifficulty,vomiting,hypoglycaemia,

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

difficultysleeping.Thesesymptomscouldbeduetoeitherserotonergiceffectsordiscontinuationsymptoms.Ina

majorityofinstancesthecomplicationsbeginimmediatelyorsoon(<24hours)afterdelivery.

Lactation

Itisexpectedthatescitalopramwillbeexcretedintohumanmilk.Consequently,breast-feedingisnotrecommended

duringtreatment.

4.7Effectsonabilitytodriveandusemachines

Althoughescitalopramhasbeenshownnottoaffectintellectualfunctionorpsychomotorperformance,any

psychoactivemedicinalproductmayimpairjudgementorskills.Patientsshouldbecautionedaboutthepotentialriskof

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4.8Undesirableeffects

Adversereactionsaremostfrequentduringthefirstorsecondweekoftreatmentandusuallydecreaseinintensityand

frequencywithcontinuedtreatment.

AdversedrugreactionsknownforSSRIsandalsoreportedforescitalopramineitherplacebo-controlledclinicalstudies

orasspontaneouspost-marketingeventsarelistedbelowbysystemorganclassandfrequency.

Frequenciesaretakenfromclinicalstudies;theyarenotplacebo-corrected.Frequenciesaredefinedas:verycommon

(1/10),common(1/100to<1/10),uncommon(1/1000to<1/100),rare(1/10000to<1/1000),veryrare

(<1/10000),ornotknown(cannotbeestimatedfromtheavailabledata).

Verycommon Common Uncommon Rare Notknown

Investigations Weight

increased Weight

decreased Liverfunctiontest

abnormal

Cardiacdisorders Tachycardia Bradycardia

Bloodand

lymphatic

disorders Thrombocytopenia

Nervoussystem

disorders Insomnia,

somnolence,

dizziness,

paraesthesia,

tremor Taste

disturbance,

sleepdisorder,

syncope Serotonin

syndrome Dyskinesia,

movement

disorder,

convulsion

Eyedisorders Mydriasis,

visual

disturbance

Earandlabyrinth

disorders Tinnitus

Respiratory,

thoracicand

mediastinal

disorders Sinusitis,

yawning Epistaxis

Gastroinstestinal

disorders Nausea Diarrhoea,

constipation,

vomiting,dry

mouth Gastrointestinal

haemorrhages

(includingrectal

haemorrhage)

Renalandurinary

disorders Urinaryretention

Skinand

subcutaneous

tissuedisorders Sweating

increased Urticaria,

alopecia,rash,

pruritus Ecchymosis,

angioedemas

Musculoskeletal,

connectivetissue

andbone

disorders Arthralgia,

myalgia

Endocrine

disorders Inappropriate

ADHsecretion

Metabolismand

nutrition

disorders Decreased

appetite,

increased

appetite Hyponatraemia

Vascular

disorders Orthostatic

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Casesofsuicidalideationandsuicidalbehaviourshavebeenreportedduringescitalopramtherapyorearlyafter

treatmentdiscontinuation(seesection4.4).

ThefollowingadversedrugreactionshavebeenreportedforthetherapeuticclassofSSRIs:psychomotor

restlessness/akathisia(seesection4.4)andanorexia.

CasesofQT-prolongationhavebeenreportedduringthepost-marketingperiod,predominantlyinpatientswithpre-

existingcardiacdisease.Nocausalrelationshiphasbeenestablished.

Discontinuationsymptomsseenwhenstoppingtreatment

DiscontinuationofSSRIs/SNRIs(particularlywhenabrupt)commonlyleadstodiscontinuationsymptoms.Dizziness,

sensorydisturbances(includingparaesthesiaandelectricshocksensations),sleepdisturbances(includinginsomniaand

intensedreams),agitationoranxiety,nauseaand/orvomiting,tremor,confusion,sweating,headache,diarrhoea,

palpitations,emotionalinstability,irritability,andvisualdisturbancesarethemostcommonlyreportedreactions.

Generallytheseeventsaremildtomoderateandareself-limiting,however,insomepatientstheymaybesevereand/or

prolonged.Itisthereforeadvisedthatwhenescitalopramtreatmentisnolongerrequired,gradualdiscontinuationby

dosetaperingshouldbecarriedout(seesections4.2and4.4).

Casesofsuicidalideationandsuicidalbehaviourshavebeenreportedduringescitalopramtherapyorearlyafter

treatmentdiscontinuation(seesection4.4)

4.9Overdose

Toxicity

Clinicaldataonescitalopramoverdosearelimitedandmanycasesinvolveconcomitantoverdosesofotherdrugs.Inthe

majorityofcasesmildornosymptomshavebeenreported.Fatalcasesofescitalopramoverdosehaverarelybeen

reportedwithescitalopramalone;themajorityofcaseshaveinvolvedoverdosewithconcomitantmedications.Doses

Generaldisorders

administration

siteconditions Fatigue,pyrexia Oedema

Immunesystem

disorders Anaphylactic

reaction

Hepatobiliary

disorders Hepatitis

Reproductive

systemandbreast

disorders Male:

ejaculation

disorder,

impotence Female:

metrorrhagia,

menorrhagia Galactorrhoea

Male:priapism,

Psychiatric

disorders Anxiety,

restlessness,

abnormal

dreams

Femaleand

male:libido

decreased

Female:

Bruxism,

agitation,

nervousness,

panicattack,

confusionalstate Aggression,

depersonalisation,

hallucination Mania,suicidal

ideation,suicidal

behaviour1

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Symptoms

Symptomsseeninreportedoverdoseofescitalopramincludesymptomsmainlyrelatedtothecentralnervoussystem

(rangingfromdizziness,tremor,andagitationtorarecasesofserotoninsyndrome,convulsion,andcoma),the

gastrointestinalsystem(nausea/vomiting),andthecardiovascularsystem(hypotension,tachycardia,QTprolongation,

andarrhythmia)andelectrolyte/fluidbalanceconditions(hypokalaemia,hyponatraemia).

Treatment

Thereisnospecificantidote.Establishandmaintainanairway,ensureadequateoxygenationandrespiratoryfunction.

Gastriclavageshouldbecarriedoutassoonaspossibleafteroralingestion.Theuseofactivatedcharcoalshouldbe

considered.Cardiacandvitalsignsmonitoringarerecommendedalongwithgeneralsymptomaticsupportivemeasures.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:antidepressants,selectiveserotoninreuptakeinhibitors

ATC-code:N06AB10

Mechanismofaction

Escitalopramisaselectiveinhibitorofserotonin(5-HT)re-uptake.Theinhibitionof5-HTre-uptakeistheonlylikely

mechanismofactionexplainingthepharmacologicalandclinicaleffectsofescitalopram.

Escitalopramhasnoorlowaffinityforanumberofreceptorsincluding5-HT

,5-HT

,DAD

andD

receptors,

-,-adrenoceptors,histamineH

,muscarinecholinergic,benzodiazepine,andopioidreceptors.

Clinicalefficacy

MajorDepressiveEpisodes

Escitalopramhasbeenfoundtobeeffectiveintheacutetreatmentofmajordepressiveepisodesinthreeoutoffour

double-blind,placebocontrolledshort-term(8-weeks)studies.Inalong-termrelapsepreventionstudy,274patients

whohadrespondedduringaninitial8-weekopenlabeltreatmentphasewithescitalopram10or20mg/day,were

randomisedtocontinuationwithescitalopramatthesamedose,ortoplacebo,forupto36weeks.Inthisstudy,patients

receivingcontinuedescitalopramexperiencedasignificantlylongertimetorelapseoverthesubsequent36weeks

comparedtothosereceivingplacebo.

SocialAnxietyDisorder

Escitalopramwaseffectiveinboththreeshort-term(12-week)studiesandinrespondersina6monthsrelapse

preventionstudyinsocialanxietydisorder.Ina24-weekdose-findingstudy,efficacyof5,10and20mgescitalopram

hasbeendemonstrated.

Generalisedanxietydisorder

Escitalopramindosesof10and20mg/daywaseffectiveinfouroutoffourplacebo-controlledstudies.

Inpooleddatafromthreestudieswithsimilardesigncomprising421escitalopram-treatedpatientsand419placebo-

treatedpatientstherewere47.5%and28.9%respondersrespectivelyand37.1%and20.8%remitters.Sustainedeffect

wasseenfromweek1.

Maintenanceofefficacyofescitalopram20mg/daywasdemonstratedina24-to76-week,randomised,maintenance

ofefficacystudyin373patientswhohadrespondedduringtheinitial12-weekopen-labeltreatment.

Obsessive-compulsivedisorder

Inarandomized,double-blind,clinicalstudy,20mg/dayescitalopramseparatedfromplaceboontheY-BOCStotal

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Preventionofrelapsewasdemonstratedfor10and20mg/dayescitalopraminpatientswhorespondedtoescitalopram

ina16-weekopen-labelperiodandwhoentereda24week,randomized,doubleblind,placebocontrolledperiod.

5.2Pharmacokineticproperties

Absorption

Tablets:Absorptionisalmostcompleteandindependentoffoodintake.(Meantimetomaximumconcentration(mean

)is4hoursaftermultipledosing).Aswithracemiccitalopram,theabsolutebio-availabilityofescitalopramis

expectedtobeabout80%.

Distribution

Theapparentvolumeofdistribution(V

/F)afteroraladministrationisabout12to26L/kg.Theplasmaprotein

bindingisbelow80%forescitalopramanditsmainmetabolites.

Biotransformation

Escitalopramismetabolisedinthelivertothedemethylatedanddidemethylatedmetabolites.Bothoftheseare

pharmacologicallyactive.Alternatively,thenitrogenmaybeoxidisedtoformtheN-oxidemetabolite.Bothparentand

metabolitesarepartlyexcretedasglucuronides.Aftermultipledosingthemeanconcentrationsofthedemethyland

didemethylmetabolitesareusually28-31%and<5%,respectively,oftheescitalopramconcentration.

BiotransformationofescitalopramtothedemethylatedmetaboliteismediatedprimarilybyCYP2C19.Some

contributionbytheenzymesCYP3A4andCYP2D6ispossible.

Elimination

Theeliminationhalf-life(t

)aftermultipledosingisabout30hoursandtheoralplasmaclearance(Cl

oral )isabout0.6

L/min.Themajormetaboliteshaveasignificantlylongerhalf-life.

Escitalopramandmajormetabolitesareassumedtobeeliminatedbyboththehepatic(metabolic)andtherenalroutes,

withthemajorpartofthedoseexcretedasmetabolitesintheurine.

Thereislinearpharmacokinetics.Steady-stateplasmalevelsareachievedinabout1week.Averagesteady-state

concentrationsof50nmol/L(range20to125nmol/L)areachievedatadailydoseof10mg.

Elderlypatients(>65years)

Escitalopramappearstobeeliminatedmoreslowlyinelderlypatientscomparedtoyoungerpatients.Systemic

exposure(AUC)isabout50%higherinelderlycomparedtoyounghealthyvolunteers(seesection4.2).

Reducedhepaticfunction

Inpatientswithmildormoderatehepaticimpairment(Child-PughCriteriaAandB),thehalf-lifeofescitalopramwas

abouttwiceaslongandtheexposurewasabout60%higherthaninsubjectswithnormalliverfunction(seesection

4.2).

Reducedrenalfunction

Withracemiccitalopram,alongerhalf-lifeandaminorincreaseinexposurehavebeenobservedinpatientswith

reducedkidneyfunction(CL

10-53ml/min).Plasmaconcentrationsofthemetaboliteshavenotbeenstudied,butthey

maybeelevated(seesection4.2).

Polymorphism

IthasbeenobservedthatpoormetaboliserswithrespecttoCYP2C19havetwiceashighaplasmaconcentrationof

escitalopramasextensivemetabolisers.Nosignificantchangeinexposurewasobservedinpoormetaboliserswith

respecttoCYP2D6(seesection4.2).

5.3Preclinicalsafetydata

Nocompleteconventionalbatteryofpreclinicalstudieswasperformedwithescitalopramsincethebridging

toxicokineticandtoxicologicalstudiesconductedinratswithescitalopramandcitalopramshowedasimilarprofile.

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Incomparativetoxicologicalstudiesinrats,escitalopramandcitalopramcausedcardiactoxicity,includingcongestive

heartfailure,aftertreatmentforsomeweeks,whenusingdosagesthatcausedgeneraltoxicity.Thecardiotoxicity

seemedtocorrelatewithpeakplasmaconcentrationsratherthantosystemicexposures(AUC).Peakplasma

concentrationsatno-effect-levelwereinexcess(8-fold)ofthoseachievedinclinicaluse,whileAUCforescitalopram

wasonly3-to4-foldhigherthantheexposureachievedinclinicaluse.ForcitalopramAUCvaluesfortheS-

enantiomerwere6-to7-foldhigherthanexposureachievedinclinicaluse.Thefindingsareprobablyrelatedtoan

exaggeratedinfluenceonbiogenicaminesi.e.secondarytotheprimarypharmacologicaleffects,resultingin

haemodynamiceffects(reductionincoronaryflow)andischaemia.However,theexactmechanismofcardiotoxicityin

ratsisnotclear.Clinicalexperiencewithcitalopram,andtheclinicaltrialexperiencewithescitalopram,donotindicate

thatthesefindingshaveaclinicalcorrelate.

Increasedcontentofphospholipidshasbeenobservedinsometissuese.g.lung,epididymidesandliveraftertreatment

forlongerperiodswithescitalopramandcitalopraminrats.Findingsintheepididymidesandliverwereseenat

exposuressimilartothatinman.Theeffectisreversibleaftertreatmentcessation.Accumulationofphospholipids

(phospholipidosis)inanimalshasbeenobservedinconnectionwithmanycationicamphiphilicmedicines.Itisnot

knownifthisphenomenonhasanysignificantrelevanceforman.

Inthedevelopmentaltoxicitystudyintheratembryotoxiceffects(reducedfoetalweightandreversibledelayof

ossification)wereobservedatexposuresintermsofAUCinexcessoftheexposureachievedduringclinicaluse.No

increasedfrequencyofmalformationswasnoted.

Apre-andpostnatalstudyshowedreducedsurvivalduringthelactationperiodatexposuresintermsofAUCinexcess

oftheexposureachievedduringclinicaluse.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Magnesiumstearate

Cellulose,microcrystalline(E460)

Cellulose,microcrystalline,silicified

Talc

Croscarmellosesodium

Tabletcoating:

“OpadryII.white33G28523”:

Hypromellose

Titaniumdioxide(E171)

Macrogol3350

Lactosemonohydrate

Glyceroltriacetate

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

18months.

6.4Specialprecautionsforstorage

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6.5Natureandcontentsofcontainer

Tabletsarepackedincoldblister(PA/Al/PVC-Al)containing14,20,28,30,50,56,98,100,200film-coatedtablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

PlivaPharmaLtd

VisionHouse

BedfordRoad

Petersfield

HampshireGU323QB

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA585/37/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:28 th

May2009

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