ESCITALOPRAM

Main information

  • Trade name:
  • ESCITALOPRAM Oral Drops Solution 20 Base mg/ml
  • Dosage:
  • 20 Base mg/ml
  • Pharmaceutical form:
  • Oral Drops Solution
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ESCITALOPRAM Oral Drops Solution 20 Base mg/ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1334/008/001
  • Authorization date:
  • 23-03-2012
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Escitalopram20mg/mlOralDropsSolution

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachmlofsolutioncontains:

20mgescitalopram(as25.56mgescitalopramoxalate).

Eachdropcontains1mgofescitalopram.

Excipients:Eachdropcontains4.7mgofethanol.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Oraldrops,solution

Aclearsolutionwithabittertaste.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofmajordepressiveepisodes.

Treatmentofpanicdisorderwithorwithoutagoraphobia.

Treatmentofsocialanxietydisorder(socialphobia).

Treatmentofgeneralisedanxietydisorder.

Treatmentofobsessive-compulsivedisorder

4.2Posologyandmethodofadministration

Posology

Safetyofdailydosesabove20mg(20drops)hasnotbeendemonstrated.

Majordepressiveepisodes

Usualdosageis10mg(10drops)oncedaily.Dependingonindividualpatientresponse,thedosemaybeincreasedtoa

maximumof20mg(20drops)daily.

Usually2-4weeksarenecessarytoobtainantidepressantresponse.Afterthesymptomsresolve,treatmentforatleast6

monthsisrequiredforconsolidationoftheresponse.

Panicdisorderwithorwithoutagoraphobia

Aninitialdoseof5mg(5drops)isrecommendedforthefirstweekbeforeincreasingthedoseto10mg(10drops)

daily.Thedosemaybefurtherincreased,uptoamaximumof20mg(20drops)daily,dependentonindividualpatient

response.

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Socialanxietydisorder

Usualdosageis10mg(10drops)oncedaily.Usually2-4weeksarenecessarytoobtainsymptomrelief.Thedosemay

subsequently,dependingonindividualpatientresponse,bedecreasedto5mg(5drops)orincreasedtoamaximumof

20mgdaily(20drops).

Socialanxietydisorderisadiseasewithachroniccourse,andtreatmentfor12weeksisrecommendedtoconsolidate

response.Long-termtreatmentofrespondershasbeenstudiedfor6monthsandcanbeconsideredonanindividual

basistopreventrelapse;treatmentbenefitsshouldbere-evaluatedatregularintervals.

Socialanxietydisorderisawell-defineddiagnosticterminologyofaspecificdisorder,whichshouldnotbeconfounded

withexcessiveshyness.Pharmacotherapyisonlyindicatedifthedisorderinterferessignificantlywithprofessionaland

socialactivities.

Theplaceofthistreatmentcomparedtocognitivebehaviouraltherapyhasnotbeenassessed.Pharmacotherapyispart

ofanoveralltherapeuticstrategy.

Generalisedanxietydisorder

Initialdosageis10mg(10drops)oncedaily.Dependingontheindividualpatientresponse,thedosemaybeincreased

toamaximumof20mg(20drops)daily.

Long-termtreatmentofrespondershasbeenstudiedforatleast6monthsinpatientsreceiving20mg(20drops)daily.

Treatmentbenefitsanddoseshouldbere-evaluatedatregularintervals(seesection5.1).

Obsessive-compulsivedisorder(OCD)

Initialdosageis10mg(10drops)oncedaily.Dependingontheindividualpatientresponse,thedosemaybeincreased

toamaximumof20mg(20drops)daily.

AsOCDisachronicdisease,patientsshouldbetreatedforasufficientperiodtoensurethattheyaresymptomfree.

Treatmentbenefitsanddoseshouldbere-evaluatedatregularintervals(seesection5.1).

Discontinuationsymptomsseenwhenstoppingtreatment

Abruptdiscontinuationshouldbeavoided.Whenstoppingtreatmentwithescitalopramthedoseshouldbegradually

reducedoveraperiodofatleastonetotwoweeksinordertoreducetheriskofdiscontinuationsymptoms(seesection

4.4and4.8).Ifintolerablesymptomsoccurfollowingadecreaseinthedoseorupondiscontinuationoftreatment,then

resumingthepreviouslyprescribeddosemaybeconsidered.Subsequently,thephysicianmaycontinuedecreasingthe

dose,butatamoregradualrate.

Specialpopulations

Elderlypatients(>65yearsofage)

Initialdosageis5mgoncedaily.Dependingonindividualpatientresponse,thedosemaybeincreasedto10mgdaily

(seesection5.2)

Theefficacyofthismedicinalproductinsocialanxietydisorderhasnotbeenstudiedinelderlypatients.

Reducedrenalfunction

Dosageadjustmentisnotnecessaryinpatientswithmildormoderaterenalimpairment.Cautionisadvisedinpatients

withseverelyreducedrenalfunction(CL

lessthan30ml/min.)(seesection5.2).

Reducedhepaticfunction

Aninitialdoseof5mgdaily(5drops)forthefirsttwoweeksoftreatmentisrecommendedinpatientswithmildor

moderatehepaticimpairment.Dependingonindividualpatientresponse,thedosemaybeincreasedto10mg(10

drops)daily.Cautionandextracarefuldosetitrationisadvisedinpatientswithseverelyreducedhepaticfunction(see

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PoormetabolisersofCYP2C19

ForpatientswhoareknowntobepoormetaboliserswithrespecttoCYP2C19,aninitialdoseof5mg(5drops)daily

duringthefirsttwoweeksoftreatmentisrecommended.Dependingonindividualpatientresponse,thedosemaybe

increasedto10mg(10drops)daily(seesection5.2).

Paediatricpopulation

Childrenandadolescents(<18years)

Thismedicinalproductshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years(see

section4.4).

Methodofadministration

Thismedicinalproductisadministeredasasingledailydoseandmaybetakenwithorwithoutfood.Itcanbemixed

withwater,orangejuiceorapplejuice.

Abottlewithadropperapplicatormaybeusedforadministration

4.3Contraindications

Hypersensitivitytoescitalopramortoanyoftheexcipients.

Concomitanttreatmentwithnon-selective,irreversiblemonoamineoxidaseinhibitors(MAO-inhibitors)is

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

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

MAO-inhibitorlinezolidiscontraindicatedduetotheriskofonsetofaserotoninsyndrome(seesection4.5).

EscitalopramiscontraindicatedinpatientswithknownQTintervalprolongationorcongenitallongQTsyndrome.

EscitalopramiscontraindicatedtogetherwithmedicinalproductsthatareknowntoprolongtheQTinterval(seesection

4.5).

4.4Specialwarningsandprecautionsforuse

ThefollowingspecialwarningsandprecautionsapplytothetherapeuticclassofSSRIs(SelectiveSerotoninRe-uptake

Inhibitors).

Useinchildrenandadolescentsunder18yearsofage

Thismedicinalproductshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years.

Suiciderelatedbehaviours(suicideattemptandsuicidalthoughts),andhostility(predominatelyaggression,

oppositionalbehaviourandanger)weremorefrequentlyobservedinclinicaltrialsamongchildrenandadolescents

treatedwithantidepressantscomparedtothosetreatedwithplacebo.If,basedonclinicalneed,adecisiontotreatis

neverthelesstaken,thepatientshouldbecarefullymonitoredfortheappearanceofsuicidalsymptoms.Inaddition,

long-termsafetydatainchildrenandadolescentsconcerninggrowth,maturationandcognitiveandbehavioural

developmentarelacking.

Paradoxicalanxiety

Somepatientswithpanicdisordermayexperienceincreasedanxietysymptomsatthebeginningoftreatmentwith

antidepressants.Thisparadoxicalreactionusuallysubsideswithintwoweeksduringcontinuedtreatment.Alow

startingdoseisadvisedtoreducethelikelihoodofananxiogeniceffect(seesection4.2).

Seizures

Escitalopramshouldbediscontinuedifapatientdevelopsseizuresforthefirsttime,orifthereisanincreaseinseizure

frequency(inpatientswithapreviousdiagnosisofepilepsy).SSRIsshouldbeavoidedinpatientswithunstable

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Mania

SSRIsshouldbeusedwithcautioninpatientswithahistoryofmania/hypomania.SSRIsshouldbediscontinuedinany

patiententeringamanicphase.

Diabetes

Inpatientswithdiabetes,treatmentwithanSSRImayalterglycaemiccontrol(hypoglycaemiaorhyperglycaemia).

Insulinand/ororalhypoglycaemicdosagemayneedtobeadjusted.

Suicide/suicidalthoughtsorclinicalworsening

Depressionisassociatedwithanincreasedriskofsuicidalthoughts,selfharmandsuicide(suicide-relatedevents).This

riskpersistsuntilsignificantremissionoccurs.Asimprovementmaynotoccurduringthefirstfewweeksormoreof

treatment,patientsshouldbecloselymonitoreduntilsuchimprovementoccurs.Itisgeneralclinicalexperiencethatthe

riskofsuicidemayincreaseintheearlystagesofrecovery.

Otherpsychiatricconditionsforwhichthismedicinalproductisprescribedcanalsobeassociatedwithanincreased

riskofsuicide-relatedevents.Inaddition,theseconditionsmaybeco-morbidwithmajordepressivedisorder.Thesame

precautionsobservedwhentreatingpatientswithmajordepressivedisordershouldthereforebeobservedwhentreating

patientswithotherpsychiatricdisorders.

Patientswithahistoryofsuicide-relatedevents,orthoseexhibitingasignificantdegreeofsuicidalideationpriorto

commencementoftreatment,areknowntobeatgreaterriskofsuicidalthoughtsorsuicideattempts,andshould

receivecarefulmonitoringduringtreatment.Ametaanalysisofplacebocontrolledclinicaltrialsofantidepressant

drugsinadultpatientswithpsychiatricdisordersshowedanincreasedriskofsuicidalbehaviourwithantidepressants

comparedtoplaceboinpatientslessthan25yearsold.Closesupervisionofpatientsandinparticularthoseathighrisk

shouldaccompanydrugtherapyespeciallyinearlytreatmentandfollowingdosechanges.

Patients(andcaregiversofpatients)shouldbealertedabouttheneedtomonitorforanyclinicalworsening,suicidal

behaviourorthoughtsandunusualchangesinbehaviourandtoseekmedicaladviceimmediatelyifthesesymptoms

present.

Akathisia/psychomotorrestlessness

TheuseofSSRIs/SNRIshasbeenassociatedwiththedevelopmentofakathisia,characterisedbyasubjectively

unpleasantordistressingrestlessnessandneedtomoveoftenaccompaniedbyaninabilitytositorstandstill.Thisis

mostlikelytooccurwithinthefirstfewweeksoftreatment.Inpatientswhodevelopthesesymptoms,increasingthe

dosemaybedetrimental.

Hyponatraemia

Hyponatraemia,probablyduetoinappropriateantidiuretichormonesecretion(SIADH),hasbeenreportedrarelywith

theuseofSSRIsandgenerallyresolvesondiscontinuationoftherapy.Cautionshouldbeexercisedinpatientsatrisk,

suchastheelderly,orpatientswithcirrhosis,orifusedincombinationwithothermedicationswhichmaycause

hyponatraemia.

Haemorrhage

Therehavebeenreportsofcutaneousbleedingabnormalities,suchasecchymosesandpurpura,withSSRIs.Cautionis

advisedinpatientstakingSSRIs,particularlyinconcomitantusewithoralanticoagulants,withmedicinalproducts

knowntoaffectplateletfunction(e.g.atypicalantipsychoticsandphenothiazines,mosttricyclicantidepressants,

acetylsalicylicacidandnon-steroidalanti-inflammatorymedicinalproducts(NSAIDs),ticlopidineanddipyridamole)

andinpatientswithknownbleedingtendencies.

ECT(electroconvulsivetherapy)

ThereislimitedclinicalexperienceofconcurrentadministrationofSSRIsandECT,thereforecautionisadvisable.

Serotoninsyndrome

Cautionisadvisableifescitalopramisusedconcomitantlywithmedicinalproductswithserotonergiceffectssuchas

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Inrarecases,serotoninsyndromehasbeenreportedinpatientsusingSSRIsconcomitantlywithserotonergicmedicinal

products.Acombinationofsymptoms,suchasagitation,tremor,myoclonusandhyperthermiamayindicatethe

developmentofthiscondition.IfthisoccurstreatmentwiththeSSRIandtheserotonergicmedicinalproductshouldbe

discontinuedimmediatelyandsymptomatictreatmentinitiated.

St.John´sWort

ConcomitantuseofSSRIsandherbalremediescontainingSt.John´sWort(Hypericumperforatum)mayresultinan

increasedincidenceofadversereactions(seesection4.5).

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).

QTintervalprolongation

Escitalopramhasbeenfoundtocauseadose-dependentprolongationoftheQTinterval.CasesofQTinterval

prolongationandventriculararrhythmiaincludingtorsadedepointeshavebeenreportedduringthepost-marketing

period,predominantlyinpatientsoffemalegender,withhypokalemia,orwithpre-existingQTintervalprolongationor

othercardiacdiseases(seesections4.3,4.5,4.8,4.9and5.1).

Cautionisadvisedinpatientswithsignificantbradycardia;orinpatientswithrecentacutemyocardialinfarctionor

uncompensatedheartfailure.

Electrolytedisturbancessuchashypokalemiaandhypomagnesaemiaincreasetheriskformalignantarrhythmiasand

shouldbecorrectedbeforetreatmentwithescitalopramisstarted.

Ifpatientswithstablecardiacdiseasearetreated,anECGreviewshouldbeconsideredbeforetreatmentisstarted.

Ifsignsofcardiacarrhythmiaoccurduringtreatmentwithescitalopram,thetreatmentshouldbewithdrawnandan

ECGshouldbeperformed.

ImportantinformationaboutsomeoftheingredientsofEscitalopram20mg/mlOralDropsSolution

Thismedicinalproductcontainssmallamountsofethanol(alcohol),lessthan100mgperdose.Eachdropcontains4.7

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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.Escitaloprammaybestarted

14daysafterdiscontinuingtreatmentwithanirreversibleMAOI.Atleast7daysshouldelapseafterdiscontinuing

escitalopramtreatment,beforestartinganon-selective,irreversibleMAOI.

Reversible,selectiveMAO-Ainhibitor(moclobemide)

Duetotheriskofserotoninsyndrome,thecombinationofescitalopramwithaMAO-Ainhibitorsuchasmoclobemide

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.

QTintervalprolongation

Pharmacokineticandpharmacodynamicstudiesofescitalopramcombinedwithothermedicinalproductsthatprolong

theQTintervalhavenotbeenperformed.Anadditiveeffectofescitalopramandthesemedicinalproductscannotbe

excluded.Therefore,co-administrationofescitalopramwithmedicinalproductsthatprolongtheQTinterval,suchas

ClassIAandIIIantiarrhythmics,antipsychotics(e.g.phenothiazinederivatives,pimozide,haloperidol),tricyclic

antidepressants,certainantimicrobialagents(e.g.sparfloxacin,moxifloxacin,erythromycinIV,pentamidine,anti-

malariantreatmentparticularlyhalofantrine),certainantihistamines(astemizole,mizolastine),iscontraindicated.

Combinationsrequiringprecautionsforuse:

Serotonergicmedicinalproducts

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

serotoninsyndrome.

Medicinalproductsloweringtheseizurethreshold

SSRIscanlowertheseizurethreshold.Cautionisadvisedwhenconcomitantlyusingothermedicinalproductscapable

ofloweringtheseizurethreshold(e.gantidepressants(tricyclics,SSRIs),neuroleptics(phenothiazines,thioxanthenes

andbutyrophenones),mefloquine,bupropionandtramadol).

Lithium,tryptophan

TherehavebeenreportsofenhancedeffectswhenSSRIshavebeengiventogetherwithlithiumortryptophan,

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St.John'sWort

ConcomitantuseofSSRIsandherbalremediescontainingSt.John´sWort(Hypericumperforatum)mayresultinan

increasedincidenceofadversereactions(seesection4.4).

Haemorrhage

Alteredanti-coagulanteffectsmayoccurwhenescitalopramiscombinedwithoralanticoagulants.Patientsreceiving

oralanticoagulanttherapyshouldreceivecarefulcoagulationmonitoringwhenescitalopramisstartedorstopped(see

section4.4).Concomitantuseofnon-steriodalanti-inflammatorydrugs(NSAIDs)mayincreasebleeding-tendency(see

section4.4).

Alcohol

Nopharmacodynamicorpharmacokineticinteractionsareexpectedbetweenescitalopramandalcohol.However,as

withotherpsychotropicmedicinalproducts,thecombinationwithalcoholisnotadvisable.

Pharmacokineticinteractions

Influenceofothermedicinalproductsonthepharmacokineticsofescitalopram:

ThemetabolismofescitalopramismainlymediatedbyCYP2C19.CYP3A4andCYP2D6mayalsocontributetothe

metabolismalthoughtoasmallerextent.ThemetabolismofthemajormetaboliteS-DCT(demethylatedescitalopram)

seemstobepartlycatalysedbyCYP2D6.

Co-administrationofescitalopramwithomeprazole30mgoncedaily(aCYP2C19inhibitor)resultedinmoderate

(approximately50%)increaseintheplasmaconcentrationsofescitalopram.

Co-administrationofescitalopramwithcimetidine400mgtwicedaily(moderatelypotentgeneralenzyme-inhibitor)

resultedinamoderate(approximately70%)increaseintheplasmaconcentrationsofescitalopram.Cautionisadvised

whenadministeringescitalopramincombinationwithcimetidine.Doseadjustmentmaybewarranted.

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.

InvitrostudieshavedemonstratedthatescitaloprammayalsocauseweakinhibitionofCYP2C19.Cautionis

recommendedwithconcomitantuseofmedicinalproductsthataremetabolisedbyCYP2C19.

4.6Fertility,pregnancyandlactation

FertilityandPregnancy

Forescitalopramonlylimitedclinicaldataareavailableregardingexposedpregnancies.

Inreproductivetoxicitystudiesperformedinratswithescitalopram,embryo-fetotoxiceffects,butnoincreased

incidenceofmalformations,wereobserved(seesection5.3).Themedicinalproductshouldnotbeusedduring

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Neonatesshouldbeobservedifmaternaluseofthismedicinalproductcontinuesintothelaterstagesofpregnancy,

particularlyinthethirdtrimester.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.

EpidemiologicaldatahavesuggestedthattheuseofSSRIsinpregnancy,particularlyinlatepregnancy,mayincrease

theriskofpersistentpulmonaryhypertensioninthenewborn(PPHN).Theobservedriskwasapproximately5casesper

1000pregnancies.Inthegeneralpopulation1to2casesofPPHNper1000pregnanciesoccur.

Lactation

Itisexpectedthatescitalopramwillbeexcretedintohumanmilk.

Consequently,breast-feedingisnotrecommendedduringtreatment.

4.7Effectsonabilitytodriveandusemachines

Althoughescitalopramhasbeenshownnottoaffectintellectualfunctionorpsychomotorperformance,any

psychoactivemedicinalproductmayimpairjudgementorskills.Patientsshouldbecautionedaboutthepotentialriskof

aninfluenceontheirabilitytodriveacarandoperatemachinery.

4.8Undesirableeffects

Adversereactionsaremostfrequentduringthefirstorsecondweekoftreatmentandusuallydecreaseinintensityand

frequencywithcontinuedtreatment.

AdversereactionsknownforSSRIsandalsoreportedforescitalopramineitherplacebo-controlledclinicalstudiesoras

spontaneouspost-marketingeventsarelistedbelowbysystemorganclassandfrequency.

Frequenciesaretakenfromclinicalstudies;theyarenotplacebo-corrected.Frequenciesaredefinedas:verycommon

(1/10),common(1/100to<1/10),uncommon(1/1,000to<1/100),rare(1/10,000to<1/1,000),veryrare

(<1/10,000),ornotknown(cannotbeestimatedfromtheavailabledata).

Systemorganclass Frequency UndesirableEffect

Bloodandlymphaticsystem

disorders Notknown Thrombocytopenia

Immunesystemdisorders Rare Anaphylacticreaction

Endocrinedisorders Notknown InappropriateADHsecretion

Metabolismandnutritiondisorders Common Decreasedappetite,increased

appetite,weightincreased

Uncommon Weightdecreased

Notknown

Hyponatraemia,anorexia 2

Psychiatricdisorders Common Anxiety,restlessness,abnormal

dreams

Femaleandmale:libidodecreased

Female:anorgasmia

Uncommon Bruxism,agitation,nervousness,

panicattack,confusionalstate

Rare Aggression,depersonalisation,

hallucination

Notknown Mania,suicidalideation,suicidal

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Casesofsuicidalideationandsuicidalbehaviourshavebeenreportedduringescitalopramtherapyorearlyafter

treatmentdiscontinuation(seesection4.4).

TheseeventshavebeenreportedforthetherapeuticclassofSSRIs.

Epidemiologicalstudies,mainlyconductedinpatients50yearsofageandolder,showanincreasedriskofbone

fracturesinpatientsreceivingSSRIsandTCAs.Themechanismleadingtothisriskisunknown.

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

Nervoussystemdisorders Common Insomnia,somnolence,dizziness,

paraesthesia,tremor

Uncommon Tastedisturbance,sleepdisorder,

syncope

Rare Serotoninsyndrome

Notknown Dyskinesia,movementdisorder,

convulsion,psychomotor

restlessness/akathisia 2

Eyedisorders Uncommon Mydriasis,visualdisturbance

Earandlabyrinthdisorders Uncommon Tinnitus

Cardiacdisorders Uncommon Tachycardia

Rare Bradycardia

Notknown ElectrocardiogramQTprolonged

Ventriculararrhythmiaincluding

torsadedepointes

Vasculardisorders Notknown Orthostatichypotension

Respiratory,thoracicand

mediastinaldisorders Common Sinusitis,yawning

Uncommon Epistaxis

Gastrointestinaldisorders Verycommon Nausea

Common Diarrhoea,constipation,vomiting,

drymouth

Uncommon Gastrointestinalhaemorrhages

(includingrectalhaemorrhage)

Hepatobiliarydisorders Notknown Hepatitis,liverfunctiontest

abnormal

Skinandsubcutaneoustissue

disorders Common Sweatingincreased

Uncommon Urticaria,alopecia,rash,pruritus

Notknown Ecchymosis,angioedemas

Musculoskeletalandconnective

tissuedisorders Common Arthralgia,myalgia

Renalandurinarydisorders Notknown Urinaryretention

Reproductivesystemandbreast

disorders Common Male:ejaculationdisorder,

impotence

Uncommon Female:metrorrhagia,

menorrhagia

Notknown Galactorrhoea

Male:priapism

Generaldisordersand

administrationsiteconditions Common Fatigue,pyrexia

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Itisthereforeadvisedthatwhenescitalopramtreatmentisnolongerrequired,gradualdiscontinuationbydosetapering

shouldbecarriedout(seesection4.2and4.4).

QTintervalprolongation

CasesofQTintervalprolongationandventriculararrhythmiaincludingtorsadedepointeshavebeenreportedduring

thepost-marketingperiod,predominantlyinpatientsoffemalegender,withhypokalemia,orwithpre-existingQT

intervalprolongationorothercardiacdiseases(seesections4.3,4.4,4.5,4.9and5.1).

4.9Overdose

Toxicity

Clinicaldataonescitalopramoverdosearelimitedandmanycasesinvolveconcomitantoverdosesofotherdrugs.Inthe

majorityofcasesmildornosymptomshavebeenreported.Fatalcasesofescitalopramoverdosehaverarelybeen

reportedwithescitalopramalone;themajorityofcaseshaveinvolvedoverdosewithconcomitantmedications.Doses

between400and800mgofescitalopramalonehavebeentakenwithoutanyseveresymptoms.

Symptoms

Symptomsseeninreportedoverdoseofescitalopramincludesymptomsmainlyrelatedtothecentralnervoussystem

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

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

andarrhythmia)andelectrolyte/fluidbalanceconditions(hypokalaemia,hyponatraemia).

Treatment

Thereisnospecificantidote.Establishandmaintainanairway,ensureadequateoxygenationandrespiratoryfunction.

Gastriclavageandtheuseofactivatedcharcoalshouldbeconsidered.Gastriclavageshouldbecarriedoutassoonas

possibleafteroralingestion.Cardiacandvitalsignsmonitoringarerecommendedalongwithgeneralsymptomatic

supportivemeasures.

ECGmonitoringisadvisedincaseofoverdoseinpatientswithcongestiveheartfailure/bradyarrhythmias,inpatients

usingconcomitantmedicationsthatprolongtheQTinterval,orinpatientswithalteredmetabolism,e.g.liver

impairment.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:antidepressants,selectiveserotoninreuptakeinhibitors

ATC-code:N06AB10

Mechanismofaction

Escitalopramisaselectiveinhibitorofserotonin(5-HT)re-uptakewithhighaffinityfortheprimarybindingsite.Italso

bindstoanallostericsiteontheserotonintransporter,witha1000foldloweraffinity.

Escitalopramhasnoorlowaffinityforanumberofreceptorsincluding5-HT

,5-HT

,DAD

andD

receptors,

-,-adrenoceptors,histamineH

,muscarinecholinergic,benzodiazepine,andopioidreceptors.

Theinhibitionof5-HTre-uptakeistheonlylikelymechanismofactionexplainingthepharmacologicalandclinical

effectsofescitalopram.

Pharmacodynamiceffects

Inadouble-blind,placebo-controlledECGstudyinhealthysubjects,thechangefrombaselineinQTc(Fridericia-

correction)was4.3ms(90%CI:2.2,6.4)atthe10mg/daydoseand10.7ms(90%CI:8.6,12.8)atthesupratherapeutic

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Clinicalefficacy

Majordepressiveepisodes

Escitalopramhasbeenfoundtobeeffectiveintheacutetreatmentofmajordepressiveepisodesinthreeoutoffour

double-blind,placebocontrolledshort-term(8-week)studies.Inalong-termrelapsepreventionstudy,274patientswho

hadrespondedduringaninitial8-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/daywasdemonstratedina24to76week,randomised,maintenanceof

efficacystudyin373patientswhohadrespondedduringtheinitial12-weekopen-labeltreatment.

Obsessive-compulsivedisorder

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

scoreafter12weeks.After24weeks,both10and20mg/dayescitalopramweresuperiorascomparedtoplacebo.

Preventionofrelapsewasdemonstratedfor10and20mg/dayescitalopraminpatientswhorespondedtoescitalopram

ina16-weekopen-labelperiodandwhoentereda24-week,randomised,double-blind,placebocontrolledperiod.

5.2Pharmacokineticproperties

Absorption

Absorptionisalmostcompleteandindependentoffoodintake.(Meantimetomaximumconcentration(meanT

)is

4hoursaftermultipledosing).Aswithracemiccitalopram,theabsolutebio-availabilityofescitalopramisexpectedto

beabout80%.

Distribution

Theapparentvolumeofdistribution(V

,/F)afteroraladministrationisabout12to26L/kg.Theplasmaprotein

bindingisbelow80%forescitalopramanditsmainmetabolites.

Biotransformation

Escitalopramismetabolisedinthelivertothedemethylatedanddidemethylatedmetabolites.Bothoftheseare

pharmacologicallyactive.Alternatively,thenitrogenmaybeoxidisedtoformtheN-oxidemetabolite.Bothparent

substanceandmetabolitesarepartlyexcretedasglucuronides.Aftermultipledosingthemeanconcentrationsofthe

demethylanddidemethylmetabolitesareusually28-31%and<5%,respectively,oftheescitalopramconcentration.

BiotransformationofescitalopramtothedemethylatedmetaboliteismediatedprimarilybyCYP2C19.Some

contributionbytheenzymesCYP3A4andCYP2D6ispossible.

Elimination

Theeliminationhalf-life(t

)aftermultipledosingisabout30hoursandtheoralplasmaclearance(Cl

oral )isabout0.6

L/min.Themajormetaboliteshaveasignificantlylongerhalf-life.Escitalopramandmajormetabolitesareassumedto

beeliminatedbyboththehepatic(metabolic)andtherenalroutes,withthemajorpartofthedoseexcretedas

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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.

Therefore,allthecitalopraminformationcanbeextrapolatedtoescitalopram.

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

hemodynamiceffects(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-andpostnatalstudyshowedreducedsurvivalduringthe

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Propylgallate

Citricacid,anhydrous

Ethanol96%

Sodiumhydroxide(forpHadjustment)

Purifiedwater

6.2Incompatibilities

Intheabsenceofcompatibilitystudies,thismedicinalproductmustnotbemixedwithothermedicinalproducts.

6.3Shelflife

2years.

Afterfirstopening,thedropsshouldbeusedwithin8weeks.

Afteropeningthebottlestorebelow25°C.

6.4Specialprecautionsforstorage

Thismedicinalproduct(unopened)doesnotrequireanyspecialtemperaturestorageconditions.

Keepbottletightlyclosedandupright.

Forstorageconditionsafterfirstopeningofthemedicinalproduct,seesection6.3.

6.5Natureandcontentsofcontainer

15mland15mlx5inaamberglassbottle(TypeIII)withdropperapplicator(PE),andchild-proofscrewcap

(PP/HDPE).

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

ChanelleHeatlhcareLimited

Loughrea

Co.Galway

Ireland

8MARKETINGAUTHORISATIONNUMBER

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:23 rd

March2012

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