ESCITALOPRAM PFIZER

Main information

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

Documents

Localization

  • Available in:
  • ESCITALOPRAM PFIZER
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0822/054/001
  • Authorization date:
  • 26-08-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

EscitalopramPfizer5mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains5mgescitalopram(asoxalate).

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Whitetooff–whitecolored,roundshaped,film-coated,biconvextabletsdebossedwith‘F’ononesideand‘53’onthe

otherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofmajordepressiveepisodes.

Treatmentofpanicdisorderwithorwithoutagoraphobia.

Treatmentofsocialanxietydisorder(socialphobia).

Treatmentofgeneralisedanxietydisorder.

Treatmentofobsessive-compulsivedisorder.

4.2Posologyandmethodofadministration

Safetyofdailydosesabove20mghasnotbeendemonstrated.

Escitalopramisadministeredasasingledailydoseandmaybetakenwithorwithoutfood.

Majordepressiveepisodes

Usualdosageis10mgoncedaily.Dependingonindividualpatientresponse,thedosemaybeincreasedtoamaximum

of20mgdaily.

Usually2-4weeksarenecessarytoobtainantidepressantresponse.Afterthesymptomsresolve,treatmentforatleast6

monthsisrequiredforconsolidationoftheresponse.

Panicdisorderwithorwithoutagoraphobia

Aninitialdoseof5mgisrecommendedforthefirstweekbeforeincreasingthedoseto10mgdaily.Thedosemaybe

furtherincreased,uptoamaximumof20mgdaily,dependentonindividualpatientresponse.

Maximumeffectivenessisreachedafterabout3months.Thetreatmentlastsseveralmonths.

Socialanxietydisorder

Usualdosageis10mgoncedaily.Usually2-4weeksarenecessarytoobtainsymptomrelief.Thedosemay

subsequently,dependingonindividualpatientresponse,bedecreasedto5mgorincreasedtoamaximumof20mg

daily.

Socialanxietydisorderisadiseasewithachroniccourse,andtreatmentfor12weeksisrecommendedtoconsolidate

response.Long-termtreatmentofrespondershasbeenstudiedfor6monthsandcanbeconsideredonanindividual

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/08/2011 CRN 2081997 page number: 1

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)

Initialtreatmentwithhalftheusuallyrecommendeddoseandalowermaximumdoseshouldbeconsidered(seesection

5.2).

TheefficacyofEscitalopraminsocialanxietydisorderhasnotbeenstudiedinelderlypatients.

Childrenandadolescents(<18years)

Escitalopramshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years(seesection

4.4).

Reducedrenalfunction

Dosageadjustmentisnotnecessaryinpatientswithmildormoderaterenalimpairment.Cautionisadvisedinpatients

withseverelyreducedrenalfunction(CL

lessthan30ml/min)(seesection5.2).

Reducedhepaticfunction

Aninitialdoseof5mgdailyforthefirsttwoweeksoftreatmentisrecommendedinpatientswithmildormoderate

hepaticimpairment.Dependingonindividualpatientresponse,thedosemaybeincreasedto10mgdaily.Cautionand

extracarefuldosetitrationisadvisedinpatientswithseverelyreducedhepaticfunction(seesection5.2).

PoormetabolisersofCYP2C19

ForpatientswhoareknowntobepoormetaboliserswithrespecttoCYP2C19,aninitialdoseof5mgdailyduringthe

firsttwoweeksoftreatmentisrecommended.Dependingonindividualpatientresponse,thedosemaybeincreasedto

10mgdaily(seesection5.2).

Discontinuationsymptomsseenwhenstoppingtreatment

Abruptdiscontinuationshouldbeavoided.Whenstoppingtreatmentwithescitalopramthedoseshouldbegradually

reducedoveraperiodofatleastonetotwoweeksinordertoreducetheriskofdiscontinuationsymptoms(seesection

4.4and4.8).Ifintolerablesymptomsoccurfollowingadecreaseinthedoseorupondiscontinuationoftreatment,then

resumingthepreviouslyprescribeddosemaybeconsidered.Subsequently,thephysicianmaycontinuedecreasingthe

dose,butatamoregradualrate.

4.3Contraindications

Hypersensitivitytoescitalopramortoanyoftheexcipients.

Concomitanttreatmentwithnon-selective,irreversiblemonoamineoxidaseinhibitors(MAO-inhibitors)is

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/08/2011 CRN 2081997 page number: 2

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

MAO-inhibitorlinezolidiscontraindicatedduetotheriskofonsetofaserotoninsyndrome(seesection4.5).

4.4Specialwarningsandprecautionsforuse

ThefollowingspecialwarningsandprecautionsapplytothetherapeuticclassofSSRIs(SelectiveSerotoninRe-uptake

Inhibitors).

Useinchildrenandadolescentsunder18yearsofage

Escitalopramshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years.Suiciderelated

behaviours(suicideattemptandsuicidalthoughts),andhostility(predominatelyaggression,oppositionalbehaviourand

anger)weremorefrequentlyobservedinclinicaltrialsamongchildrenandadolescentstreatedwithantidepressants

comparedtothosetreatedwithplacebo.If,basedonclinicalneed,adecisiontotreatisneverthelesstaken,thepatient

shouldbecarefullymonitoredfortheappearanceofsuicidalsymptoms.Inaddition,long-termsafetydatainchildren

andadolescentsconcerninggrowth,maturationandcognitiveandbehaviouraldevelopmentarelacking.

Paradoxicalanxiety

Somepatientswithpanicdisordermayexperienceincreasedanxietysymptomsatthebeginningoftreatmentwith

antidepressants.Thisparadoxicalreactionusuallysubsideswithintwoweeksduringcontinuedtreatment.Alow

startingdoseisadvisedtoreducethelikelihoodofananxiogeniceffect(seesection4.2).

Seizures

Escitalopramshouldbediscontinuedifapatientdevelopsseizuresforthefirsttime,orifthereisanincreaseinseizure

frequency(inpatientswithapreviousdiagnosisofepilepsy).SSRIsshouldbeavoidedinpatientswithunstable

epilepsyandpatientswithcontrolledepilepsyshouldbecloselymonitored.

Mania

SSRIsshouldbeusedwithcautioninpatientswithahistoryofmania/hypomania.SSRIsshouldbediscontinuedinany

patiententeringamanicphase.

Diabetes

Inpatientswithdiabetes,treatmentwithanSSRImayalterglycaemiccontrol(hypoglycaemiaorhyperglycaemia).

Insulinand/ororalhypoglycaemicdosagemayneedtobeadjusted.

Suicide/suicidalthoughtsorclinicalworsening

Depressionisassociatedwithanincreasedriskofsuicidalthoughts,selfharmandsuicide(suicide-relatedevents).This

riskpersistsuntilsignificantremissionoccurs.Asimprovementmaynotoccurduringthefirstfewweeksormoreof

treatment,patientsshouldbecloselymonitoreduntilsuchimprovementoccurs.Itisgeneralclinicalexperiencethatthe

riskofsuicidemayincreaseintheearlystagesofrecovery.

OtherpsychiatricconditionsforwhichEscitalopramPfizerisprescribedcanalsobeassociatedwithanincreasedrisk

ofsuicide-relatedevents.Inaddition,theseconditionsmaybeco-morbidwithmajordepressivedisorder.Thesame

precautionsobservedwhentreatingpatientswithmajordepressivedisordershouldthereforebeobservedwhentreating

patientswithotherpsychiatricdisorders.

Patientswithahistoryofsuicide-relatedevents,orthoseexhibitingasignificantdegreeofsuicidalideationpriorto

commencementoftreatment,areknowntobeatgreaterriskofsuicidalthoughtsorsuicideattempts,andshould

receivecarefulmonitoringduringtreatment.Ametaanalysisofplacebocontrolledclinicaltrialsofantidepressant

drugsinadultpatientswithpsychiatricdisordersshowedanincreasedriskofsuicidalbehaviourwithantidepressants

comparedtoplaceboinpatientslessthan25yearsold.Closesupervisionofpatientsandinparticularthoseathighrisk

shouldaccompanydrugtherapyespeciallyinearlytreatmentandfollowingdosechanges.Patients(andcaregiversof

patients)shouldbealertedabouttheneedtomonitorforanyclinicalworsening,suicidalbehaviourorthoughtsand

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/08/2011 CRN 2081997 page number: 3

Akathisia/psychomotorrestlessness

TheuseofSSRIs/SNRIshasbeenassociatedwiththedevelopmentofakathisia,characterisedbyasubjectively

unpleasantordistressingrestlessnessandneedtomoveoftenaccompaniedbyaninabilitytositorstandstill.Thisis

mostlikelytooccurwithinthefirstfewweeksoftreatment.Inpatientswhodevelopthesesymptoms,increasingthe

dosemaybedetrimental.

Hyponatraemia

Hyponatraemia,probablyduetoinappropriateantidiuretichormonesecretion(SIADH),hasbeenreportedrarelywith

theuseofSSRIsandgenerallyresolvesondiscontinuationoftherapy.Cautionshouldbeexercisedinpatientsatrisk,

suchaselderly,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

sumatriptanorothertriptans,tramadolandtryptophan.

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-limitingandusually

resolvewithin2weeks,thoughinsomeindividualstheymaybeprolonged(2-3monthsormore).Itistherefore

advisedthatescitalopramshouldbegraduallytaperedwhendiscontinuingtreatmentoveraperiodofseveralweeksor

months,accordingtothepatient’sneeds(see“Discontinuationsymptomsseenwhenstoppingtreatment”,section4.2).

Coronaryheartdisease

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/08/2011 CRN 2081997 page number: 4

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.

Atleast7daysshouldelapseafterdiscontinuingescitalopramtreatment,beforestartinganon-selective,irreversible

MAOI.

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.Cautionisadvisedwhenconcomitantlyusingothermedicinalproductscapable

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

andbutyrophenones),mefloquin,bupropionandtramadol).

Lithium,tryptophan

TherehavebeenreportsofenhancedeffectswhenSSRIshavebeengiventogetherwithlithiumortryptophan,

thereforeconcomitantuseofSSRIswiththesemedicinalproductsshouldbeundertakenwithcaution.

St.John’sWort

ConcomitantuseofSSRIsandherbalremediescontainingSt.John´sWort(Hypericumperforatum)mayresultinan

increasedincidenceofadversereactions(seesection4.4).

Haemorrhage

Alteredanti-coagulanteffectsmayoccurwhenescitalopramiscombinedwithoralanticoagulants.Patientsreceiving

oralanticoagulanttherapyshouldreceivecarefulcoagulationmonitoringwhenescitalopramisstartedorstopped(see

section4.4).

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/08/2011 CRN 2081997 page number: 5

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.

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

Pregnancy

Forescitalopramonlylimitedclinicaldataareavailableregardingexposedpregnancies.

Inreproductivetoxicitystudiesperformedinratswithescitalopram,embryo-fetotoxiceffects,butnoincreased

incidenceofmalformations,wereobserved(seesection5.3).

Escitalopramshouldnotbeusedduringpregnancyunlessclearlynecessaryandonlyaftercarefulconsiderationofthe

risk/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.

EpidemiologicaldatahavesuggestedthattheuseofSSRIsinpregnancy,particularlyinlatepregnancy,mayincrease

theriskofpersistentpulmonaryhypertensioninthenewborn(PPHN).Theobservedriskwasapproximately5casesper

1000pregnancies.Inthegeneralpopulation1to2casesofPPHNper1000pregnanciesoccur.

Lactation

Itisexpectedthatescitalopramwillbeexcretedintohumanmilk.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/08/2011 CRN 2081997 page number: 6

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

Metabolismandnutrition

disorders 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

behaviour 1

Nervoussystemdisorders Common Insomnia,somnolence,dizziness,

paraesthesia,tremor

Uncommon Tastedisturbance,sleepdisorder,

syncope

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/08/2011 CRN 2081997 page number: 7

Casesofsuicidalideationandsuicidalbehaviourshavebeenreportedduringescitalopramtherapyorearlyafter

treatmentdiscontinuation(seesection4.4).

TheseeventshavebeenreportedforthetherapeuticclassofSSRIs.

CasesofQT-prolongationhavebeenreportedduringthepost-marketingperiod,predominantlyinpatientswithpre-

existingcardiacdisease.Inadouble-blind,placebocontrolledECGstudyinhealthysubjects,thechangefrombaseline

inQTc(Fridericia-correction)was4.3msecatthe10mg/daydoseand10.7msecatthe30mg/daydose.

Epidemiologicalstudies,mainlyconductedinpatients50yearsofageandolder,showanincreasedriskofbone

Notknown Dyskinesia,movementdisorder,

convulsion,psychomotor

restlessness/akathisia 2

Eyedisorders Uncommon Mydriasis,visualdisturbance

Earandlabyrinthdisorders Uncommon Tinnitus

Cardiacdisorders Uncommon Tachycardia

Rare Bradycardia

Notknown ElectrocardiogramQTprolonged

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

Skinandsubcutaneous

tissuedisorders Common Sweatingincreased

Uncommon Urticaria,alopecia,rash,pruritus

Notknown Ecchymosis,angioedemas

Musculoskeletaland

connectivetissuedisorders Common Arthralgia,myalgia

Renalandurinary

disorders Notknown Urinaryretention

Reproductivesystemand

breastdisorders Common Male:ejaculationdisorder,

impotence

Uncommon Female:metrorrhagia,menorrhagia

Notknown Galactorrhoea

Male:priapism

Generaldisordersand

administrationsite

conditions Common Fatigue,pyrexia

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/08/2011 CRN 2081997 page number: 8

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(seesection4.2and4.4).

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.

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.

Clinicalefficacy

MajorDepressiveEpisodes

Escitalopramhasbeenfoundtobeeffectiveintheacutetreatmentofmajordepressiveepisodesinthreeoutoffour

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

whohadrespondedduringaninitial8-weekopenlabeltreatmentphasewithescitalopram10or20mg/day,were

randomisedtocontinuationwithescitalopramatthesamedose,ortoplacebo,forupto36weeks.Inthisstudy,patients

receivingcontinuedescitalopramexperiencedasignificantlylongertimetorelapseoverthesubsequent36weeks

comparedtothosereceivingplacebo.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/08/2011 CRN 2081997 page number: 9

Escitalopramwaseffectiveinboththreeshort-term(12-week)studiesandinrespondersina6monthsrelapse

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

hasbeendemonstrated.

Generalisedanxietydisorder

Escitalopramindosesof10and20mg/daywaseffectiveinfouroutoffourplacebocontrolledstudies.

Inpooleddatafromthreestudieswithsimilardesigncomprising421escitalopramtreatedpatientsand419placebo-

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

wasseenfromweek1.

Maintenanceofefficacyofescitalopram20mg/daywasdemonstratedina24-to76-week,randomised,maintenanceof

efficacystudyin373patientswhohadrespondedduringtheinitial12-weekopen-labeltreatment.

Obsessive-compulsivedisorder

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

scoreafter12weeks.After24weeks,both10and20mg/dayescitalopramweresuperiorascomparedtoplacebo.

Preventionofrelapsewasdemonstratedfor10and20mg/dayescitalopraminpatientswhorespondedtoescitalopram

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

5.2Pharmacokineticproperties

Absorption

Absorptionisalmostcompleteandindependentoffoodintake.(Meantimetomaximumconcentration(meanTmax)is

4hoursaftermultipledosing).Aswithracemiccitalopram,theabsolutebio-availabilityofescitalopramisexpectedto

beabout80%.

Distribution

Theapparentvolumeofdistribution(Vd,/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(t½)aftermultipledosingisabout30hoursandtheoralplasmaclearance(Cl

oral )isabout

0.6l/min.Themajormetaboliteshaveasignificantlylongerhalf-life.Escitalopramandmajormetabolitesareassumed

tobeeliminatedbyboththehepatic(metabolic)andtherenalroutes,withthemajorpartofthedoseexcretedas

metabolitesintheurine.

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

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/08/2011 CRN 2081997 page number: 10

Reducedrenalfunction

Withracemiccitalopram,alongerhalf-lifeandaminorincreaseinexposurehavebeenobservedinpatientswith

reducedkidneyfunction(CLcr10-53ml/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)andischemia.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

lactationperiodatexposuresintermsofAUCinexcessoftheexposureachievedduringclinicaluse.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Silicifiedmicrocrystallinecellulose

Butylatedhydroxyltoluene(E321)

Butylatedhydroxylanisole(E320)

Croscarmellosesodium

Cellulosemicrocrystalline

Silica,colloidalanhydrous

Talc

Magnesiumstearate

Film-coating:

Hypromellose

Macrogol400

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/08/2011 CRN 2081997 page number: 11

6.2Incompatibilities

Notapplicable.

6.3Shelflife

2years

6.4Specialprecautionsforstorage

Nospecialprecautionsforstorage.

6.5Natureandcontentsofcontainer

ThetabletsareavailableinPVC/Aclar–AluminiumblistersandHDPEbottlepacks.

Packsizes

PVC/Aclar–Aluminiumblisterpacks:7,10,14,15,20,28,30,49,50,56,60,84,90,98,100,200and500tablets

HDPEbottlepacks:30,100and500tablets

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements

7MARKETINGAUTHORISATIONHOLDER

PfizerHealthcareIreland

9Riverwalk

NationalDigitalPark

CitywestBusinessCampus

Dublin24

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA822/54/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:26August2011

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/08/2011 CRN 2081997 page number: 12