ESCIPREX

Main information

  • Trade name:
  • ESCIPREX Film Coated Tablet 15 Milligram
  • Dosage:
  • 15 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ESCIPREX Film Coated Tablet 15 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0711/153/003
  • Authorization date:
  • 06-03-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995,asamended

MedicinalProducts(ControlofPlacingontheMarket)Regulations,2007,asamended

PA0711/153/003

CaseNo:2084305

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

RowexLtd

Bantry,Co.Cork,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Esciprex15mgFilm-coatedTablets

theparticularsofwhicharesetoutintheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsasmaybespecifiedin

thesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom15/07/2010until05/03/2014.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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Date Printed 16/08/2010 CRN 2084305 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Esciprex15mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains15mgescitalopram(asoxalate)

Excipient:130.01mglactose(asmonohydrate)

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Film-coatedtablet.

White,ovalfilm-coatedtabletwithtwobreakingnotchesonbothsides.

Thetabletscanbedividedintothreeequalparts.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofmajordepressiveepisodes.

4.2Posologyandmethodofadministration

Safetyofdailydosesabove20mghasnotbeendemonstrated.

Escitalopramisadministeredasasingledailydoseandmaybetakenwithorwithoutfood.

Usualdosageis10mgoncedaily.Dependingonindividualpatientresponse,thedoesmaybeincreasedtoamaximum

of20mgdaily.

Usually2-4weeksarenecessarytoobtainantidepressantresponse.Afterthesymptomsresolve,treatmentforatleast6

monthsisrequiredforconsolidationoftheresponse.

Elderlypatients(>65yearsofage)

Initialtreatmentwithhalftheusuallyrecommendeddoseandalowermaximumdoseshouldbeconsidered(seesection

5.2).

Childrenandadolescents(<18years)

Escitalopramshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years(seesection

4.4).

Reducedrenalfunction

Dosageadjustmentisnotnecessaryinpatientswithmildormoderaterenalimpairment.

Cautionisadvisedinpatientswithseverelyreducedrenalfunction(CLCRlessthan30ml/min)(seesection5.2).

Reducedhepaticfunction

Aninitialdoseof5mgdailyforthefirsttwoweeksoftreatmentisrecommendedinpatientswithmildormoderate

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Cautionandextracarefuldosetitrationisadvisedinpatientswithseverelyreducedhepaticfunction(seesection5.2).

PoormetaboliserswithrespecttoCYP2C19

ForpatientswhoareknowntobepoormetaboliserswithrespecttoCYP2C19,aninitialdoseof5mgdailyduringthe

firsttwoweeksoftreatmentisrecommended.

Dependingonindividualpatientresponse,thedosemaybeincreasedto10mgdaily(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)iscontraindicatedduetotheriskofserotoninesyndromewithagitation,tremor,hyperthermiaetc.

(seesection4.5).

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

MAO-inhibitorlinezolidiscontraindicatedduetotheriskofonsetofaserotoninsyndrome(seesection4.5).

4.4Specialwarningsandprecautionsforuse

ThefollowingspecialwarningsandprecautionsapplytothetherapeuticclassofSSRIs(SelectiveSerotoninRe-uptake

Inhibitors).

Useinchildrenandadolescentsunder18yearsofage

Escitalopramshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years.Suiciderelated

behaviours(suicideattemptandsuicidalthoughts),andhostility(predominantlyaggression,oppositionalbehaviourand

anger)weremorefrequentlyobservedinclinicaltrialsamongchildrenandadolescentstreatedwithantidepressants

comparedtothosetreatedwithplacebo.If,basedonclinicalneed,adecisiontotreatisneverthelesstaken,thepatient

shouldbecarefullymonitoredfortheappearanceofsuicidalsymptoms.Inaddition,long-termsafetydatainchildren

andadolescentsconcerninggrowth,maturationandcognitiveandbehaviouraldevelopmentarelacking.

Suicide/suicidalthoughtsorclinicalworsening

Depressionisassociatedwithanincreasedriskofsuicidalthoughts,selfharmandsuicide(suicide-relatedevents).This

riskpersistsuntilsignificantremissionoccurs.Asimprovementmaynotoccurduringthefirstfewweeksormoreof

treatment,patientsshouldbecloselymonitoreduntilsuchimprovementoccurs.Itisgeneralclinicalexperiencethatthe

riskofsuicidemayincreaseintheearlystagesofrecovery.

Patientswithahistoryofsuicide-relatedevents,orthoseexhibitingasignificantdegreeofsuicidalideationpriorto

commencementoftreatmentareknowntobeatgreaterriskofsuicidalthoughtsorsuicideattempts,andshouldreceive

carefulmonitoringduringtreatment.Ameta-analysisofplacebo-controlledclinicaltrialsofantidepressantdrugsin

adultpatientswithpsychiatricdisordersshowedanincreasedriskofsuicidalbehaviorwithantidepressantscompared

toplaceboinpatientslessthan25yearsold.

Closesupervisionofpatientsandinparticularthoseathighriskshouldaccompanydrugtherapyespeciallyinearly

treatmentandfollowingdosechanges.Patients(andcaregiversofpatients)shouldbealertedabouttheneedtomonitor

foranyclinicalworsening,suicidalbehaviororthoughtsandunusualchangesinbehaviorandtoseekmedicaladvice

immediatelyifthesesymptomspresent.

Seizures

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SSRIsshouldbeavoidedinpatientswithunstableepilepsyandpatientswithcontrolledepilepsyshouldbecarefully

monitored.SSRIsshouldbediscontinuedifthereisanincreaseinseizurefrequency.

Mania

SSRIsshouldbeusedwithcautioninpatientswithahistoryofmania/hypomania.

SSRIsshouldbediscontinuedinanypatiententeringamanicphase.

Diabetes

Inpatientswithdiabetes,treatmentwithanSSRImayalterglycaemiccontrol(hypoglycaemiaorhyperglycaemia).

Insulinand/ororalhypoglycaemicdosagemayneedtobeadjusted.

Akathisia/psychomotorrestlessness

TheuseofSSRIs/SNRIshasbeenassociatedwiththedevelopmentofakathisia,characterisedbyasubjectively

unpleasantordistressingrestlessnessandneedtomoveoftenaccompaniedbyaninabilitytositorstandstill.Thisis

mostlikelytooccurwithinthefirstfewweeksoftreatment.Inpatientswhodevelopthesesymptoms,increasingthe

dosemaybedetrimental.

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.

Reversible,selectiveMAO-Ainhibitors

ThecombinationofescitalopramwithMAO-Ainhibitorsisgenerallynotrecommendedduetotheriskofonsetofa

serotoninsyndrome(seesection4.5).

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

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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).

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnottakeEscitalopram.

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-Ainhibitoriscontraindicated(see

section4.3).Ifthecombinationprovesnecessary,itshouldbestartedattheminimumrecommendeddosageand

clinicalmonitoringshouldbereinforced.

Reversible,non-selectiveMAO-inhibitor(linezolid)

Theantibioticlinezolidisareversiblenon-selectiveMAO-inhibitorandshouldnotbegiventopatientstreatedwith

escitalopram.Ifthecombinationprovesnecessary,itshouldbegivenwithminimumdosagesandundercloseclinical

monitoring(seesection4.3).

Combinationsrequiringprecautionsforuse:

Irreversible,selectiveMAO-Binhibitor(selegiline)

Incombinationwithselegiline(irreversibleMAO-Binhibitor),cautionisrequiredduetotheriskofdeveloping

serotoninsyndrome.Selegilinedosesupto10mg/dayhavebeensafelyco-administeredwithracemiccitalopram.

Serotonergicmedicinalproducts

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

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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).

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

withmedicinalproductsthataremainlymetabolizedbythisenzyme,andthathaveanarrowtherapeuticindex,e.g.

flecainide,propafenoneandmetoprolol(whenusedincardiacfailure),orsomeCNSactingmedicinalproductsthatare

mainlymetabolisedbyCYP2D6,e.g.antidepressantssuchasdesipramine,clomipramineandnortriptylineor

antipsychoticslikerisperidone,thioridazineandhaloperidol.Dosageadjustmentmaybewarranted.

Co-administrationwithdesipramineormetoprololresultedinbothcasesinatwofoldincreaseintheplasmalevelsof

thesetwoCYP2D6substrates.

InvitrostudieshavedemonstratedthatescitaloprammayalsocauseweakinhibitionofCYP2C19.Cautionis

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4.6Pregnancyandlactation

Pregnancy

Forescitalopramonlylimitedclinicaldataareavailableregardingexposedpregnancies.Inreproductivetoxicitystudies

performedinratswithescitalopram,embryo-fetotoxiceffects,butnoincreasedincidenceofmalformations,were

observed(seesection5.3).

Escitalopramshouldnotbeusedduringpregnancyunlessclearlynecessaryandonlyaftercarefulconsiderationofthe

risk/benefit.

NeonatesshouldbeobservedifmaternaluseofEscitalopramcontinuesintothelaterstagesofpregnancy,particularly

inthethirdtrimester.Abruptdiscontinuationshouldbeavoidedduringpregnancy.

ThefollowingsymptomsmayoccurintheneonateaftermaternalSSRI/SNRIuseinlaterstagesofpregnancy:

respiratorydistress,cyanosis,apnoea,seizures,temperatureinstability,feedingdifficulty,difficultyinsuckling,

vomiting,hypoglycaemia,hypertonia,hypotonia,hyperreflexia,tremor,jitteriness,irritability,lethargy,constant

crying,somnolenceanddifficultysleeping.Thesesymptomscouldbeduetoeitherserotonergiceffectsor

discontinuationsymptoms.Inamajorityofinstancesthecomplicationsbeginimmediatelyorsoon(<24hours)after

delivery.

EpidemiologicaldatahavesuggestedthattheuseofSSRIsinpregnancy,particularinlatepregnancy,mayincreasethe

riskofpersistentpulmonaryhypertensioninthenewborn(PPHN).Theobservedriskwasapproximately5casesper

1000pregnancies.Inthegeneralpopulation1to2casesofPPHNper1000pregnanciesoccur.

Lactation

Itisexpectedthatescitalopramwillbeexcretedintohumanmilk.

Consequently,breast-feedingisnotrecommendedduringtreatment.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectofescitalopramontheabilitytodriveandusemachineshavebeenperformed.Although

escitalopramhasbeenshownnottoaffectintellectualfunctionorpsychomotorperformance,anypsychoactive

medicinalproductmayimpairjudgementorskills.

Patientsshouldbecautionedaboutthepotentialriskofaninfluenceontheirabilitytodriveacarandoperate

machinery.

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

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Very

Common

≥1/10) Common

≥1/100to

<1/10) Uncommon

≥1/1000to

≤1/100) Rare( ≥1/10000

≤1/1000) NotKnown(cannot

beestimatedfrom

theavailabledata)

Investigations Weight

increased Weightdecreased Liverfunctiontest

abnormal

Cardiac

disorders Tachycardia Bradycardia

Bloodand

lymphatic

disorders Thrombocytopenia

Nervoussystem

disorders Insomnia,

somnolence,

dizziness,

paraesthesia,

tremor Tastedisturbance,

sleepdisorder,

syncope Serotonin

syndrome Dyskinesia,

movementdisorder,

convulsion

Eyedisorders Mydriasis,visual

disturbance

Earand

labyrinth

disorders Tinnitus

Respiratory,

thoracicand

mediastinal

disorders Sinusitis,

yawning Epistaxis

Gastroinstestinal

disorders Nausea Diarrhoea,

constipation,

vomiting,dry

mouth Gastrointestinal

haemorrhages

(includingrectal

haemorrhage)

Renaland

urinarydisorders Urinaryretention

Skinand

subcutaneous

tissuedisorders Sweating

increased Urticaria,alopecia,

rash,pruritus Ecchymosis,

angioedemas

Musculoskeletal,

connective

tissueandbone

disorders Arthralgia,

myalgia

Endocrine

disorders InappropriateADH

secretion

Metabolismand

nutrition

disorders Decreased

appetite,

increased

appetite Hyponatraemia

Vascular

disorders Orthostatic

hypotension

General

disordersand

administration

siteconditions Fatigue,

pyrexia Oedema

Immunesystem

disorders Anaphylactic

reaction

Hepatobiliary

disorders Hepatitis

Reproductive

systemand

breastdisorders Male:

ejaculation

disorder,

impotence Female:

metrorrhagia,

menorrhagia Male:priapism,

galactorrhoea

Psychiatric

disorders Anxiety,

restlessness,

abnormal

dreamsFemale

andmale:

libido

decreased

female: Bruxism,agitation,

nervousness,panic

attack,confusional

state Aggression,

depersonalisation,

hallucination, Mania,

suicidalideationand

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*Casesofsuicidalideationandsuicidalbehaviourshavebeenreportedduringescitalopramtherapyorearlyafter

treatmentdiscontinuation(seesection4.4).

Classeffects

ThefollowingadversedrugreactionshavebeenreportedforthetherapeuticclassofSSRIs:psychomotor

restlessness/akathisia(seesection4.4)andanorexia.Epidemiologicalstudies,mainlyconductedinpatients50yearsof

ageandolder,showanincreasedriskofbonefracturesinpatientsreceivingSSRIsandTCAs.Themechanismleading

tothisriskisunknown.

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(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

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:antidepressants,selectiveserotoninreuptakeinhibitors

ATC-code:N06AB10

Mechanismofaction

Escitalopramisaselectiveinhibitorofserotonin(5-HT)re-uptakewithhighaffinityfortheprimarybindingsite.Italso

bindstoanallostericsiteontheserotonintransporter,witha1000foldloweraffinity.

Escitalopramhasnoorlowaffinityforanumberofreceptorsincluding5-HT ,5-HT,DADandDreceptors, -,

-,-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.

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 )isabout

0.6L/min.Themajormetaboliteshaveasignificantlylongerhalf-life.Escitalopramandmajormetabolitesareassumed

tobeeliminatedbyboththehepatic(metabolic)andtherenalroutes,withthemajorpartofthedoseexcretedas

metabolitesintheurine.

Thereislinearpharmacokinetics.Steady-stateplasmalevelsareachievedinabout1week.Averagesteady-state

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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(CL10-53ml/min).Plasmaconcentrationsofthemetaboliteshavenotbeenstudied,butthey

maybeelevated(seesection4.2).

Polymorphism

IthasbeenobservedthatpoormetaboliserswithrespecttoCYP2C19havetwiceashighaplasmaconcentrationof

escitalopramasextensivemetabolisers.Nosignificantchangeinexposurewasobservedinpoormetaboliserswith

respecttoCYP2D6(seesection4.2).

5.3Preclinicalsafetydata

Nocompleteconventionalbatteryofpreclinicalstudieswasperformedwithescitalopramsincethebridging

toxicokineticandtoxicologicalstudiesconductedinratswithescitalopramandcitalopramshowedasimilarprofile.

Therefore,allthecitalopraminformationcanbeextrapolatedtoescitalopram.

Nogenotoxicityorcarcinogenicitystudieswereperformedwithescitalopram.Citalopram(theracemate)wasnot

genotoxicinallinvivoandmostoftheinvitrogenotoxicityassaysperformed.Carcinogenicitystudieswithoral

administrationofcitalopramtomiceandratsshowedanincreasedincidenceofsmallintestinecarcinomasinrats,

whichwasconsideredtobepossiblyrelatedtotheadministrationofcitalopram.Itisunclearifthisfindingcanbe

extrapolatedtoescitalopramoritsrelevancetohumans.

Incomparativetoxicologicalstudiesinrats,escitalopramandcitalopramcausedcardiactoxicity,includingcongestive

heartfailure,aftertreatmentforsomeweeks,whenusingdosagesthatcausedgeneraltoxicity.Thecardiotoxicity

seemedtocorrelatewithpeakplasmaconcentrationsratherthantosystemicexposures(AUC).

Peakplasmaconcentrationsatno-effect-levelwereinexcess(8-fold)ofthoseachievedinclinicaluse,whileAUCfor

escitalopramwasonly3-to4-foldhigherthantheexposureachievedinclinicaluse.ForcitalopramAUCvaluesforthe

S-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

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Lactosemonohydrate

Microcrystallinecellulose

CroscarmelloseSodium

Hypromellose

Magnesiumstearate

Silicacolloidalanhydrous

Coating:

Hypromellose

Macrogol6000

Titaniumdioxide(E171)

Talc

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

OPA-Al-PVC/Alblister

18months

HDPE-bottle

2years

6monthsafterfirstopeningoftheHDPE-bottle

6.4Specialprecautionsforstorage

OPA-Al-PVC/Alblister

Donotstoreabove25°C

HDPE-bottle

Storeintheoriginalpackageinordertoprotectfrommoisture.

AfterfirstopeningoftheHDPE-bottle:donotstoreabove25°C.

6.5Natureandcontentsofcontainer

OPA-Al-PVC/Alblisterpackincarton

7,10,14,20,28,30,50,56,56x1,60,60x1,90,98,98x1,100,100x1,200and500tablets

HDPEbottleswithPPscrewcapincludingdryingplug

28,30,56,60,98,100and250tablets

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

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7MARKETINGAUTHORISATIONHOLDER

RowexLtd

Bantry

Co.Cork

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA711/153/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:06 th

March2009

10DATEOFREVISIONOFTHETEXT

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