CITALOPRAM PFIZER

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0822/034/002
  • Authorization date:
  • 16-09-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

CitalopramPfizer20mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains20mgcitalopramascitalopramhydrobromide.

Excipient:

Eachfilm-coatedtabletcontains45.72mglactosemonohydrate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

White,biconvex,capsuleshaped,film-coatedtabletsdebossedwith‘A’ononesideandwithascorelineinbetween

‘0’and‘6’ontheotherside.

Thetabletscanbedividedintoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Majordepressiveepisodes.

Panicdisorderwithorwithoutagoraphobia.

4.2Posologyandmethodofadministration

Majordepressiveepisodes:

Followingtreatmentinitiation,anantidepressanteffectshouldnotbeexpectedforatleasttwoweeks.Patientswith

depressionshouldbetreatedforasufficientperiodoftimeandtreatmentshouldbecontinueduntilthepatienthasbeen

freeofsymptomsfor4-6months.Citalopramshouldbewithdrawnslowly:itisadvisedthatthedoseisgradually

reducedover1-2weekperiods(seesection4.4)

Adults:Therecommendedstartingdoseis20mgperday.Ifnecessary,thedosecanbeincreasedupto40mgperday,

dependingontheindividualresponseofthepatient.

Themaximumdoseis60mgperday.

Panicdisorder:

Initialdoseis10mgdaily.Aweeklater,thedoseshouldbeincreasedto20mgdaily.

Theoptimumdosageis20-30mgdaily.Iftheindividualpatient’sresponsetotreatmentisinsufficient,thedosemay

beincreasedgraduallyuptoamaximumof60mgdaily.

Fulltherapeuticresponsemaytakeupto3monthstodevelop.Itmaybenecessarytocontinuetreatmentforseveral

months.

Elderlypatients(>65yearsofage):

Therecommendeddailydoseis20mg.Dependentonindividualpatientresponsethismaybeincreasedtoamaximum

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Childrenandadolescents(<18yearsofage)

Citalopramshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years(seesection4.4).

Reducedhepaticfunction

Astartingdoseof10mgperdayduringthefirst2weeksoftreatmentisrecommendedforpatientswithmildto

moderateliverimpairment.Dependingontheindividualthisresponsemaybeincreasedto30mgperday.Prudence

andextracarefuldosetitrationisadvisedinpatientswithseverelyreducedliverfunction(seesection5.2).

Reducedrenalfunction

Adjustmentofdoseisnotrequiredwhenthepatienthasmildtomoderaterenalimpairment.Cautionisadvisedin

patientswithsevererenalimpairment(creatinineclearancelessthan30mL/min,seesection5.2),becausethereareno

clinicaldataavailableforthisgroupofpatients.

Withdrawalsymptomsseenondiscontinuation

Abruptdiscontinuationshouldbeavoided.Whenstoppingtreatmentwithcitalopram,thedoseshouldbegradually

reducedoveraperiodofatleastonetotwoweeksinordertoreducetheriskofwithdrawalreactions(seesections4.4

and4.8).Ifunacceptablesymptomsoccurfollowingadecreaseinthedoseorupondiscontinuationoftreatment,then

resumingthepreviouslyprescribeddosemaybeconsidered.Subsequently,thephysicianmaycontinuedecreasingthe

dose,butatamoregradualrate.

PoormetabolisersofCYP2C19

InpatientswithknownpoormetabolismofCYP2C19,aninitialdailydoseof10mgforthefirsttwoweeksis

recommended.Dependingontheresultoftreatment,thedosecansubsequentlybeincreasedto20mg(seesection5.2).

MethodofAdministration

Citalopramshouldbeadministeredasasingleoraldose,eitherinthemorningorintheevening.Thetabletscanbe

takenwithorwithoutfood,butwithfluid.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients(seesection6.1).

MAOIs(monoamineoxidaseinhibitors)

Somecasespresentedwithfeaturesresemblingserotoninsyndrome.

CitalopramshouldnotbegiventopatientsreceivingMonoamineOxidaseInhibitors(MAOIs)includingselegilinein

dailydosesexceeding10mg/day.

CitalopramshouldnotbegivenforfourteendaysafterdiscontinuationofanirreversibleMAOIorforthetime

specifiedafterdiscontinuationofareversibleMAOI(RIMA)asstatedintheprescribingtextoftheRIMA.MAOIs

shouldnotbeintroducedforsevendaysafterdiscontinuationofcitalopram(seesection4.5).

Citalopramiscontraindicatedincombinationwithlinezolidunlesstherearefacilitiesforcloseobservationand

monitoringofbloodpressure(seesection4.5).

Citalopramshouldnotbeusedconcomitantlywithpimozide(seealsosection4.5).

4.4Specialwarningsandprecautionsforuse

Treatmentofelderlypatientsandpatientswithreducedrenalandhepaticfunction,seesection4.2.

Useinchildrenandadolescentsunder18yearsofage

Citalopramshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years.Suiciderelated

behaviours(suicideattemptandsuicidalthoughts),andhostility(predominantlyaggression,oppositionalbehaviourand

anger)weremorefrequentlyobservedinclinicaltrialsamongchildrenandadolescentstreatedwithantidepressants

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If,basedonclinicalneed,adecisiontotreatisneverthelesstaken,thepatientshouldbecarefullymonitoredforthe

appearanceofsuicidalsymptoms.

Inaddition,long-termsafetydatainchildrenandadolescentsconcerninggrowth,maturationandcognitiveand

behaviouraldevelopmentarelacking.

Suicide/suicidalthoughtsorclinicalworsening

Depressionisassociatedwithanincreasedriskofsuicidalthoughts,selfharmandsuicide(suicide-relatedevents).This

riskpersistsuntilsignificantremissionoccurs.

Asimprovementmaynotoccurduringthefirstfewweeksormoreoftreatment,patientsshouldbecloselymonitored

untilsuchimprovementoccurs.Itisgeneralclinicalexperiencethattheriskofsuicidemayincreaseintheearlystages

ofrecovery.

Otherpsychiatricconditionsforwhichcitalopramisprescribedcanalsobeassociatedwithanincreasedriskofsuicide-

relatedevents.Inaddition,theseconditionsmaybeco-morbidwithmajordepressivedisorder.Thesameprecautions

observedwhentreatingpatientswithmajordepressivedisordershouldthereforebeobservedwhentreatingpatients

withotherpsychiatricdisorders.

Patientswithahistoryofsuicide-relatedevents,orthoseexhibitingasignificantdegreeofsuicidalideationpriorto

commencementoftreatmentareknowntobeatgreaterriskofsuicidalthoughtsorsuicideattempts,andshouldreceive

carefulmonitoringduringtreatment.Ameta-analysisofplacebo-controlledclinicaltrialsofantidepressantdrugsin

adultpatientswithpsychiatricdisordersshowedanincreasedriskofsuicidalbehaviourwithantidepressantscompared

toplaceboinpatientslessthan25yearsold.

Closesupervisionofpatientsandinparticularthoseathighriskshouldaccompanydrugtherapyespeciallyinearly

treatmentandfollowingdosechanges.Patients(andcaregiversofpatients)shouldbealertedabouttheneedtomonitor

foranyclinicalworsening,suicidalbehaviourorthoughtsandunusualchangesinbehaviourandtoseekmedicaladvice

immediatelyifthesesymptomspresent.

Paradoxicalanxiety

Somepatientswithpanicdisordermayexperienceintensifiedanxietysymptomsatthestartoftreatmentwith

antidepressants.Thisparadoxicalreactionusuallysubsideswithinthefirsttwoweeksofstartingtreatment.Alow

startingdoseisadvisedtoreducethelikelihoodofaparadoxicalanxiogeniceffect(seesection4.2).

Hyponatraemia

Hyponatraemia,probablyduetoinappropriateantidiuretichormonesecretion(SIADH),hasbeenreportedasarare

adversereactionwiththeuseofSSRIsandgenerallyreverseondiscontinuationoftherapy.Elderlyfemalepatients

seemtobeatparticularlyhighrisk.

Akathisia/psychomotorrestlessness

Theuseofcitalopramhasbeenassociatedwiththedevelopmentofakathisia,characterisedbyasubjectivelyunpleasant

ordistressingrestlessnessandneedtomoveoftenaccompaniedbyaninabilitytositorstandstill.Thisismostlikelyto

occurwithinthefirstfewweeksoftreatment.Inpatientswhodevelopthesesymptoms,increasingthedosemaybe

detrimental.

Mania

Inpatientswithmanic-depressiveillnessachangetowardsthemanicphasemayoccur.Shouldthepatiententera

manicphasecitalopramshouldbediscontinued.

Seizures

Seizuresareapotentialriskwithantidepressantdrugs.Citalopramshouldbediscontinuedinanypatientwhodevelops

seizures.Citalopramshouldbeavoidedinpatientswithunstableepilepsyandpatientswithcontrolledepilepsyshould

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Diabetes

Inpatientswithdiabetes,treatmentwithaSSRImayalterglycaemiccontrol.Insulinand/ororalhypoglycaemicdosage

mayneedtobeadjusted.

Serotoninsyndrome

Inrarecases,serotoninsyndromehasbeenreportedinpatientsusingSSRIs.Acombinationofsymptomssuchas

agitation,tremor,myoclonus,aidhyperthermiamayindicatethedevelopmentofthiscondition.Treatmentwith

citalopramshouldbediscontinuedimmediatelyandsymptomatictreatmentinitiated.

Serotonergicmedicines

Citalopramshouldnotbeusedconcomitantlywithmedicinalproductswithserotonergiceffectssuchassumatriptanor

othertriptans,tramadol,oxitriptan,andtryptophan.

Haemorrhage

Therehavebeenreportsofprolongedbleedingtimeand/orbleedingabnormalitiessuchasecchymoses,gynaecological

haemorrhages,gastrointestinalbleedings,andothercutaneousormucousbleedingswithSSRIs(seesection4.8).

CautionisadvisedinpatientstakingSSRIs,particularlywithconcomitantuseofactivesubstancesknowntoaffect

plateletfunctionorotheractivesubstancesthatcanincreasetheriskofhaemorrhage,aswellasinpatientswitha

historyofbleedingdisorders(seesection4.5).

ECT(electroconvulsivetherapy)

Thereislimitedclinicalexperienceofconcurrentadministrationofcitalopram;thereforecautionisadvisable.

Reversible,selectiveMAO-Ainhibitors

ThecombinationofcitalopramwithMAO-Ainhibitorsisgenerallynotrecommendedduetotheriskofonsetofa

serotoninsyndrome(seesection4.5).

Forinformationonconcomitanttreatmentwithnon-selective,irreversibleMAOinhibitorsseesection4.5.

St.John'sWort

UndesirableeffectsmaybemorecommonduringconcomitantuseofcitalopramandherbalpreparationscontainingSt.

John'swort(Hypericumperforatum).ThereforecitalopramandSt.John'swortpreparationsshouldnotbetaken

concomitantly(seesection4.5).

WithdrawalsymptomsseenondiscontinuationofSSRItreatment

Withdrawalsymptomswhentreatmentisdiscontinuedarecommon,particularlyifdiscontinuationisabrupt(see

section4.8).Inarecurrencepreventionclinicaltrialwithcitalopram,adverseeventsafterdiscontinuationofactive

treatmentwereseenin40%ofpatientsversus20%inpatientscontinuingcitalopram.

Theriskofwithdrawalsymptomsmaybedependentonseveralfactorsincludingthedurationanddoseoftherapyand

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

insomniaandintensedreams),agitationoranxiety,nauseaand/orvomiting,tremor,confusion,sweating,headache,

diarrhoea,palpitations,emotionalinstability,irritability,andvisualdisturbancesarethemostcommonlyreported

reactions.Generallythesesymptomsaremildtomoderate,however,insomepatientstheymaybesevereinintensity.

Theyusuallyoccurwithinthefirstfewdaysofdiscontinuingtreatment,buttherehavebeenveryrarereportsofsuch

symptomsinpatientswhohaveinadvertentlymissedadose.

Generallythesesymptomsareself-limitingandusuallyresolvewithin2weeks,thoughinsomeindividualstheymay

beprolonged(2-3monthsormore).Itisthereforeadvisedthatcitalopramshouldbegraduallytaperedwhen

discontinuingtreatmentoveraperiodofseveralweeksormonths,accordingtothepatient'sneeds(see“Withdrawal

SymptomsSeenonDiscontinuationofSSRI”,Section4.2).

Psychosis

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QTprolongation

Elevatedlevelsofaminormetaboliteofcitalopram(didemethylcitalopram)couldtheoreticallyprolongtheQTinterval

insusceptiblepatients,patientswithsuspectedcongenitallyprolongedQTsyndromeorinpatientswith

hypokalaemia/hypomagnesiaemia.ECGmonitoringmaybeadvisableincaseofoverdoseorconditionsofaltered

metabolismwithincreasedpeaklevels,e.g.liverimpairment.

Excipients

Thetabletscontainlactosemonohydrate.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnotreceivethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Pharmacodynamicinteractions

Atthepharmacodynamiclevelcasesofserotoninsyndromewithcitalopramandmoclobemideandbuspironehave

beenreported.

Contraindicatedcombinations

MAO-inhibitors

ThesimultaneoususeofcitalopramandMAO-inhibitorscanresultinsevereundesirableeffects,includingthe

serotoninsyndrome(seesection4.3).

CasesofseriousandsometimesfatalreactionshavebeenreportedinpatientsreceivinganSSRIincombinationwitha

monoamineoxidaseinhibitor(MAOI),includingtheirreversibleMAOIselegilineandthereversibleMAOIslinezolid

andmoclobemideandinpatientswhohaverecentlydiscontinuedandSSRIandhavebeenstartedonaMAOI.

Somecasespresentedwithfeaturesresemblingserotoninsyndrome.

SymptomsofanactivesubstanceinteractionwithaMAOIinclude:agitation,tremor,myoclonus,andhyperlhermia.

Pimozide

Co-administrationofasingledoseofpimozide2mgtosubjectstreatedwithracemiccitalopram40mg/dayfor11days

causedanincreaseinAUCandCmaxofpimozide,althoughnotconsistentlythroughoutthestudy.Theco-

administrationofpimozideandcitalopramresultedinameanincreaseintheQTcintervalofapproximately10msec.

Duetotheinteractionnotedatalowdoseofpimozide,concomitantadministrationofcitalopramandpimozideis

contraindicated.

Combinationsrequiringprecautionforuse

Selegiline(selectiveMAO-Binhibitor)

Apharmacokinetic/pharmacodynamicinteractionstudywithconcomitantlyadministeredcitalopram(20mgdaily)

andselegiline(10mgdaily)(aselectiveMAO-Binhibitor)demonstratednoclinicallyrelevantinteractions.The

concomitantuseofcitaloprarnandselegiline(indosesabove10mgdaily)isnotrecommended.

Serotonergicmedicinalproducts

LithiumandtryptophanNopharmacodynamicinteractionshavebeenfoundinclinicalstudiesinwhichcitalopramhas

beengivenconcomitantlywithlithium.HowevertherehavebeenreportsofenhancedeffectswhenSSRIshavebeen

givenwithlithiumortryptophanandthereforetheconcomitantuseofcitalopramwiththesemedicinalproductsshould

beundertakenwithcaution.Routinemonitoringoflithiumlevelsshouldbecontinuedasusual.

Co-administrationwithserotonergicmedicinalproducts(e.g.tramadol,sumatriptan)mayleadtoenhancementof5-HT

associatedeffects.

Untilfurtherinformationisavailable,thesimultaneoususeofcitalopramand5-HTagonists,suchassumatriptanand

othertriptans,isnotrecommended(seesection4.4).

St.John'sWort

DynamicinteractionsbetweenSSRIsandherbalremedySt.John'swort(Hypericumperforatum)canoccur,resultingin

anincreaseinundesirableeffects(seesection4.4).

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Haemorrhage

Cautioniswarrantedforpatientswhoarebeingtreatedsimultaneouslywithanticoagulants,medicinalproductsthat

affecttheplateletfunction,suchasnonsteroidalanti-inflammatorydrugs(NSAIDs),acetylsalicylicacid,dipyridamol,

andticlopidineorothermedicines(e.g.atypicalantipsychotics,phenothiazines,tricyclicdepressants)thatcanincrease

theriskofhaemorrhage(seesection4.4).

ECT(electroconvulsivetherapy)

Therearenoclinicalstudiesestablishingtherisksorbenefitsofthecombineduseofelectroconvulsivetherapy(ECT)

andcitalopram(seesection4.4).

Alcohol

Nopharmacodynamicorpharmacokineticinteractionshavebeendemonstratedbetweencitalopramandalcohol.

However,thecombinationofcitalopramandalcoholisnotadvisable.

MedicinalproductsinducingQTprolongationorhypokalaemia/hypomagnesaemia

CautioniswarrantedforconcomitantuseofotherQTintervalprolongingmedicinesor

hypokalaemia/hypomagnesaemiainducingdrugsasthey,likecitalopram,potentiallyprolongtheQTinterval.

Medicinalproductsloweringtheseizurethreshold

SSRIscanlowertheseizurethreshold.Cautionisadvisedwhenconcomitantlyusingothermedicinalproductscapable

ofloweringtheseizurethreshold(e.g.antidepressants[tricyclics,SSRIs],neuroleptics[phenothiazines,thioxanthenes,

andbutyrophenones]),mefloquin,bupropionandtramadol).

Desipramine,imipramine

Inapharmacokineticstudynoeffectwasdemonstratedoneithercitalopramorimipraminelevels,althoughthelevelof

desipramine,theprimarymetaboliteofimipraminewasincreased.Whendesipramineiscombinedwithcitalopram,an

increaseofthedesipramineplasmaconcentrationhasbeenobserved.Areductionofthedesipraminedosemaybe

needed.

Neuroleptics

Experiencewithcitalopramhasnotrevealedanyclinicallyrelevantinteractionswithneuroleptics.However,aswith

otherSSRIs,thepossibilityofapharmacodynamicinteractioncannotbeexcluded.

Pharmacokineticinteractions

BiotransformationofcitalopramtodemethylcitalopramismediatedbyCYP2C19(approx.38%),CYP3A4(approx.

31%)andCYP2D6(approx.31%)isozymesofthecytochromeP450system.Thefactthatcitalopramismetabolisedby

morethanoneCYPmeansthatinhibitionofitsbiotransformationislesslikelyasinhibitionofoneenzymemaybe

compensatedbyanother.Thereforeco-administrationofcitalopramwithothermedicinalproductsinclinicalpractice

hasverylowlikelihoodofproducingpharmacokineticmedicinalproductinteractions.

Food

Theabsorptionandotherpharmacokineticpropertiesofcitalopramhavenotbeenreportedtobeaffectedbyfood.

Influenceofothermedicinalproductsonthepharmacokineticsofcitalopram

Co-administrationwithketoconazole(potentCYP3A4inhibitor)didnotchangethepharmacokineticsofcitalopram.

Apharmacokineticinteractionstudyoflithiumandcitalopramdidnotrevealanypharmacokineticinteractions(seealso

above).

Cimetidine

Cimetidine,aknownenzyme-inhibitor,causedaslightriseintheaveragesteady-statecitalopramlevels.Cautionis

thereforerecommendedwhenadministeringhighdosesofcitalopramincombinationwithhighdosesofcimetidine.

Co-administrationofescitalopram(theactiveenantiomerofcitalopram)withomeprazole30mgoncedaily(a

CYP2C19inhibitor)resultedinmoderate(approximately50%)increaseintheplasmaconcentrationsofescitalopram.

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

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Areductioninthedoseofcitaloprammaybenecessarybasedonmonitoringofundesirableeffectsduringconcomitant

treatment.

Metoprolol

Escitalopram(theactiveenantiomerofcitalopram)isaninhibitoroftheenzymeCYP2D6.Cautionisrecommended

whencitalopramisCo-administeredwithmedicinalproductsthataremainlymetabolisedbythisenzyme,andthathave

anarrowtherapeuticindex,e.g.flecainide,propafenoneandmetoprolol(whenusedincardiacfailure),orsomeCNS

actingmedicinalproductsthataremainlymetabolisedbyCYP2D6,e.g.antidepressantssuchasdesipramine,

clomipramineandnortriptylineorantipsychoticslikerisperidone,thioridazineandhaloperidol.Dosageadjustmentmay

bewarranted.Co-administrationwithmetoprololresultedinatwofoldincreaseintheplasmalevelsofmetoprolol,but

didnotstatisticallysignificantincreasetheeffectofmetoprololonthebloodpressureandcardiacrhythm.

Effectsofcitalopramonothermedicinalproducts

Apharmacokinetic/pharmacodynamicinteractionstudywithconcomitantadministrationofcitalopramandmetoprolol

(aCYP2D6substrate)showedatwofoldincreaseinmetoprololconcentrations,butnostatisticallysignificantincrease

intheeffectofmetoprololonbloodpressureandheartrateinhealthyvolunteers.

CitalopramanddemethylcitalopramarenegligibleinhibitorsofCYP2C9,CYP2E1andCYP3A4,andonlyweak

inhibitorsofCYPlA2,CYP2C19andCYP2D6ascomparedtootherSSRIsestablishedassignificantinhibitors.

Levomepromazine,digoxin,carbamazepine

Thusnochangeoronlyverysmallchangesofnoclinicalimportancewereobservedwhencitalopramwasgivenwith

CYP1A2substrates(clozapineandtheophylline),CYP2C9(warfarin),CYP2C19(imipramineandmephenytoin),

CYP2D6(sparteine,imipramine,amitriptyline,risperidone)andCYP3A4(warfarin,carbamazepine(anditsmetabolite

carbamazepineepoxid)andtriazolam).

Nopharmacokineticinteractionwasobservedbetweencitalopramandlevomepromazine,ordigoxin,(indicatingthat

citalopramneitherinducenorinhibitPglycoprotein).

4.6Fertility,pregnancyandlactation

Pregnancy

Alargeamountofdataonpregnantwomen(morethan2500exposedoutcomes)indicatenomalformativefeto/neonatal

toxicity.Citalopramcanbeusedduringpregnancyifclinicallyneeded,takingintoaccounttheaspectsmentioned

below.

Neonatesshouldbeobservedifmaternaluseofcitalopramcontinuesintothelaterstagesofpregnancy,particularinthe

thirdtrimester.Abruptdiscontinuationshouldbeavoidedduringpregnancy.

ThefollowingsymptomsmayoccurintheneonatesaltermaternalSSRI/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,particularinlatepregnancy,mayincreasethe

riskofpersistentpulmonaryhypertensioninthenewborn(PPHN).Theobservedriskwasapproximately5casesper

1000pregnancies.Inthegeneralpopulation1to2casesofPPHNper1000pregnanciesoccur.

Lactation

Citalopramisexcretedintobreastmilk.Itisestimatedthatthesuckinginfantwillreceiveabout5%oftheweight

relatedmaternaldailydose(inmg/kg).Nooronlyminoreventshavebeenobservedintheinfants.However,the

existinginformationisinsufficientforassessmentoftherisktothechild.Cautionisrecommended.

4.7Effectsonabilitytodriveandusemachines

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Psychoactivemedicinalproductscanreducetheabilitytomakejudgementsandtoreacttoemergencies.Patients

shouldbeinformedoftheseeffectsandbewarnedthattheirabilitytodriveacaroroperatemachinerycouldbe

affected.

4.8Undesirableeffects

Adverseeffectsobservedwithcitalopramareingeneralmildandtransient.Theyaremostfrequentduringthefirstone

ortwoweeksoftreatmentandusuallyattenuatesubsequently.TheadversereactionsarepresentedattheMedDRA

PreferredTermLevel.

Forthefollowingreactionsadose-responsewasdiscovered:Sweatingincreased,drymouth,insomnia,somnolence,

diarrhoea,nauseaandfatigue.

ThetableshowsthepercentageofadversedrugreactionsassociatedwithSSRIsand/orcitalopramseenineither 1%

ofpatientsindouble-blindplacebo-controlledtrialsorinthepost-marketingperiod.Frequenciesaredefinedas:very

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

(1/10000),notknown(cannotbeestimatedfromavailabledata).

MedDRASOC Frequency Preferredterm

Bloodand

lymphatic

disorders Notknown Thrombocytopenia

Immunesystem

disorders Notknown Hypersensitivity,anaphylacticreaction

Endocrine

disorders Notknown InappropriateADHsecretion

Metabolismand

nutrition

disorders Common Appetitedecreased,weightdecreased

Uncommon Increasedappetite,weightincreased

Rare Hyponatremia

Notknown Hypokalaemia

Psychiatric

disorders Common Agitation,libidodecreased,anxiety,

nervousness,confusionalstate,abnormal

orgasm(female),abnormaldreams

Uncommon Aggression,depersonalization,

hallucination,mania

Notknown Panicattack,bruxism,restlessness,

suicidalideation,suicidalbehaviour 2

Nervoussystem

disorders Verycommon Somnolence,insomnia

Common Tremor,paraesthesia,dizziness,

disturbanceinattention

Uncommon Syncope

Rare Convulsiongrandmal,dyskinesia,taste

disturbance

Notknown Convulsions,serotoninsyndrome,

extrapyramidaldisorder,akathisia,

movementdisorder

Eyedisorders Uncommon Mydriasis

Notknown Visualdisturbance

Earandlabyrinth

disorders Common Tinnitus

Cardiacdisorders Uncommon Bradycardia,tachycardia

Notknown QT-prolongation 1

Vascular

disorders Rare Haemorrhage

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Numberofpatients:Citalopram/placebo=1346/545

1CasesofQT-prolongationhavebeenreportedduringthepost-marketingperiod,predominantlyinpatientswith

preexistingcardiacdisease

2Casesofsuicidalideationandsuicidalbehaviourshavebeenreportedduringcitalopramtherapyorearlyafter

treatmentdiscontinuation(seesection4.4).

Thefollowingadditionaladverseeventshavealsobeenreportedinclinicaltrials:

Verycommon:Headache,asthenia,sleepdisorder.

Common:Migraine,palpitation,tasteperversion,impairedconcentration,amnesia,anorexia,apathy,dyspepsia,

abdominalpain,flatulence,increasedsalivations,rhinitis.

Rare:Increasedlibido,coughing,malaise.

Classeffects

Epidemiologicalstudies,mainlyconductedinpatients50yearsofageandolder,showanincreasedriskofbone

fracturesinpatientsreceivingSSRIsandTCAs.Themechanismleadingtothisriskisunknown.

WithdrawalsymptomsseenondiscontinuationofSSRItreatment

Discontinuationofcitalopram(particularlywhenabrupt)commonlyleadstowithdrawalsymptoms.Dizziness,sensory

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

nauseaand/orvomiting,tremor,confusion,sweating,headache,diarrhoea,palpitations,emotionalinstability,

irritability,andvisualdisturbancesarethemostcommonlyreportedreactions.Generallytheseeventsaremildto

Respiratory

thoracicand

mediastinal

disorders Common Yawning

Notknown Epistaxis

Gastrointestinal

disorders Verycommon Drymouth,nausea

Common Diarrhoea,vomiting,constipation

Notknown Gastrointestinalhaemorrhage(including

rectalhaemorrhage)

Hepatobiliary

disorders Rare Hepatitis

Notknown Liverfunctiontestabnormal

Skinand

subcutaneous

tissuedisorders Verycommon Sweatingincreased

Common Pruritus

Uncommon Urticaria,alopecia,rash,purpura,

photosensitivityreaction

Notknown Ecchymosis,angioedemas

Musculoskeletal,

connectivetissue

andbone

disorders Common Myalgia,arthralgia

Renaland

urinarydisorders Uncommon Urinaryretention

Reproductive

systemandbreast

disorders Common Impotence,ejaculationdisorder,

ejaculationfailure

Uncommon Female:Menorrhagia

Notknown Female:Metrorrhagia;Male:Priapism,

galactorrhoea

Generaldisorders

administration

siteconditions Common Fatigue

Uncommon Oedema

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ItisthereforeadvisedthatwhenCitalopramtreatmentisnolongerrequired,gradualdiscontinuationbydosetapering

shouldbecarriedout(seesection4.2PosologyandMethodofAdministrationandsection4.4SpecialWarningsand

SpecialPrecautionsforuse).

4.9Overdose

Toxicity

Comprehensiveclinicaldataoncitalopramoverdosearelimitedandmanycasesinvolveconcomitantoverdosesof

otherdrugs/alcohol.Fatalcasesofcitalopramoverdosehavebeenreportedwithcitalopramalone;however,the

majorityoffatalcaseshaveinvolvedoverdosewithconcomitantmedications.

Symptoms

Thefollowingsymptomshavebeenseeninreportedoverdoseofcitalopram:

convulsion,tachycardia,somnolence,QTprolongation,coma,vomiting,tremor,hypotension,cardiacarrest,nausea,

serotoninsyndrome,agitation,bradycardia,dizziness,bundlebranchblock,QRSprolongation,hypertension,

mydriasis,torsadedepointes,stupor,sweating,cyanosis,hyperventilation,andatrialandventriculararrhythmia.

Treatment

Thereisnoknownspecificantidotetocitalopram.Treatmentshouldbesymptomaticandsupportive.Activated

charcoal,osmoticallyworkinglaxative(suchassodiumsulphate)andstomachevacuationshouldbeconsidered.If

consciousnessisimpairedthepatientshouldbeintubated.ECGandvitalsignsshouldbemonitored.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antidepressant,Selectiveserotoninreuptakeinhibitors

ATC-code:N06AB04

Tolerancetotheinhibitoryeffectofcitalopramon5-HTuptakedoesnotoccurduringlong-termtreatment.

Theantidepressanteffectisprobablyconnectedwiththespecificinhibitionofserotoninuptakeinthebrainneurons.

Citalopramhasalmostnoeffectontheneuronaluptakeofnoradrenaline,dopamineandgamma-aminobutyricacid.

Citalopramshowsnoaffinity,oronlyverylittle,forcholinergic,histaminergicandavarietyofadrenergic,serotonergic

anddopaminergicreceptors.

Citalopramisabi-cyclicisobenzophurane-derivativethatischemicallynotrelatedtotricyclicandtetracyclic

antidepressantsorotheravailableantidepressants.Themainmetabolitesofcitalopramarealsoselectiveserotonin

uptakeinhibitors,thoughtoalesserdegree.Themetabolitesarenotreportedtocontributetotheoverallantidepressant

effect.

5.2Pharmacokineticproperties

Absorption:

Citalopramisrapidlyabsorbedfollowingoraladministration:themaximumplasmaconcentrationisreachedon

averageafter4(1-7)hours.Absorptionisindependentoffoodintake.Oralbioavailabilityisapproximately80%.

Distribution:

Theapparentdistributionvolumeis12-17l/kg.Theplasma-proteinbindingofcitalopramanditsmetabolitesisbelow

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Bio-transformation:

Citalopramismetabolisedintodemethylcitalopram,didemethylcitalopram,citalopram-N-oxideandthedeaminated

propionicacid-derivative.Thepropionicacid-derivativeispharmacologicallyinactive.Demethylcitalopram,

didemethylcitalopramandcitalopram-N-oxideareselectiveserotoninuptakeinhibitors,althoughweakerthanthe

parentcompound.

ThemainmetabolisingenzymeisCYP2C19.SomecontributionfromCYP3A4andCYP2D6ispossible.

Elimination:

Theplasmahalf-lifeisapproximately1.5days.Aftersystemicadministration,theplasmaclearanceisapproximately

0.3-0.4l/minandafteroraladministrationtheplasmaclearanceisapproximately0.4l/min.

Citalopramismainlyeliminatedviatheliver(85%),butalsopartly(15%)viathekidneys.Ofthequantityof

citalopramadministered,12-23%iseliminatedunalteredviatheurine.Hepaticclearanceisapproximately0.3l/min

andrenalclearanceis0.05-0.08l/min.

Steady-stateconcentrationsarereachedafter1-2weeks.Alinearrelationshiphasbeendemonstratedbetweenthe

steady-stateplasmalevelandthedoseadministered.

Atadoseof40mgperday,anaverageplasmaconcentrationofapproximately300nmol/lisreached.Thereisnoclear

relationshipbetweencitalopramplasmalevelsandtherapeuticresponseorundesirableeffects.

Specialpopulations

Elderlypatients(65years):

Longerhalf-livesanddecreasedclearancevaluesduetoareducedrateofmetabolismhavebeendemonstratedin

elderlypatients.

Reducedhepaticfunction:

Citalopramiseliminatedmoreslowlyinpatientswithreducedhepaticfunction.Thehalf-lifeofcitalopramisabout

twiceaslongandsteadystatecitalopramconcentrationsatagivendosewillbeabouttwiceashighasinpatientswith

normalliverfunction.

Reducedrenalfunction:

Inpatientswithamildlytomoderatelyreducedrenalfunctionalongerhalf-lifeandasmallincreaseintheexposureof

citalopramhasbeenobserved.Citalopramiseliminatedmoreslowly,withoutanimportanteffectonthe

pharmacokineticsofcitalopram.Thereisnoinformationavailableaboutthepharmacokineticsinpatientssuffering

fromseriouskidneyfunctiondysfunction.

Polymorphism:

SlowmetabolisersofCYP2C19havebeenobservedtohaveplasmaconcentrationsofescitalopramtwiceashighas

thoseofrapidmetabolisers.NosignificantalterationinexposurehasbeenobservedinslowmetabolisersofCYP2D6

(seesection4.2).

5.3Preclinicalsafetydata

Preclinicaldatarevealnospecialhazardforhumans.Thesedataarefromconventionalstudiesofsafetypharmacology,

genotoxicityandcarcinogenicpotential.

Phospholipidosishasbeenobservedinvariousorgansfollowingmultipledosingofrats.Theeffectwasreversibleafter

discontinuation.Accumulationofphospholipidshasbeenobservedinlong-termanimalstudieswithmanycation-

amphophilicdrugs.Theclinicalrelevancethisisnotclear.

Reproductivetoxicitystudiesinratshaveshownskeletalabnormalitiesinoffspring,butnoincreasedfrequencyof

malformations.Theseeffectscanrelatedtothepharmacologicaleffect,butcanalsobecausedbymaternaltoxicity.

Peri-andpostnatalstudieshaveadecreasedsurvivaloftheoffspringduringlactationdemonstrated.Thepotentialrisk

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Lactosemonohydrate

Maizestarch

Copovidone

Croscarmellosesodium

Cellulosemicrocrystalline

Magnesiumstearate

Tabletfilmcoat:

OpadryWhite03B58902contains

Hypromellose

Macrogol400

Titaniumdioxide(E171).

6.2Incompatibilities

Notapplicable.

6.3Shelflife

3years

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

BlisterPack:ClearPVC/PVDCaluminiumblister.

Packagesizes:10,14,20,28,30,50,56,60,84,90,100,112or120tablets.

WhiteopaqueHDPEcontainerwithwhiteopaquepolypropyleneclosure:

20mgtablets:30,100andhospitalpacksof200,250,500and1000tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements

7MARKETINGAUTHORISATIONHOLDER

PfizerHealthcareIreland

9Riverwalk

NationalDigitalPark

CitywestBusinessCampus

Dublin24

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8MARKETINGAUTHORISATIONNUMBER

PA822/34/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:16September2011

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