CITALOPRAM

Main information

  • Trade name:
  • CITALOPRAM Film Coated Tablet 10 Milligram
  • Dosage:
  • 10 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CITALOPRAM Film Coated Tablet 10 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1063/017/001
  • Authorization date:
  • 04-02-2005
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Citalopram10mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each10mgtabletcontains:

10mgCitalopram(ashydrobromide)

Excipients:Eachtabletcontains11.55mgofanhydrouslactose.

Forafulllistofexcipientsseesection6.1

3PHARMACEUTICALFORM

Film-coatedtablet.

Citalopram10mgtabletsareround,whitefilmcoated,embossed'B'ononesideand'46'onthereverse.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofdepressiveillnessintheinitialphaseandasmaintenanceagainstpotentialrelapse/recurrence.

Citalopramtabletsisalsoindicatedinthetreatmentofpanicdisorderwithorwithoutagoraphobia

4.2Posologyandmethodofadministration

TreatingDepression

Citalopramshouldbeadministeredasasingleoraldoseof20mgdaily.Dependentonindividualpatientresponsethis

maybeincreasedtoamaximumof60mgdaily.Thedosemaybetakeninthemorningoreveningwithoutregardfor

food.

Atreatmentperiodofatleast6monthsisusuallynecessarytoprovideadequatemaintenanceagainstthepotentialfor

relapse.

PanicDisorder

Patientsshouldbestartedon10mg/dayandthedosegraduallyincreasedin10mgstepsaccordingtothepatient’s

responseuptotherecommendeddose.Therecommendeddoseis20-30mgdaily.Alowinitialstartingdoseis

recommendedtominimisethepotentialworseningofpanicsymptoms,whichisgenerallyrecognisedtooccurearlyin

thetreatmentofthisdisorder.Althoughtheremaybeanincreasedpotentialforundesirableeffectsathigherdoses,if

aftersomeweeksontherecommendeddoseinsufficientresponseisseensomepatientsmaybenefitfromhavingtheir

doseincreasedgraduallyuptoamaximumof60mg/day.(seesection5.1).Dosageadjustmentsshouldbemademore

carefullyonanindividualpatientbasis,tomaintainthepatientsatthelowesteffectivedose.

Patientswithpanicdisordershouldbetreatedforasufficientperiodtoensurethattheyarefreefromsymptoms.This

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Elderlypatients

Treatmentofmajordepressiveepisodes

Therecommendeddailydoseis20mg.Thedosemaybeincreasedtoamaximumof40mgperdaydependingon

individualresponse.

Treatmentofpanicdisorder

Therecommendeddailydoseis10mg.Dependentonindividualpatientresponsethismaybeincreasedtoamaximum

of40mgdaily.

Children

Citalopramtabletsshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years.Referto

section4.4SpecialwarningsandSpecialprecautionsforuse.

Reducedhepaticfunction

Dosageshouldberestrictedtothelowerendofthedoserange.

Reducedrenalfunction

Dosageadjustmentisnotnecessaryincasesofmildormoderaterenalimpairment.Noinformationisavailableincases

ofsevererenalimpairment(creatinineclearance<20mL/min).

Withdrawalsymptomsseenondiscontinuationofcitalopram

Abruptdiscontinuationshouldbeavoided.Whenstoppingtreatmentwithcitalopramthedoseshouldbegradually

reducedoveraperiodofatleasttwoweeksinordertoreducetheriskofwithdrawalreactions(seesection4.4Special

WarningsandSpecialPrecautionsforUseandsection4.8UndesirableEffects).Ifintolerablesymptomsoccur

followingadecreaseinthedoseorupondiscontinuationoftreatment,thenresumingthepreviouslyprescribeddose

maybeconsidered.Subsequently,thephysicianmaycontinuedecreasingthedose,butatamoregradualrate.

Methodofadministration

Citalopramtabletsareadministeredasasingledailydose.Citalopramtabletscanbetakenanytimeofthedaywithout

regardtofoodintake.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients(seesection6.1).

MAOIs(monoamineoxidaseinhibitors)

Somecasespresentedwithfeaturesresemblingserotoninsyndrome.SymptomsofadruginteractionwithaMAOIinclude:

hyperthermia,rigidity,myoclonus,autonomicinstabilitywithpossiblerapidfluctuationsofvitalsigns,mentalstatuschangesthat

includeconfusion,irritabilityandextremeagitationprogressingtodeliriumandcoma.

CitalopramshouldnotbegiventopatientsreceivingMonoamineOxidaseInhibitors(MAOIs)includingselegilineindailydoses

exceeding10mg/day.

CitalopramshouldnotbegivenforfourteendaysafterdiscontinuationofanirreversibleMAOIorforthetimespecifiedafter

discontinuationofareversibleMAOI(RIMA)asstatedintheprescribingtextoftheRIMA.MAOIsshouldnotbeintroducedfor

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Citalopramiscontraindicatedinthecombinationwithlinezolidunlesstherearefacilitiesforcloseobservationandmonitoringof

bloodpressure(seesection4.5).

Citalopramshouldnobeusedconcomitantlywithpimozide(seealsosection4.5).

4.4Specialwarningsandprecautionsforuse

Treatmentofelderlypatientsandpatientswithreducedkidneyandliverfunction,seesection4.2.

Useinchildrenandadolescentsunder18yearsofage

Antidepressantsshouldnotbeusedinthetreatmentofchildrenandadolescentsunderageof18years.Suiciderelatedbehaviours

(suicideattemptandsuicidalthoughts),andhostility(predominantlyaggression,oppositionalbehaviourandanger)weremore

frequentlyobservedinclinicaltrialsamongchildrenandadolescentstreatedwithantidepressantscomparedtothosetreatedwith

placebo.If,basedonclinicalneed,adecisiontotreatisneverthelesstaken,thepatientshouldbecarefullymonitoredforthe

appearanceofsuicidalsymptoms.Inaddition,long-termsafetydatainchildrenandadolescentsconcerninggrowth,maturation

andcognitiveandbehaviouraldevelopmentarelacking.

Paradoxicalanxiety

Somepatientswithpanicdisordermayexperienceintensifiedanxietysymptomsatthestartoftreatmentwithantidepressants.

Thisparadoxicalreactionusuallysubsideswithinthefirsttwoweeksofstartingtreatment.Alowstartingdoseisadvisedto

reducethelikelihoodofaparadoxicalanxiogeniceffect(seesection4.2).

Hyponatraemia

Hyponatraemia,probablyduetoinappropriateantidiuretichormonesecretion(SIADH),hasbeenreportedasarareadverse

reactionwiththeuseofSSRIsandgenerallyreverseondiscontinuationoftherapy.Elderlyfemalepatientsseemtobeat

particularlyhighrisk.

Suicide/suicidalthoughtsorclinicalworsening

Depressionisassociatedwithanincreasedriskofsuicidalthoughts,selfharmandsuicide(suicide-relatedevents).Thisrisk

persistsuntilsignificantremissionoccurs.Asimprovementmaynotoccurduringthefirstfewweeksormoreoftreatment,

patientsshouldbecloselymonitoreduntilsuchimprovementoccurs.Itisgeneralclinicalexperiencethattheriskofsuicidemay

increaseintheearlystagesofrecovery.

OtherpsychiatricconditionsforwhichCitalopramTabletsisprescribedcanalsobeassociatedwithanincreasedriskof

suicide-relatedevents.Inaddition,theseconditionsmaybeco-morbidwithmajordepressivedisorder.Thesameprecautions

observedwhentreatingpatientswithmajordepressivedisordershouldthereforebeobservedwhentreatingpatientswithother

psychiatricdisorders.

Patientswithahistoryofsuicide-relatedevents,orthoseexhibitingasignificantdegreeofsuicidalideationpriorto

commencementoftreatmentareknowntobeatgreaterriskofsuicidalthoughtsorsuicideattempts,andshouldreceivecareful

monitoringduringtreatment.Ameta-analysisofplacebo-controlledclinicaltrialsofantidepressantdrugsinadultpatientswith

psychiatricdisordersshowedanincreasedriskofsuicidalbehaviourwithantidepressantscomparedtoplaceboinpatientslessthan

25yearsold.

Closesupervisionofpatientsandinparticularthoseathighriskshouldaccompanydrugtherapyespeciallyinearlytreatmentand

followingdose changes.Patients(andcaregiversofpatients)shouldbealertedabouttheneedtomonitorforanyclinical

worsening,suicidalbehaviourorthoughtsandunusualchangesinbehaviourandtoseekmedicaladviceimmediatelyifthese

symptomspresent.

Akathisia/psychomotorrestlessness

TheuseofSSRIs/SNRIshasbeenassociatedwiththedevelopmentofakathisia,characterisedbyasubjectivelyunpleasantor

distressingrestlessnessandneedtomoveoftenaccompaniedbyaninabilitytositorstandstill.Thisismostlikelytooccurwithin

thefirstfewweeksoftreatment.Inpatientswhodevelopthesesymptoms,increasingthedosemaybedetrimental.

Mania

Inpatientswithmanic-depressiveillnessachangetowardsthemanicphasemayoccur.Shouldthepatiententeramanicphase

citalopramshouldbediscontinued.

Seizures

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Citalopramshouldbeavoidedin patientswithunstableepilepsyandpatientswithcontrolledepilepsyshouldbecarefully

monitored.Citalopramshouldbediscontinuedifthereisanincreaseinseizurefrequency.

Diabetes

Inpatientswithdiabetes,treatmentwithanSSRImayalterglycaemiccontrol.Insulinand/ororalhypoglycaemicdosagemay

needtobeadjusted.

Serotoninsyndrome

Inrarecases,serotoninsyndromehasbeenreportedinpatientsusingSSRIs.Acombinationofsymptomssuchasagitation,

tremor,myoclonus,andhyperthermiamayindicatethedevelopmentofthiscondition.Treatmentwithcitalopramshouldbe

discontinuedimmediatelyandsymptomatictreatmentinitiated.

Serotonergicmedicines

Citalopramshouldnotbeusedconcomitantlywithmedicinalproductswithserotonergiceffectssuchassumatriptanorother

triptans,tramadol,oxitriptan,andtryptophan.

Haemorrhage

Therehavebeenreportsofprolongedbleedingtimeand/orbleedingabnormalitiessuchasecchymoses,gynaecological

haemorrhages,gastrointestinalbleedings,andothercutaneousormucousbleedingswithSSRIs(seesection4.8).Caution

isadvisedinpatientstakingSSRIs,particularlywithconcomitantuseofactivesubstancesknowntoaffectplateletfunctionor

otheractivesubstancesthatcanincreasetheriskofhaemorrhage,aswellasinpatientswithahistoryofbleedingdisorders(see

section4.5).

ECT(electroconvulsivetherapy)

ThereislimitedclinicalexperienceofconcurrentadministrationofSSRIsandECT;thereforecautionisadvisable.

Reversible,selectiveMAO-Ainhibitors

ThecombinationofcitalopramwithMAO-Ainhibitorsisgenerallynotrecommendedduetotheriskofonsetofaserotonin

syndrome(seesection4.5).

Forinformationonconcomitanttreatmentwithnon-selective,irreversibleMAO-inhibitorsseesection4.5.

St.John´sWort

UndesirableeffectsmaybemorecommonduringconcomitantuseofcitalopramandherbalpreparationscontainingStJohn’swort

(Hypericumperforatum).ThereforecitalopramandStJohn’swortpreparationsshouldnotbetakenconcomitantly(seesection

4.5).

WithdrawalsymptomsseenondiscontinuationofSSRItreatment

Withdrawalsymptomswhentreatmentisdiscontinuedarecommon,particularlyifdiscontinuationisabrupt(seesection4.8).Ina

recurrencepreventionclinicaltrialwithcitalopram,adverseeventsafterdiscontinuationofactivetreatmentwereseenin40%of

patientsversus20%inpatientscontinuingcitalopram.

Theriskofwithdrawalsymptomsmaybedependentonseveralfactorsincludingthedurationanddoseoftherapyandtherateof

dosereduction.Dizziness,sensorydisturbances(includingparaesthesia),sleepdisturbances(includinginsomniaandintense

dreams),agitationoranxiety,nauseaand/orvomiting,tremor,confusion,sweating,headache,diarrhoea,palpitations,emotional

instability,irritability,andvisualdisturbancesarethemostcommonlyreportedreactions.Generallythesesymptomsaremildto

moderate,however,insomepatientstheymaybesevereinintensity.

Theyusuallyoccurwithinthefirstfewdaysofdiscontinuingtreatment,buttherehavebeenveryrarereportsofsuchsymptomsin

patientswhohaveinadvertentlymissedadose.

Generallythesesymptomsareself-limitingandusuallyresolvewithin2weeks,thoughinsomeindividualstheymaybeprolonged

(2-3monthsormore).Itisthereforeadvisedthatcitalopramshouldbegraduallytaperedwhendiscontinuingtreatmentovera

periodofseveralweeksormonths,accordingtothepatient’sneeds(see“WithdrawalSymptomsSeenonDiscontinuationof

SSRI,Section4.2).

Psychosis

Treatmentofpsychoticpatientswithdepressiveepisodesmayincreasepsychoticsymptoms.

QTprolongation

Elevatedlevelsofasidemetabolite(didemethylcitalopram)cantheoreticallyprolongtheQTintervalinpatientspredisposed,

patientswithcongenitallyprolongedQTsyndromeorinpatientswithhypokalaemia/hypomagnesiaemia.ECGmonitoringmaybe

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Excipients

Thetabletscontainlactosemonohydrate.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactase

deficiencyorglucose-galactosemalabsorptionshouldnotreceivethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Pharmacodynamicinteractions

Atthepharmacodynamiclevelcasesofserotoninsyndromewithcitalopramandmoclobemideandbuspironehavebeenreported.

Contraindicatedcombinations

MAO-inhibitors

ThesimultaneoususeofcitalopramandMAO-inhibitorscanresultinsevereundesirableeffects,includingtheserotoninsyndrome

(seesection4.3).

CasesofseriousandsometimesfatalreactionshavebeenreportedinpatientsreceivinganSSRIincombinationwithamonoamine

oxidaseinhibitor(MAOI),includingtheirreversibleMAOIselegilineandthereversibleMAOIslinezolidandmoclobemideand

inpatientswhohaverecentlydiscontinuedandSSRIandhavebeenstartedonaMAOI.

Somecasespresentedwithfeaturesresemblingserotoninsyndrome.SymptomsofanactivesubstanceinteractionwithaMAOI

include:agitation,tremor,myoclonus,andhyperthermia.

Pimozide

Coadministrationofasingledoseofpimozide2mgtosubjectstreatedwithracemiccitalopram40mg/dayfor11dayscausedan

increaseinAUCandCmaxofpimozide,althoughnotconsistentlythroughoutthestudy.Theco-administrationofpimozideand

citalopramresultedinameanincreaseintheQTcintervalofapproximately10msec.Duetotheinteractionnotedatalowdose

ofpimozide,concomitantadministrationofcitalopramandpimozideiscontraindicated.

Combinationsrequiringprecautionforuse

Selegiline(selectiveMAO-Binhibitor)

Apharmacokinetic/pharmacodynamicinteractionstudywithconcomitantlyadministeredcitalopram(20mgdaily)andselegiline

(10mgdaily)(aselectiveMAO-Binhibitor)demonstratednoclinicallyrelevantinteractions.Theconcomitantuseofcitalopram

andselegiline(indosesabove10mgdaily)isnotrecommended.

Serotonergicmedicinalproducts

Lithiumandtryptophan

Nopharmacodynamicinteractionshavebeenfoundinclinicalstudiesinwhichcitalopramhasbeengivenconcomitantlywith

lithium.HowevertherehavebeenreportsofenhancedeffectswhenSSRIshavebeengivenwithlithiumortryptophanand

thereforetheconcomitantuseofcitalopramwiththesemedicinalproductsshouldbeundertakenwithcaution.Routinemonitoring

oflithiumlevelsshouldbecontinuedasusual.

Coadministrationwithserotonergicmedicinalproducts(e.g.tramadol,sumatriptan)mayleadtoenhancementof5-HTassociated

effects.

Untilfurtherinformationisavailable,thesimultaneoususeofcitalopramand5-HTagonists,suchassumatriptanandother

triptans,isnotrecommended(seesection4.4).

St.John’sWort

DynamicinteractionsbetweenSSRIsandherbalremedyStJohn’swort(Hypericumperforatum)canoccur,resultinginan

increaseinundesirableeffects(seesection4.4).Pharmacokineticinteractionshavenotbeeninvestigated.

Haemorrhage

Cautioniswarrantedforpatientswhoarebeingtreatedsimultaneouslywithanticoagulants,medicinalproductsthataffectthe

plateletfunction,suchasnonsteroidalanti-inflammatorydrugs(NSAIDs),acetylsalicylicacid,dipyridamol,andticlopidineor

othermedicines(e.g.atypicalantipsychotics,phenothiazines,tricyclicdepressants)thatcanincreasetheriskofhaermorrhage(see

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ECT(electroconvusivetherapy)

Therearenoclinicalstudiesestablishingtherisksorbenefitsofthecombineduseofelectroconvulsivetherapy(ECT)and

citalopram(seesection4.4).

Alcohol

Nopharmacodynamicorpharmacokineticinteractionshavebeendemonstratedbetweencitalopramandalcohol.However,the

combinationofcitalopramandalcoholisnotadvisable.

MedicinalproductsinducingQTprolongationorhypokalaemia/hypomagnesaemia

CautioniswarrantedforconcomitantuseofotherQTintervalprolongingmedicinesorhypokalaemia/hypomagnesaemiainducing

drugsasthey,likecitalopram,potentiallyprolongtheQTinterval.

Medicinalproductsloweringtheseizurethreshold

SSRIscanlowertheseizurethreshold.Cautionisadvisedwhenconcomitantlyusingothermedicinalproductscapableoflowering

theseizurethreshold(e.g.antidepressants[tricyclics,SSRIs],neuroleptics[phenothiazines,thioxanthenes,andbutyrophenones]),

mefloquin,bupropionandtramadol).

Desipramine,imipramine

Inapharmacokineticstudynoeffectwasdemonstratedoneithercitalopramorimipraminelevels,althoughthelevelof

desipramine,theprimarymetaboliteofimipraminewasincreased.Whendesipramineiscombinedwithcitalopram,anincreaseof

thedesipramineplasmaconcentrationhasbeenobserved.Areductionofthedesipraminedosemaybeneeded.

Neuroleptics

Experiencewithcitalopramhasnotrevealedanyclinicallyrelevantinteractionswithneuroleptics.However,aswithotherSSRIs,

thepossibilityofapharmacodynamicinteractioncannotbeexcluded

Pharmacokineticinteractions

BiotransformationofcitalopramtodemethylcitalopramismediatedbyCYP2C19(approx.38%),CYP3A4(approx.31%)and

CYP2D6(approx.31%)isozymesofthecytochromeP450system.ThefactthatcitalopramismetabolisedbymorethanoneCYP

meansthatinhibitionofitsbiotransformationislesslikelyasinhibitionofoneenzymemaybecompensatedbyanother.Therefore

co-administrationofcitalopramwithothermedicinalproductsinclinicalpracticehasverylowlikelihoodofproducing

pharmacokineticmedicinalproductinteractions.

Food

Theabsorptionandotherpharmacokineticpropertiesofcitalopramhavenotbeenreportedtobeaffectedbyfood.

Influenceofothermedicinalproductsonthepharmacokineticsofcitalopram

Co-administrationwithketoconazole(potentCYP3A4inhibitor)didnotchangethepharmacokineticsofcitalopram.

Apharmacokineticinteractionstudyoflithiumandcitalopramdidnotrevealanypharmacokineticinteractions(seealsoabove).

Cimetidine

Cimetidine,aknownenzyme-inhibitor,causedaslightriseintheaveragesteady-statecitalopramlevels.Cautionistherefore

recommendedwhenadministeringhighdosesofcitalopramincombinationwithhighdosesofcimetidine.Co-administrationof

escitalopram(theactiveenantiomerofcitalopram)withomeprazole30mgoncedaily(aCYP2C19inhibitor)resultedinmoderate

(approximately50%)increaseintheplasmaconcentrationsofescitalopram.Thus,cautionshouldbeexercisedwhenused

concomitantlywithCYP2C19inhibitors(e.g.omeprazole,esomeprazole,fluvoxamine,lansoprazole,ticlopidine)orcimetidine.A

reductioninthedoseofcitaloprammaybenecessarybasedonmonitoringofundesirableeffectsduring concomitant

treatment.

Metoprolol

Escitalopram(theactiveenantiomerofcitalopram)isaninhibitoroftheenzymeCYP2D6.Cautionisrecommendedwhen

citalopramisco-administeredwithmedicinalproductsthataremainlymetabolisedbythisenzyme,andthathaveanarrow

therapeuticindex,e.g.flecainide,propafenoneandmetoprolol(whenusedincardiacfailure),orsomeCNSactingmedicinal

productsthataremainlymetabolisedbyCYP2D6,e.g.antidepressantssuchasdesipramine,clomipramineandnortriptylineor

antipsychoticslikerisperidone,thioridazineandhaloperidol.Dosageadjustmentmaybewarranted.Co-administrationwith

metoprololresultedinatwofoldincreaseintheplasmalevelsofmetoprolol,butdidnotstatisticallysignificantincreasetheeffect

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Effectsofcitalopramonothermedicinalproducts

Apharmacokinetic/pharmacodynamicinteractionstudywithconcomitantadministrationofcitalopramandmetoprolol(a

CYP2D6substrate)showeda twofoldincreaseinmetoprololconcentrations,butnostatisticallysignificantincreaseintheeffect

ofmetoprololonbloodpressureandheartrateinhealthyvolunteers.

CitalopramanddemethylcitalopramarenegligibleinhibitorsofCYP2C9,CYP2E1andCYP3A4,andonlyweakinhibitorsof

CYP1A2,CYP2C19andCYP2D6ascomparedtootherSSRIsestablishedassignificantinhibitors.

Levomepromazine,digoxin,carbamazepine

ThusnochangeoronlyverysmallchangesofnoclinicalimportancewereobservedwhencitalopramwasgivenwithCYP1A2

substrates(clozapineandtheophylline),CYP2C9(warfarin),CYP2C19(imipramineandmephenytoin),CYP2D6(sparteine,

imipramine,amitriptyline,risperidone)andCYP3A4(warfarin,carbamazepine(anditsmetabolitecarbamazepineepoxid)and

triazolam).

Nopharmacokineticinteractionwasobservedbetweencitalopramandlevomepromazine,ordigoxin,(indicatingthatcitalopram

neitherinducenorinhibitP-glycoprotein).

4.6Pregnancyandlactation

Pregnancy

Alargeamountofdataonpregnantwomen(morethan2500exposedoutcomes)indicatenomalformativefeto/neonataltoxicity.

Citalopramcanbeusedduringpregnancyifclinicallyneeded,takingintoaccounttheaspectsmentionedbelow

NeonatesshouldbeobservedifmaternaluseofCitalopramTabletscontinuesintothelaterstagesofpregnancy,particularinthe

thirdtrimester.Abrupt

discontinuationshouldbeavoidedduringpregnancy.

ThefollowingsymptomsmayoccurintheneonatesaftermaternalSSRI/SNRIuseinlaterstagesofpregnancy:respiratory

distress,cyanosis,apnoea,seizures,temperatureinstability,feedingdifficulty,vomiting,hypoglycaemia,hypertonia,hypotonia,

hyperreflexia,tremor,jitteriness,irritability,lethargy,constantcrying,somnolenceanddifficultysleeping.Thesesymptomscould

beduetoeitherserotonergiceffectsordiscontinuationsymptoms.Inamajorityofinstancesthecomplicationsbeginimmediately

orsoon(<24hours)afterdelivery.

EpidemiologicaldatahavesuggestedthattheuseofSSRIsinpregnancy,particularinlatepregnancy,mayincreasetheriskof

persistentpulmonaryhypertensioninthenewborn(PPHN).Theobservedriskwasapproximately5casesper1000pregnancies.

Inthegeneralpopulation1to2casesofPPHNper1000pregnanciesoccur.

Lactation

Citalopramisexcretedintobreastmilk.Itisestimatedthatthesucklinginfantwillreceiveabout5%oftheweightrelated

maternaldailydose(inmg/kg).Nooronlyminoreventshavebeenobservedintheinfants.However,theexistinginformationis

insufficientforassessmentoftherisktothechild.

Cautionisrecommended.

4.7Effectsonabilitytodriveandusemachines

Citalopramhasminorormoderateinfluenceontheabilitytodriveandusemachines.

Psychoactivemedicinalproductscanreducetheabilitytomakejudgementsandtoreacttoemergencies.Patientsshouldbe

informedoftheseeffectsandbewarnedthattheirabilitytodriveacaroroperatemachinerycouldbeaffected.

4.8Undesirableeffects

Adverseeffectsobservedwithcitalopramareingeneralmildandtransient.Theyaremostfrequentduringthefirstone

ortwoweeksoftreatmentandusuallyattenuatesubsequently.Theadversereactionsarepresentedatthe

MedDRAPreferredTermLevel.

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

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ThetableshowsthepercentageofadversedrugreactionsassociatedwithSSRIs and/orcitalopramseenineither ≥

1%ofpatientsindouble-blindplacebo-controlled trialsorinthepost-marketingperiod.Frequenciesaredefinedas:

verycommon( ≥1/10);common(≥1/100,<1/10);uncommon(≥1/1000,≤1/100);rare(≥1/10000,≤1/1000);very

rare( ≤1/10000),notknown(cannotbeestimatedfromavailabledata).

MedDRASOC Frequency PreferredTerm

Bloodandlymphatic

disorders NotKnown Thrombocytopenia

Immunesystem

disorders NotKnown Hypersensitivity,anaphylacticreaction

Endocrinedisorders NotKnown InappropriateADHsecretion

Metabolismand

nutritiondisorders Common Appetitedecreased ,

weightdecreased

Uncommon Increasedappetite,weightincreased

Rare Hyponatremia

NotKnown Hypokalaemia

Psychiatricdisorders Common Agitation,libidodecreased,anxiety,

nervousness,confusionalstate,abnormal

orgasm(female),abnormaldreams

Uncommon Aggression,depersonalization,hallucination,

mania

NotKnown Panicattack,bruxism,restlessness,suicidal

ideation,suicidalbehaviour 2

Nervoussystem

disorders Verycommon Somnolence,insomnia

Common Tremor,paraesthesia,dizziness,disturbancein

attention

Uncommon Syncope

Rare Convulsiongrandmal,dyskinesia,taste

disturbance

NotKnown Convulsions,serotoninsyndrome,

extrapyramidaldisorder,akathisia,movement

disorder

Eyedisorders Uncommon Mydriasis

NotKnown Visualdisturbance

Earandlabyrinth

disorders Common Tinnitus

Cardiacdisorders Uncommon Bradycardia,tachycardia

NotKnown QT-prolongation 1

Vasculardisorders Rare Haemorrhage

NotKnown Orthostatichypotension

Respiratorythoracicand

mediastinaldisorders Common Yawning

NotKnown Epistaxis

Gastrointestinal

disorders Verycommon Drymouth,Nausea

Common Diarrhoeavomiting,Constipation

NotKnown

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Numberofpatients:Citalopram/placebo=1346/545

CasesofQT-prolongationhavebeenreportedduringthepost-marketingperiod,predominantlyinpatientswithpre-

existingcardiacdisease

Casesofsuicidalideationandsuicidalbehaviourshavebeenreportedduringcitalopramtherapyorearlyafter

treatmentdiscontinuation(seesection4.4).

Classeffects

Epidemiologicalstudies,mainlyconductedinpatients50yearsofageandolder,showanincreasedriskofbone

fracturesinpatientsreceivingSSRIsandTCAs(Tricyclicanti-depressants).Themechanismleadingtothisriskis

unknown.

WithdrawalsymptomsseenondiscontinuationofSSRItreatment

DiscontinuationofCitalopram(particularlywhenabrupt)commonlyleadstowithdrawalsymptoms.Dizziness,sensory

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

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

irritability,andvisualdisturbancesarethemostcommonlyreportedreactions.Generallytheseeventsaremildto

moderateandareself-limiting,however,insomepatientstheymaybesevereand/orprolonged.Itisthereforeadvised

thatwhencitalopramtreatmentisnolongerrequired,gradualdiscontinuationbydosetaperingshouldbecarriedout

(seesection4.2Posology andMethodofAdministrationandsection4.4SpecialWarningsandSpecialPrecautions

foruse).

4.9Overdose

Toxicity

Comprehensiveclinicaldataoncitalopramoverdosearelimitedandmanycasesinvolveconcomitantoverdosesof

otherdrugs/alcohol.Fatalcasesofcitalopramoverdosehavebeenreportedwithcitalopramalone;however,the

haemorrhage)

Hepatobiliarydisorders Rare Hepatitis

NotKnown Liverfunctiontestabnormal

Skinandsubcutaneous

tissuedisorders Verycommon Sweatingincreased

Common Pruritus

Uncommon Urticaria,alopecia,rash,purpura,

photosensitivityreaction

NotKnown Ecchymosis,angioedemas

Musculoskeletal,

connectivetissueand

bonedisorders Common Myalgia,arthralgia

Renalandurinary

disorders Uncommon Urinaryretention

Reproductivesystem

andbreastdisorders Common Impotence,ejaculationdisorder,ejaculation

failure

Uncommon Female:Menorrhagia

NotKnown Female:MetrorrhagiaMale:Priapism,

galactorrhoea

Generaldisordersand

administrationsite

conditions Common Fatigue

Uncommon Oedema

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Symptoms

Thefollowingsymptomshavebeenseeninreportedoverdoseofcitalopram:convulsion,tachycardia,somnolence,QT

prolongation,coma,vomiting,tremor,hypotension,cardiacarrest,nausea,serotoninsyndrome,agitation,

bradycardia,dizziness,bundlebranchblock,QRSprolongation,hypertension,mydriasis,torsadedepointes,stupor,

sweating,cyanosis,hyperventilation,andatrialandventriculararrythmia.

Treatment

Thereisnoknownspecificantidotetocitalopram.Treatmentshouldbesymptomaticandsupportive.Activated

charcoal,osmoticallyworkinglaxative(suchassodiumsulphate)andstomachevacuationshouldbeconsidered.If

consciousnessisimpairedthepatientshouldbeintubated.ECGandvitalsignsshouldbemonitored.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATC-code:N06AB04

Biochemicalandbehaviouralstudieshaveshownthatcitalopramisapotentinhibitorofserotonin(5-HT)-uptake.

Tolerancetotheinhibitionof5-HT-uptakeisnotinducedbylong-termtreatmentwithcitalopram.

CitalopramisthemostSelectiveSerotoninReuptakeInhibitor(SSRI)yetdescribed,withno,orminimal,effecton

noradrenaline(NA),dopamine(DA)andgammaaminobutyricacid(GABA)uptake.

IncontrasttomanytricyclicantidepressantsandsomeofthenewerSSRIs,citalopramhasnoorverylowaffinityfora

seriesofreceptorsincluding5-HT

,5-HT

,DAD

andD

receptors,

-adrenoceptors,histamineH

muscarinecholinergic,benzodiazepine,andopioidreceptors.Aseriesoffunctionalinvitrotestsinisolatedorgansas

wellasfunctionalinvivotestshaveconfirmedthelackofreceptoraffinity.Thisabsenceofeffectsonreceptorscould

explainwhycitalopramproducesfewerofthetraditionalside-effectssuchasdrymouth,bladderandgutdisturbance,

blurredvision,sedation,cardiotoxicityandorthostatichypotension.

Suppressionofrapideyemovement(REM)sleepisconsideredapredictorofantidepressantactivity.Liketricyclic

antidepressants,otherSSRIsandMAOinhibitors,citalopramsuppressesREM-sleepandincreasesdeepslow-wave

sleep.

Althoughcitalopramdoesnotbindtoopioidreceptorsitpotentiatestheanti-nociceptiveeffectofcommonlyused

opioidanalgesics.Therewaspotentiationofd-amphetamine-inducedhyperactivityfollowingadministrationof

citalopram.

ThemainmetabolitesofcitalopramareallSSRIsalthoughtheirpotencyandselectivityratiosarelowerthanthoseof

citalopram.However,theselectivityratiosofthemetabolitesarehigherthanthoseofmanyofthenewerSSRIs.The

metabolitesdonotcontributetotheoverallantidepressanteffect.

Inhumanscitalopramdoesnotimpaircognitive(intellectualfunction)andpsychomotorperformanceandhasnoor

minimalsedativeproperties,eitheraloneorincombinationwithalcohol.

Citalopramdidnotreducesalivaflowinasingledosestudyinhumanvolunteersandinnoneofthestudiesinhealthy

volunteersdidcitalopramhavesignificantinfluenceoncardiovascularparameters.Citalopramhasnoeffectonthe

serumlevelsofprolactinandgrowthhormone.

5.2Pharmacokineticproperties

Absorption

Absorptionisalmostcompleteandindependentoffoodintake(T

average/mean3.8hours).Oralbioavailabilityis

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Distribution

Theapparentvolumeofdistribution(V

isabout12.3L/kg.Theplasmaproteinbindingisbelow80%forcitalopram

anditsmainmetabolites.

Biotransformation

Citalopramismetabolizedtotheactivedemethylcitalopram,didemethylcitalopram,citalopram-N-oxideandaninactive

deaminatedproprionicacidderivative.AlltheactivemetabolitesarealsoSSRIs,althoughweakerthantheparent

compound.Unchangedcitalopramisthepredominantcompoundinplasma.

Elimination

Theeliminationhalf-life(T)isabout1.5daysandthesystemiccitalopramplasmaclearance(Cl

)isabout0.33L/min,

andoralplasmaclearance(Cl

oral )isabout0.41L/min.

Citalopramisexcretedmainlyviatheliver(85%)andtheremainder(15%)viathekidneys.About12%ofthedaily

doseisexcretedinurineasunchangedcitalopram.Hepatic(residual)clearanceisabout0.35L/minandrenalclearance

about0.068L/min.

Thekineticsarelinear.Steadystateplasmalevelsareachievedin1-2weeks.Averageconcentrationsof250nmol/L

(100-500nmol/L)areachievedatadailydoseof40mg.Thereisnoclearrelationshipbetweencitalopramplasma

levelsandtherapeuticresponseorside-effects.

Elderlypatients(>65years)

Longerhalf-livesanddecreasedclearancevaluesduetoareducedrateofmetabolismhavebeendemonstratedin

elderlypatients.

Reducedhepaticfunction

Citalopramiseliminatedmoreslowlyinpatientswithreducedhepaticfunction.Thehalf-lifeofcitalopramisabout

twiceaslongandsteadystatecitalopramconcentrationsatagivendosewillbeabouttwiceashighasinpatientswith

normalliverfunction.

Reducedrenalfunction

Citalopramiseliminatedmoreslowlyinpatientswithmildtomoderatereductionofrenalfunction,withoutanymajor

impactonthepharmacokineticsofcitalopram.Atpresentnoinformationisavailablefortreatmentofpatientswith

severelyreducedrenalfunction(creatinineclearance<20mL/min).

5.3Preclinicalsafetydata

Citalopramhaslowacutetoxicity.Inchronictoxicitystudiestherewerenofindingsofconcernforthetherapeuticuse

ofcitalopram.Basedondatafromreproductiontoxicitystudies(segmentI,IIandIII)thereisnoreasontohavespecial

concernfortheuseofcitalopraminwomenofchild-bearingpotential.Citalopramhasnomutagenicorcarcinogenic

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Microcrystallinecellulose

Lactose,anhydrous

Maizestarch

Copovidone

Glycerol85%

Croscarmellosesodium

Magnesiumstearate

Coating:

Opadry-Y-I-7000

[titaniumdioxide(E171),

Hypromellose,

Macrogol400]

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

3years

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

6.5Natureandcontentsofcontainer

BlisterpackscomposedofPVC/PVdCandaluminiumfoil.

Packsizes:10,12,14,20,28,30,50,56,98,100and250tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements

7MARKETINGAUTHORISATIONHOLDER

NicheGenericsLtd

1TheCamCentre

WilburyWay

Hitchin,Herts

SG40TW

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8MARKETINGAUTHORISATIONNUMBER

PA1063/17/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:04February2005

Dateoflastrenewal:19September2008

10DATEOFREVISIONOFTHETEXT

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