CITALOPRAM

Main information

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

Documents

Localization

  • Available in:
  • CITALOPRAM Film Coated Tablet 20 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1063/017/002
  • Authorization date:
  • 04-02-2005
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Citalopram20mgTablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each20mgtabletcontains:

20mgcitalopram(ashydrobromide)

Excipients:Eachtabletcontains23.10mgofanhydrouslactose.

Forafulllistofexcipientsseesection6.1

3PHARMACEUTICALFORM

Film-coatedtablet.

Citalopram20mgtabletsareovalwhitefilmcoatedembossed'B'and'8'oneithersideofabreaklineononesideand

plainonthereverse.Thescorelineisonlytofacilitatebreakingforeaseofswallowingandnottodivideintoequal

doses.

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

sevendaysafterdiscontinuationofcitalopram(seesection4.5).

Citalopramiscontraindicatedinthecombinationwithlinezolidunlesstherearefacilitiesforcloseobservationandmonitoringof

bloodpressure(seesection4.5).

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4.4Specialwarningsandprecautionsforuse

Treatmentofelderlypatientsandpatientswithreducedkidneyandliverfunction,seesection4.2.

Useinchildrenandadolescentsunder18yearsofage

Antidepressantsshouldnotbeusedinthetreatmentofchildrenandadolescentsunderageof18years.Suiciderelatedbehaviours

(suicideattemptandsuicidalthoughts),andhostility(predominantlyaggression,oppositionalbehaviourandanger)weremore

frequentlyobservedinclinicaltrialsamongchildrenandadolescentstreatedwithantidepressantscomparedtothosetreatedwith

placebo.

If,basedonclinicalneed,adecisiontotreatisneverthelesstaken,thepatientshouldbecarefullymonitoredfortheappearanceof

suicidalsymptoms.

Inaddition,long-termsafetydatainchildrenandadolescentsconcerninggrowth,maturationandcognitiveandbehavioural

developmentarelacking.

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

followingdosechanges.Patients(andcaregiversofpatients)shouldbealertedabouttheneedtomonitorforanyclinical

worsening,suicidalbehaviourorthoughtsandunusualchangesinbehaviourandtoseekmedicaladviceimmediatelyifthese

symptomspresent.

Akathisia/psychomotorrestlessness

TheuseofSSRIs/SNRIshasbeenassociatedwiththedevelopmentofakathisia,characterisedbyasubjectivelyunpleasantor

distressingrestlessnessandneedtomoveoftenaccompaniedbyaninabilitytositorstandstill.Thisismostlikelytooccurwithin

thefirstfewweeksoftreatment.Inpatientswhodevelopthesesymptoms,increasingthedosemaybedetrimental.

Mania

Inpatientswithmanic-depressiveillnessachangetowardsthemanicphasemayoccur.Shouldthepatiententeramanicphase

citalopramshouldbediscontinued.

Seizures

Seizuresareapotentialriskwithantidepressantdrugs.Citalopramshouldbediscontinuedinanypatientwhodevelopsseizures.

Citalopramshouldbeavoidedinpatientswithunstableepilepsyandpatientswithcontrolledepilepsyshouldbecarefully

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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).Cautionis

advisedinpatientstakingSSRIs,particularlywithconcomitantuseofactivesubstancesknowntoaffectplateletfunctionorother

activesubstancesthatcanincreasetheriskofhaemorrhage,aswellasinpatientswithahistoryofbleedingdisorders(seesection

4.5).

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.Symptomsof anactivesubstanceinteractionwithaMAOI

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

section4.4).

ECT(electroconvusivetherapy)

Therearenoclinicalstudiesestablishingtherisksorbenefitsofthecombineduseofelectroconvulsivetherapy(ECT)and

citalopram(seesection4.4).

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Nopharmacodynamicorpharmacokineticinteractionshavebeendemonstratedbetweencitalopramandalcohol.However,the

combinationofcitalopramandalcoholisnotadvisable.

MedicinalproductsinducingQTprolongationorhypokalaemia/hypomagnesaemia

CautioniswarrantedforconcomitantuseofotherQTintervalprolongingmedicinesorhypokalaemia/hypomagnesaemiainducing

drugsasthey,like citalopram,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.

Areductioninthedoseofcitaloprammaybenecessarybasedonmonitoringofundesirableeffectsduring 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

ofmetoprololonthebloodpressureandcardiacrhythm.

Effectsofcitalopramonothermedicinalproducts

Apharmacokinetic/pharmacodynamicinteractionstudywithconcomitantadministrationofcitalopramandmetoprolol(a

CYP2D6substrate)showeda twofoldincreaseinmetoprololconcentrations,butnostatisticallysignificantincreaseintheeffect

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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.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

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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 Gastrointestinalhaemorrhage(includingrectal

haemorrhage)

Hepatobiliarydisorders Rare Hepatitis

NotKnown Liverfunctiontestabnormal

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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

(seesection4.2PosologyandMethodofAdministrationandsection4.4SpecialWarningsandSpecialPrecautionsfor

use).

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,

Skinandsubcutaneous

tissuedisorders 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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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

about80%.

Distribution

Theapparentvolumeofdistribution(V

isabout12.3L/kg.Theplasmaproteinbindingisbelow80%forcitalopram

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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

potential.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Microcrystallinecellulose

Lactose,anhydrous

Maizestarch

Copovidone

Glycerol85%

Croscarmellosesodium

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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

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA1063/17/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:04February2005

Dateoflastrenewal:19September2008

10DATEOFREVISIONOFTHETEXT

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