BELLCITAL

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0408/061/001
  • Authorization date:
  • 25-02-2005
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Bellcital10mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilmcoatedtabletcontains12.5mgofcitalopramhydrobromideequivalentto10mgcitalopram.

EachtabletalsocontainsLactosemonohydrate

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Whitetooff-whitecircularbiconvexfilm-coatedtablet,debossedwith“10”ononesideandplainontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Majordepressiveepisodes.

Panicdisorderwithorwithoutagoraphobia.

4.2Posologyandmethodofadministration

BellcitalTabletsareadministeredasasingledailydose.BellcitalTabletscanbetakenanytimeofthedaywithout

regardtofoodintakebutwithfluid.

Adults

Majordepressiveepisodes:Citalopramshouldbeadministeredasasingleoraldoseof20mgdaily.Ifnecessary,the

dosecanbeincreasedgraduallyby10mg.Dependentonindividualpatientresponse,thismaybeincreasedtoa

maximumof40-60mgdaily.Followingtreatmentinitiation,anantidepressanteffectshouldnotbeexpectedforat

leasttwoweeks.Atreatmentdurationofatleast4-6monthsisusuallynecessarytoprovideadequatemaintenance

againstthepotentialforrelapse.

Panicdisorder:Asingledoseof10mgperdayforthefirstweekisrecommended;afterthisthedosemaybe

increasedto20mgperday.Thedosemaycontinuetobeincreasedtoamaximumdoseof40-60mgperday

dependingonindividualpatientresponse.Maximumeffectisreachedafter3months.Dependentonindividualpatient

responseitmaybenecessarytocontinuetreatmentforseveralmonths.

Elderlypatients(>65yearsold)

TreatmentofMajorDepressiveEpisodes

ForElderlypatientsthedoseshouldbereducedto10–20mgdaily,dependingonindividualpatientresponsethismay

beincreasedtoamaximumof30-40mgdaily.

TreatmentofPanicDisorder

Theinitialdoseis10mgoncedaily,afteroneweekthedosemaybeincreasedto20mgdaily.Dependingonindividual

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Childrenandadolescentsundertheageof18

Notrecommended,assafetyandefficacyhavenotbeenestablishedinthispopulation.

Reducedhepaticfunction

Patientswithhepaticimpairmentshouldreceiveastartingdoseof10mg/day.Thedoseshouldnotexceed30mgfor

patientswithhepaticimpairment.Thesepatientsshouldbeclinicallymonitored.

Reducedrenalfunction

Dosageadjustmentisnotnecessaryincasesofmildormoderaterenalimpairment.Sincetherearenoadequatedata,

useofCitalopraminpatientswithsevererenalfailure(creatinineclearancebelow20ml/min)isnotrecommended.

Citalopramshouldbewithdrawnslowly.Itisadvisedthatthedoseisgraduallyreducedover1-2weekperiods.

4.3Contraindications

Citalopramiscontraindicatedinpatientswithhypersensitivitytotheactivesubstance,Citalopramortoanyofthe

excipients(seesection6.1).

Monoamineoxidaseinhibitors

Citalopramshouldnotbeusedincombinationwithamonoamineoxidaseinhibitors(MAOI).Citalopramshouldnotbe

giventopatientsreceivingMAOIsincludingselegilineindailydosesexceeding10mg/day.

Casesofseriousandsometimesfatalreactionshavebeenreportedinpatientsreceivingaselectiveserotoninreuptake

inhibitor(SSRI)incombinationwithMAOI,includingtheselectiveMAOIselegilineandthereversibleMAOI

(RIMA),moclobemideandinpatientswhohaverecentlydiscontinuedanSSRIandhavebeenstartedonaMAOI.

Somecasespresentedwithfeaturesresemblingserotoninsyndrome.SymptomsofadruginteractionwithaMAOI

include:hyperthermia,rigidity,myoclonus,autonomicinstabilitywithpossiblerapidfluctuationsofvitalsigns,mental

statuschangesthatincludeconfusion,irritabilityandextremeagitationprogressingtodeliriumandcoma.

CitalopramshouldnotbegivenforfourteendaysafterdiscontinuingtreatmentwithanirreversibleMAOIorforthe

timespecifiedafterdiscontinuingtreatmentwithareversibleMAOI(RIMA)asstatedintheprescribingtextofthe

RIMA.Atleast7daysshouldelapseafterdiscontinuingcitalopramtreatmentbeforestartingaMAOIorRIMA(see

section4.5).

5-HT-agonists

Sumatriptan’sserotonergiceffectsaresuspectedtobeenhancedbySSRI’s.Untilfurtherevidenceisavailableitis

advisednottousecitalopramsimultaneouslywith5-HTagonistsegSumatriptan.

Citalopramiscontraindicatedinthecombinationwithlinezolidunlesstherearefacilitiesforcloseobservationand

monitoringofbloodpressure(seesection4.5).

Citalopramshouldnotbeusedconcomitantlywithpimozide(ssalsosection4.5).

4.4Specialwarningsandprecautionsforuse

Suicide/suicidalthoughtsorclinicalworsening

Depressionisassociatedwithanincreasedriskofsuicidalthoughts,selfharmandsuicide(suicide-relatedevents).This

riskpersistsuntilsignificantremissionoccurs.

Asimprovementmaynotoccurduringthefirstfewweeksormoreoftreatment,patientsshouldbecloselymonitored

untilsuchimprovementoccurs.Itisgeneralclinicalexperiencethattheriskofsuicidemayincreaseagainintheearly

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OtherpsychiatricconditionsforwhichCitalopramisprescribedcanalsobeassociatedwithanincreasedriskof

suicide-relatedevents.Inaddition,theseconditionsmaybeco-morbidwithmajordepressivedisorder.Thesame

precautionsobservedwhentreatingpatientswithmajordepressivedisordershouldthereforebeobservedwhentreating

patientswithotherpsychiatricdisorders.

Patientswithahistoryofsuicide-relatedevents,orthoseexhibitingasignificantdegreeofsuicidalideationpriorto

commencementoftreatmentareknowntobeatgreaterriskofsuicidalthoughtsorsuicideattempts,andshouldreceive

carefulmonitoringduringtreatment.Ameta-analysisofplacebo-controlledclinicaltrialsofantidepressantdrugsin

adultpatientswithpsychiatricdisordersshowedanincreasedriskofsuicidalbehaviourwithantidepressantscompared

toplaceboinpatientslessthan25yearsold.

Closesupervisionofpatientsandinparticularthoseathighriskshouldaccompanydrugtherapyespeciallyinearly

treatmentandfollowingdosechanges.Patients(andcaregiversofpatients)shouldbealertedabouttheneedtomonitor

foranyclinicalworseningsuicidalbehaviourorthoughtsandunusualchangesinbehaviourandtoseekmedicaladvice

immediatelyifthesesymptomspresent.

Useinchildrenandadolescentsunder18yearsofage

BellcitalTabletsshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years.Suicide-

relatedbehaviours(suicideattemptandsuicidalthoughts),andhostility(predominantlyaggression,oppositional

behaviourandanger)weremorefrequentlyobservedinclinicaltrialsamongchildrenandadolescentstreatedwith

antidepressantscomparedtothosetreatedwithplacebo.If,basedonclinicalneed,adecisiontotreatisnevertheless

taken;thepatientshouldbecarefullymonitoredfortheappearanceofsuicidalsymptoms.

Inaddition,long-termsafetydatainchildrenandadolescentsconcerninggrowth,maturationandcognitiveand

behaviouraldevelopmentarelacking.

Paradoxicalanxiety

Somepatientswithpanicdisordermayexperienceintensifiedanxietysymptomsatthestartoftreatmentwith

antidepressants.Thisparadoxicalreactionusuallysubsideswithinthefirsttwoweeksofstartingtreatment.Alow

startingdoseisadvisedtoreducethelikelihoodofofaparadoxicalanxiogeniceffect(seesection4.2)

Hyponatraemia

Hyponatraemia,probablyduetoinappropriateanti-diuretichormonesecretion(SIADH)hasbeenreportedasarare

adversereactionwiththeuseofSSRIs,andgenerallyreverseondiscontinuationoftherapy.Elderlyfemalepatients

seemtobeatparticularlyhighrisk.

Akathisia/psychomotorrestlessness

TheuseofCitalopramhasbeenassociatedwiththedevelopmentofakathisia,characterisedbyasubjectively

unpleasantordistressingrestlessnessandneedtomoveoftenaccompaniedbyaninabilitytositorstandstill.Thisis

mostlikelytooccurwithinthefirstfewweeksoftreatment.Inpatientswhodevelopthesesymptoms,increasingthe

dosemaybedetrimentalanditmaybenecessarytoreviewtheuseofCitalopram.

Mania

Citalopramshouldbeusedwithcautioninpatientswithahistoryofmania/hypomania.Inpatientswithmanic-

depressiveillnessachangetowardsthemanicphasemayoccur.Citalopramshouldbediscontinuedinanypatient

enteringamanicphase.

Seizures

Seizuresareapotentialriskwithantidepressantdrugs.Citalopramshouldbediscontinuedinanypatientwhodevelops

seizures.Citalopramshouldbeavoidedinpatientswithunstableepilepsyandpatientswithcontrolledepilepsyshould

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Serotoninsyndrome

Inrarecases,aserotoninsyndromehasbeenreportedinpatientsusingSSRIs.Acombinationofsymptoms,suchas

agitation,tremor,myoclonusandhyperthermiamayindicatethedevelopmentofthiscondition.Treatmentwith

citalopramshouldbediscontinuedimmediatelyandsymptomatictreatmentinitiated.

Serotonergicmedicines

Citalopramshouldnotbeusedconcomitantlywithmedicinalproductswithserotonergiceffectssuchastramadol,

tryptophan,oxitriptan,sumatriptanorothertriptans(seesection4.3).

StJohn'sWort

Anincreaseinserotoninergiceffects,suchasserotoninsyndrome,mayoccurwithconcomitantuseofcitalopramand

herbalpreparationscontainingStJohn’swort(Hypericumperforatum).ThereforecitalopramandStJohn'swort

preparationsshouldnotbetakenconcomitantly(seesection4.5).

Psychosis

Treatmentofpsychoticpatientswithdepressiveepisodesmayincreasepsychoticsymptoms

Diabetes

Inpatientswithdiabetes,treatmentwithanSSRImayalterglycaemiccontrol.Insulinand/ororalhypoglycaemic

dosagemayneedtobeadjusted.

Haemorrhage

Therehavebeenreportsofprolongedbleedingtimeand/orbleedingabnormalitiessuchasecchymosesandpurpura,

gynaecologicalhaemorrhages,gastrointestinalbleedingsandothercutaneousormucousbleedingswithSSRIs(see

section4.8).

CautionisadvisedinpatientstakingCitalopram,particularlyinconcomitantusewithoralanticoagulants,active

substancesknowntoaffectplateletfunctionorotheractivesubstancesthatcanincreasetheriskofhaemorrhage(e.g.

atypicalantipsychoticsand

phenothiazines,mosttricyclicantidepressants,acetylsalicylicacid,non-steroidalanti-inflammatorydrugs(NSAIDs),

ticlopidineanddipyridamol,aswellasinpatientswithahistoryofbleedingdisorders(seesection4.5).

ElectroconvulsiveTherapy(ECT)

ThereislimitedclinicalexperienceofconcurrentadministrationofcitalopramandECT,thereforecautionisadvisable.

QTprolongation

Considerationshouldbegiventofactorswhichmayaffectthedispositionofaminormetaboliteofcitalopram

(didemethylcitalopram)sinceincreasedlevelsofthismetabolitecouldtheoreticallyprolongtheQTcintervalinpatients

predisposed,patientswithcongenitallyprolongedQTsyndromeorinpatientswithhypokalaemia/hypomagnesiaemia.

However,inECGmonitoringof2500patientsinclinicaltrials,including277patientswithpre-existingcardiac

conditions,noclinicallysignificantchangeswerenoted.ECGmonitoringmaybeadvisableincaseofoverdoseor

conditionsofalteredmetabolismwithincreasedpeaklevels,e.g.liverimpairment.

MonoamineOxidaseInhibitors(MAOIs)

MAOIsshouldnotbeusedincombinationwithSSRIs(seesection4.3).

Reversible,selectiveMAO-Ainhibitors

ThecombinationofcitalopramwithMAO-Ainhibitorsisgenerallynotrecommendedduetotheriskofonsetofa

serotoninsyndrome(seesection4.5).

Forinformationonconcomitanttreatmentwithnon-selective,irreversibleMAOinhibitorsseesection4.5.

Theuseofcitalopraminpatientswithsevererenalimpairment(creatinineclearancelessthan20ml/min.)isnot

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Incasesofimpairedhepaticfunctiondosereductionisrecommended(seesection4.2)andliverfunctionhastobe

closelymonitored.

WithdrawalsymptomsseenondiscontinuationofCitalopramtreatmentWithdrawalsymptomswhentreatmentis

discontinuedarecommon,particularlyifdiscontinuationisabrupt(seesection4.8).Inarecurrencepreventionclinical

trialwithcitalopram,adverseeventsafterdiscontinuationofactivetreatmentwereseenin40%ofpatientsversus20%

inpatientscontinuingcitalopram.

Theriskofwithdrawalsymptomsmaybedependentonseveralfactorsincludingthedurationanddoseoftherapyand

therateofdosereduction.Dizziness,sensorydisturbance(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

discontinuingtreatmentoveraperiodofseveralweeksormonth,accordingtothepatient’sneeds(see“Withdrawal

SymptomsSeenonDiscontinuationofCitalopram”,section4.2).

Excipients

Thesetabletscontainlactosemonohydrate.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucosegalactosemalabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Pharmacodynamicinteractions

Atthepharmacodynamiclevelcasesofserotoninsyndromewithcitalopramand

moclobemideandbuspironehavebeenreported.

Contraindicatedcombinations

MAO-inhibitors

ThesimultaneoususeofcitalopramandMAO-inhibitorscanresultinsevereundesirableeffects,includingthe

serotoninsyndrome(seesection4.3).

CasesofseriousandsometimesfatalreactionshavebeenreportedinpatientsreceivinganSSRIincombinationwitha

monoamineoxidaseinhibitor(MAOI),includingtheirreversibleMAOIselegilineandthereversibleMAOIslinezolid

andmoclobemideandinpatientswhohaverecentlydiscontinuedanSSRIandhavebeenstartedonaMAOI.

Somecasespresentedwithfeaturesresemblingserotoninsyndrome.Symptomsofanactivesubstanceinteractionwith

aMAOIinclude:agitation,tremor,myoclonus,andhyperthermia.

Pimozide

Coadministrationofasingledoseofpimozide2mgtosubjectstreatedwithracemiccitalopram40mg/dayfor11days

causedanincreaseinAUCandCmaxofpimozide,althoughnotconsistentlythroughoutthestudy.Theco-

administrationofpimozideandcitalopramresultedinameanincreaseintheQTcintervalofapproximately10msec.

Duetotheinteractionnotedatalowdoseofpimozide,concomitantadministrationofcitalopramandpimozideis

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Combinationsrequiringprecautionforuse

Selegiline(selectiveMAO-Binhibitor)

Apharmacokinetic/pharmacodynamicinteractionstudywithconcomitantlyadministeredcitalopram(20mgdaily)

andselegiline(10mgdaily)(aselective

MAO-Binhibitor)demonstratednoclinicallyrelevantinteractions.Theconcomitantuseofcitalopramandselegiline

(indosesabove10mgdaily)isnotrecommended.

Serotonergicmedicinalproducts

Lithiumandtryptophan

Nopharmacodynamicinteractionshavebeenfoundinclinicalstudiesinwhich

citalopramhasbeengivenconcomitantlywithlithium.Howevertherehavebeenreportsofenhancedeffectswhen

SSRIshavebeengivenwithlithiumortryptophanandthereforetheconcomitantuseofcitalopramwiththese

medicinalproductsshouldbeundertakenwithcaution.Routinemonitoringoflithiumlevelsshouldbecontinuedas

usual.

Co-administrationwithserotonergicmedicinalproducts(e.g.tramadol,dextromethorphan,pethidine,tryptophan,

oxitriptan,sumatriptanandothertriptans)mayleadtoenhancementof5-HTassociatedeffects;serotoninsyndrome.In

combinationwithtriptans,thereisapotentialriskofcoronaryvasoconstrictionandhypertensiontoo.Therefore,the

simultaneoususeofcitalopramandtheseactivesubstancesisnotrecommended(seesection4.3).

St.John’sWort

DynamicinteractionsbetweencitalopramandherbalremedyStJohn'sWort

(Hypericumperforatum)canoccur,resultinginanincreaseinundesirableeffects(seesection4.4).Pharmacokinetic

interactionshavenotbeeninvestigated.

Haemorrhage

Cautioniswarrantedforpatientswhoarebeingtreatedsimultaneouslywithoralanticoagulants,medicinalproducts

thataffectplateletfunction,orothermedicinesthatcanincreasetheriskofhaemorrhage(e.g.nonsteroidalanti-

inflammatorydrugs(NSAIDs),acetylsalicylicacid,dipyridamol,ticlopidine,atypicalantipsychotics,phenothiazines,

tricyclicanti-depressants)(seesection4.4).

ECT(electroconvusivetherapy)

Therearenoclinicalstudiesestablishingtherisksorbenefitsofthecombineduseof

electroconvulsivetherapy(ECT)andcitalopram(seesection4.4).

Alcohol

Clinicalstudieshaverevealednopharmacodynamicorpharmacokineticinteractionsbetweencitalopramandalcohol.

However,thecombinationofcitalopramandalcoholisnotadvisable

MedicinalproductsinducingQTprolongationorhypokalaemia/hypomagnesaemia

Caution is warranted for concomitant use of other QT interval prolonging medicines or

hypokalaemia/hypomagnesaemiainducingdrugsasthey,likecitalopram,potentiallyprolongtheQTinterval.

Medicinalproductsloweringtheseizurethreshold

SSRIscanlowertheseizurethreshold.Cautionisadvisedwhenconcomitantlyusingothermedicinalproductscapable

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

andbutyrophenones]),mefloquin,bupropionandtramadol).

Desipramine,imipramine

Inapharmacokineticstudynoaffectwasdemonstratedoneithercitalopramorimipraminelevels,althoughthelevelof

desipramine,theprimarymetaboliteofimipramine,wasincreased.WhendesipramineiscombinedwithCitalopram,an

increaseofthedesipramineplasmaconcentrationhasbeenobserved.Areductionofthedesipraminedosemaybe

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Neuroleptics

Experiencewithcitalopramhasnotrevealedanyclinicallyrelevantinteractionswithneuroleptics.However,aswith

otherSSRIs,thepossibilityofapharmacodynamicinteractioncannotbeexcluded.

Pharmacokineticinteractions

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

31%)andCYP2D6(approx.31%)isozymesofthe

cytochromeP450system.Thefactthatcitalopramismetabolisedbymorethanone

CYPmeansthatinhibitionofitsbiotransformationislesslikelyasinhibitionofoneenzymemaybecompensatedby

another.Proteinbindingisrelativelylow(<80%).

Thereforeco-administrationofcitalopramwithothermedicinalproductsinclinicalpracticehasverylowlikelihoodof

producingpharmacokineticmedicinalproductinteractions.

Food

Theabsorptionandotherpharmacokineticpropertiesofcitalopramhavenotbeenreportedtobeaffectedbyfood.

Influenceofothermedicinalproductsonthepharmacokineticsofcitalopram

Co-administrationwithketoconazole(potentCYP3A4inhibitor)didnotchangethepharmacokineticsofcitalopram.

Apharmacokineticinteractionstudyoflithiumandcitalopramdidnotrevealanypharmacokineticinteractions(see

alsoabove).

Cimetidine

Cimetidine,aknownenzyme-inhibitor,causedaslightriseintheaveragesteady-statecitalopramlevels.Cautionis

thereforerecommendedwhenadministeringhighdosesofcitalopramincombinationwithhighdosesofcimetidine.

Co-administrationofescitalopram(theactiveenantiomerofcitalopram)withomeprazole30mgoncedaily(a

CYP2C19inhibitor)resultedinmoderate(approximately50%)increaseintheplasmaconcentrationsofescitalopram.

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

fluvoxamine,lansoprazole,ticlopidine)orcimetidine.Areductioninthedoseofcitaloprammaybenecessarybasedon

monitoringofundesirableeffectsduringconcomitanttreatment.

Metoprolol

Escitalopram(theactiveenantiomerofcitalopram)isaninhibitoroftheenzymeCYP2D6.Cautionisrecommended

whencitalopramisco-administeredwithmedicinalproductsthataremainlymetabolisedbythisenzyme,andthathave

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

actingmedicinalproductsthataremainlymetabolisedbyCYP2D6,e.g.antidepressantssuchasdesipramine,

clomipramineandnortriptylineorantipsychoticslikerisperidone,thioridazineandhaloperidol.Dosageadjustmentmay

bewarranted.Co-administrationwithmetoprololresultedinatwo-foldincreaseintheplasmalevelsofmetoprolol,but

didnotstatisticallysignificantincreasetheeffectofmetoprololonbloodpressureandcardiacrhythm.

Effectsofcitalopramonothermedicinalproducts

Apharmacokinetic/pharmacodynamicinteractionstudywithconcomitantadministrationofcitalopramandmetoprolol

(aCYP2D6substrate)showedatwofoldincreaseinmetoprololconcentrations,butnostatisticallysignificantincrease

intheeffectofmetoprololonbloodpressureandheartrateinhealthyvolunteers.

CitalopramanddemethylcitalopramarenegligibleinhibitorsofCYP2C9,CYP2E1andCYP3A4,andonlyweak

inhibitorsofCYP1A2,CYP2C19andCYP2D6ascomparedtootherSSRIsestablishedassignificantinhibitors.

Levomepromazine,digoxin,carbamazepine

Thusnochangeoronlyverysmallchangesofnoclinicalimportancewereobservedwhencitalopramwasgivenwith

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

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

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However,sincecarbamazepineisamicrosomalenzymeinducer,thepossibilitythatcarbamazepinemayincreasethe

clearanceofcitalopramshouldbeconsideredifthetwodrugsaregivenconcomitantly.

Nopharmacokineticinteractionwasobservedbetweencitalopramandlevomepromazine,ordigoxin,(indicatingthat

citalopramneitherinducenorinhibitPglycoprotein).

4.6Fertility,pregnancyandlactation

Pregnancy:

Alargeamountofdataonpregnantwomen(morethan2500exposedoutcomes)indicatenomalformativefeto/

neonataltoxicity.Animalstudiesshowedreproductivetoxicity,butdidnotindicatedirectharmfuleffectswithrespect

topregnancy,embryonic/foetaldevelopment,parturitionorpostnataldevelopment(seesection5.3).

Citalopramcanbeusedduringpregnancyifclinicallyneeded,takingintoaccounttheaspectsmentionedbelow.

NeonatesshouldbeobservedifmaternaluseofCitalopramcontinuesintothelaterstagesofpregnancy,particularin

thethirdtrimester.Abruptdiscontinuationshouldbeavoidedduringpregnancy.

ThefollowingsymptomsmayoccurintheneonatesaftermaternalSSRI/SNRIuseinlaterstagesofpregnancy:

respiratorydistress,cyanosis,apnoea,seizures,temperatureinstability,difficultyinsucklingorinsleeping,vomiting,

hypoglycaemia,hypertonia,hypotonia,hyperreflexia,tremor,jitteriness,irritability,lethargy,constantcryingand

somnolence.

Thesesymptomscouldbeduetoeithersertoninergiceffectsorwithdrawalsyndrome.Inamajorityofinstancesthe

complicationsbeginimmediatelyorsoon(<24hours)afterdelivery.

EpidemiologicaldatahavesuggestedthattheuseofSSRIsinpregnancy,particularinlatepregnancy,mayincreasethe

riskofpersistentpulmonaryhypertensioninthenewborn(PPHN).Theobservedriskwasapproximately5casesper

1000pregnancies.Inthegeneralpopulation1to2casesofPPHNper1000pregnanciesoccur.

Breastfeeding:

Citalopramisexcretedintobreastmilk.Itisestimatedthatthesucklinginfantwillreceiveabout5%oftheweight

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

existinginformationisinsufficientforassessmentoftherisktothechild.Cautionisrecommended.

Theadvantagesofbreastfeedingshouldoutweighthepotentialadverseeffectsforthechild.

4.7Effectsonabilitytodriveandusemachines

Citalopramhasminorormoderateinfluenceontheabilitytodriveandusemachines.

Psychoactivemedicinalproductscanreducetheabilitytomakejudgementsandtoreacttoemergencies.Patientswho

areprescribedpsychotropicmedicationmaybeexpectedtohavesomeimpairmentofgeneralattentionand

concentrationeitherduetotheillnessitself,themedicationorbothandshouldbewarnedthattheirabilitytodriveacar

oroperatemachinerycouldbeaffected.

4.8Undesirableeffects

Adverseeffectsobservedwithcitalopramareingeneralmildandtransient.Theyaremostfrequentduringthefirstone

ortwoweeksoftreatmentandusuallyattenuatesubsequently.TheadversereactionsarepresentedattheMedDRA

PreferredTermLevel.

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

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ThelistbelowshowsthepercentageofadversedrugreactionsassociatedwithSSRIsand/orcitalopramseenineither ≥

1%ofpatientsindouble-blindplacebo-controlledtrialsorinthepost-marketingperiod.

Frequenciesaredefinedasfollows:Verycommon( ≥1/10),common(≥1/100,<1/10),uncommon(≥1/1,000,<

1/100),rare( ≥1/10000,<1/1000),veryrare(<1/10000),notknown(cannotbeestimatedfromtheavailabledata)

Bloodandlymphaticsystemdisorders

Notknown:Thrombocytopenia

Immunesystemdisorders

Uncommon:Allergicreactions

Veryrare:Anaphylactoidreactions

Notknown:Hypersensitivity,anaphylacticreaction

Endocrinedisorders

Veryrare:Prolactinaemia

Notknown:InappropriateADHsecretion

Metabolismandnutritiondisorders

Common:Appetitedecreased,weightdecreased

Uncommon:Increasedappetite,weightincreased

Rare:Hyponatremia

Notknown:Hypokalaemia

Psychiatricdisorders

Verycommon:insomnia

Common:Agitation,nervousness,sleepdisorders,abnormalorgasm(female),abnormaldreams,amnesia,anxiety,

decreasedlibido,apathyandconfusion.

Uncommon:Aggression,hallucinations,mania,depersonalisation,euphoriaandincreasedlibido

Notknown:Panicattack(thesesymptomsmaybeduetotheunderlyingdisease),bruxism,restlessness,suicidal

ideation,suicidalbehaviour

Nervoussystemdisorders

Verycommon:Somnolence,headache,dizziness

Common:Migraine,tremor,dizziness,disturbanceinattentionandparaesthesia

Uncommon:Syncope

Rare:Convulsiongrandmal,dyskinesia,tastedisturbance

Notknown:Convulsions,serotoninsyndrome,extrapyramidaldisorder,akathisia,

movementdisorder

Eyedisorders

Verycommon:Abnormalaccommodation

Common:Abnormalitiesofvision

Uncommon:Mydriasis

Notknown:Visualdisturbance

Earandlabyrinthdisorders

Common:tinnitus

Cardiacdisorders

Verycommon:Palpitations

Uncommon:Bradycardia,tachycardia

Veryrare:Supraventricularandventriculararrhythmia

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Vasculardisorders

Common:Hypotension,hypertension

Rare:Haemorrhage

Notknown:Orthostatichypotension

Respiratory,thoracicandmediastinaldisorders

Common:Rhinitis,yawningandsinusitis

Uncommon:Coughing

Notknown:Epistaxis

Gastrointestinaldisorders

Verycommon:Nausea,drymouth

Common:Dyspepsia,diarrhoea,vomiting,constipation,abdominalpain,flatulenceandincreasedsalivation

Notknown:Gastrointestinalhaemorrhage(includingrectalhaemorrhage)

Hepatobiliarydisorders

Rare:Hepatitis

Notknown:Liverfunctiontestabnormal

Skinandsubcutaneoustissuedisorders

Verycommon:Increasedsweating

Common:Pruritus

Uncommon:Urticaria,alopecia,rash,purpura,photosensitivityreaction

Notknown:Ecchymosis,angiodema

Musculoskeletalandconnectivetissuedisorders

Common:Myalgia,arthralgia

Classeffects

Epidemiologicalstudies,mainlyconductedinpatients50yearsofageandolder,showanincreasedriskofbone

fracturesinpatientsreceivingSSRIsandTCAs.Themechanismleadingtothisriskisunknown.

Renalandurinarydisorders

Common:Micturitiondisorderandpolyuria

Uncommon:Urinaryretention

Reproductivesystemandbreastdisorders

Common:Ejaculationfailure,ejaculationdisorder,dysmenorrhoeaandimpotence

Uncommon:Female:Menorrhagia

Notknown:Female:Metrorrhagia,Male:Priapism,galactorrhoea

Generaldisordersandadministrationsiteconditions

Verycommon:Asthenia

Common:Fatigue

Uncommon:Malaise,oedema

Rare:Pyrexia

Numberofpatients:Citalopram/placebo=1346/545

Casesofsuicidalideationandsuicidalbehaviourshavebeenreportedduring

citalopramtherapyorearlyaftertreatmentdiscontinuation(seesection4.4).

CasesofQT-prolongationhavebeenreportedduringthepost-marketingperiod,predominantlyinpatientswithpre-

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Withdrawalsymptomsseenondiscontinuationofcitalopramtreatment

Discontinuationofcitalopram(particularlywhenabrupt)commonlyleadstowithdrawalsymptoms.Dizziness,sensory

disturbance(includeparaesthesia),sleepdisturbance(includinginsomniaandintensedreams),agitationoranxiety,

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

irritability,andvisualdisturbancesarethemostcommonlyreportedreactions.

Generallytheseeventsaremildtomoderateandareself-limiting,however,insomepatientstheymaybesevereand/or

prolonged.Itisthereforeadvisedthatwhencitalopramtreatmentisnolongerrequired,gradualdiscontinuationbydose

taperingshouldbecarriedout(seesections4.2andsection4.4).

4.9Overdose

Toxicity:

Comprehensiveclinicaldataoncitalopramoverdosearelimitedandmanycasesinvolveconcomitantoverdosesof

otherdrugs/alcohol.Citalopramisgiventopatientsatpotentialriskofsuicideandsomereportsofattemptedsuicide

havebeenreceived.

Detailisoftenlackingregardingprecisedose.Fatalcasesofcitalopramoverdosehavebeenreportedwithcitalopram

alone;however,themajorityoffatalcaseshaveinvolvedoverdosewithconcomitantmedications.Fataldoseisnot

known.Patientshavesurvivedingestionofupto2gcitalopram.Theeffectswillbepotentiatedbyalcoholtakenatthe

sametime.PotentialinteractionwithtricyclicantidepressantsandMAOIs.

Symptoms:

Thefollowingsymptomshavebeenseeninreportedoverdoseofcitalopram:Nausea,drowsiness,dystonia,

convulsions,tachycardia,somnolence,QTprolongation,coma,vomiting,tremor,hypotension,cardiacarrest,serotonin

syndrome,agitation,bradycardia,dizziness,bundlebranchblock,QRSprolongation,hypertension,mydriasis,torsade

depointes,stupor,sweating,cyanosis,hyperventilation,hyperpyrexiaandatrialandventriculararrythmia."Serotonin

syndrome"includesalterationofmentalstatus,neuromuscularhyperactivityandautonomicinstability.Theremaybe

hyperpyrexiaandelevationofserumcreatinekinase.Rhabdomyolysisisrare.

Treatment:

Thereisnoknownspecificantidotetocitalopram.Treatmentissymptomaticandsupportive.Iftheamountofmedicine

islargeandingestionveryrecent,gastriclavagecanbeconsidered(ifthepatienthaslostconsciousness,intubation

mustbeperformedfirst).Theuseofactivatedcharcoal,toreducefurtherabsorption,shouldbeconsidered.Speeding

upthepassageusingosmoticallyworkinglaxatives,e.g.,sodiumsulphatecanalsobeconsidered.ECGandvitalsigns

shouldbemonitored.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:SelectiveSerotoninReuptakeInhibitors

ATC-Code:N06AB04,

Biochemicalandbehaviouralstudieshaveshownthatcitalopramisapotentinhibitorofserotonin(5-HT)-uptake.

Tolerancetotheinhibitionof5-HT-uptakeisnotinducedbylong-termtreatmentwithcitalopram.

CitalopramisthemostSelectiveSerotoninReuptakeInhibitor(SSRI)yetdescribed,withno,orminimal,effecton

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IncontrasttomanytricyclicantidepressantsandsomeoftheotherSSRIs,citalopramhasnoorverylowaffinityfora

seriesofreceptorsincluding5-HT

5-HT

,DAD

andD

receptors,

-,-adrenoceptors,histamineH

muscarine,cholinergic,benzodiazepine,andopioidreceptors.Aseriesoffunctionalinvitrotestsinisolatedorgansas

wellasfunctionalinvivotestshaveconfirmedthelackofreceptoraffinity.Thisabsenceofeffectsonreceptorscould

explainwhycitalopramproducesfewerofthetraditionalsideeffectssuchasdrymouth,bladderandgutdisturbance,

blurredvision,sedation,cardiotoxicityandorthostatichypotension.

Suppressionofrapideyemovement(REM)sleepisconsideredapredictorofantidepressantactivity.Liketricyclic

antidepressants,otherSSRIsandMAOinhibitors,citalopramsuppressesREM-sleepandincreasesdeepslow-wave

sleep.

Althoughcitalopramdoesnotbindtoopioidreceptorsitpotentiatestheanti-nociceptiveeffectofcommonlyused

opioidanalgesics.Therewaspotentiationofd-amphetamine-inducedhyperactivityfollowingadministrationof

citalopram.

ThemainmetabolitesofcitalopramareallSSRIsalthoughtheirpotencyandselectivityratiosarelowerthanthoseof

citalopram.However,theselectivityratiosofthemetabolitesarehigherthanthoseofmanyoftheotherSSRIs.The

metabolitesdonotcontributetotheoverallantidepressanteffect.

5.2Pharmacokineticproperties

Absorption

Absorptionofcitalopramisalmostcompleteandindependentoffoodintake(T

average/mean3.8hours).Oral

bioavailabilityisabout80%.

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

)isabout0.33

L/min,andoralplasmaclearance(Cl

oral )isabout0.41L/min.

Citalopramisexcretedmainlyviatheliver(85%)andtheremainder(15%)viathekidneys.About12–23%ofthe

dailydoseisexcretedinurineasunchangedcitalopram.Hepatic(residual)clearanceisabout0.35L/minandrenal

clearanceabout0.068L/min.

Thekineticsarelinear.Steadystateplasmalevelsareachievedin1-2weeks.Averageconcentrationsof250nmol/L

(100-500nmol/L)areachievedatadailydoseof40mg.Thereisnoclearrelationshipbetweencitalopramplasma

levelsandtherapeuticresponseorside-effects.

Elderlypatients(65years)

Longerhalf-livesanddecreasedclearancevaluesduetoareducedrateofmetabolismhavebeendemonstratedin

elderlypatients.

Reducedhepaticfunction

Citalopramiseliminatedmoreslowlyinpatientswithreducedhepaticfunction.Thehalf-lifeofcitalopramisabout

twiceaslongandsteadystatecitalopramconcentrationsatagivendosewillbeabouttwiceashighasinpatientswith

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Reducedrenalfunction

Citalopramiseliminatedmoreslowlyinpatientswithmildtomoderatereductionofrenalfunction,withoutanymajor

impactonthepharmacokineticsofcitalopram.Atpresentnoinformationisavailablefortreatmentofpatientswith

severelyreducedrenalfunction(creatinineclearance<20mL/min).

5.3Preclinicalsafetydata

Inchronictoxicitystudiestherewerenofindingsofconcernforthetherapeuticuseofcitalopram.Citalopramhasno

mutagenicorcarcinogenicpotential.Embryotoxicitystudieshaveshownskeletalanomaliesatmaternaltoxicdoses.

Theeffectsmayberelatedtothepharmacologicalactivityorcouldbeanindirecteffectduetomaternaltoxicity.Peri-

andpostnatalstudieshaverevealedreducedsurvivalinoffspringduringthelactationperiod.Thepotentialriskfor

humansisunknown.

Phospholipidosishasbeenobservedinseveralorgansfollowingmultipleadministrationinrats.Theeffectwas

reversibleatdiscontinuation.Accumulationofphospholipidshasbeenobservedinlongtermanimalstudieswithmany

cation-amphophilicdrugs.Theclinicalrelevanceoftheseresultsisnotclear.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

CoreTablets

Lactosemonohydrate

Microcrystallinecellulose

Maizestarch

Copovidone

Croscarmellosesodium

Magnesiumstearate

FilmCoating

OpadryWhite20H58983

Hypromellose

TitaniumdioxideE171

Propyleneglycol

Hydroxypropylcellulose

Talc

6.2Incompatibilities

Notapplicable.

6.3Shelflife

3years.

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

1,14,20,28,30,50,56,98,100or250filmcoatedtabletsinaPVC/PVdC/Aluminiumblister

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6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

RanbaxyIrelandLimited

Spafield

CorkRoad

Cashel

CoTipperary

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA0408/061/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:25February2005

Dateoflastrenewal:8September2008

10DATEOFREVISIONOFTHETEXT

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