CIPROTAN 40MG FILM-COATED TABLETS

Main information

  • Trade name:
  • CIPROTAN 40MG FILM-COATED TABLETS
  • Dosage:
  • 40 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CIPROTAN 40MG FILM-COATED TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0126/131/003
  • Authorization date:
  • 17-11-2004
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Ciprotan40mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains49.98mgcitalopramhydrobromide,equivalentto40mgcitalopram.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

Round,whitetabletswithabreak-lineanddiameterof10mm.

Thetabletscanbedividedintoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofmajordepressiveepisodes.

4.2Posologyandmethodofadministration

Citalopramshouldbeadministeredasasingleoraldose,eitherinthemorningorintheevening.Thetabletscanbe

takenwithorwithoutfood,butwithfluid.

Followingtreatmentinitiation,anantidepressanteffectshouldnotbeexpectedforatleasttwoweeks.Treatmentshould

continueuntilthepatienthasbeenfreeofsymptomsfor4-6months.Citalopramshouldbewithdrawnslowly;itis

advisedthatthedoseisgraduallyreducedover1-2weekperiods.

Adults:

Therecommendedstartingdoseis20mgperday.Ifnecessary,thedosecanbeincreasedupto40mgperday,

dependingontheindividualresponseofthepatient.Themaximumdoseis60mgperday.

Elderlypatients(>65yearsofage):

Forelderlypatientsthedoseshouldbedecreasedtohalfoftherecommendeddose,e.g.10-20mgperday.Depending

ontheindividualresponseofthepatient,thedosecanbeincreased.Therecommendedmaximumdosefortheelderly

is40mg/day.

Childrenandadolescentsundertheageof18:

Citalopramshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years(seesection4.4).

Reducedrenalfunction:

Dosageadjustmentisnotrequiredifthepatienthasmildtomoderaterenalimpairment.Cautionisadvisedinpatients

withsevererenalimpairment(creatinineclearancelessthan30mL/min,seesection5.2).

Reducedhepaticfunction:

Aninitialdoseof10mgdailyforthefirsttwoweeksoftreatmentisrecommendedinpatientswithmildormoderate

hepaticimpairment.Dependingonindividualpatientresponse,thedosemaybeincreasedto30mgdaily.Cautionand

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PoormetabolisersregardingCYP2C19

ForknownpoorCYP2C19metabolisersaninitialdoseof10mgdailythefirsttwoweeksoftreatmentis

recommended.Dependingontheoutcomeofthetreatmentthedosecanthereafterbeincreasedto20mg(seesection

5.2).

Withdrawalsymptomsseenondiscontinuation

Abruptdiscontinuationshouldbeavoided.WhenstoppingtreatmentwithCitalopramthedoseshouldbegradually

reducedoveraperiodofatleastonetotwoweeksinordertoreducetheriskofwithdrawalreactions(seesection4.4

andsection4.8).Ifintolerablesymptomsoccurfollowingadecreaseinthedoseupondiscontinuationoftreatment,then

resumingthepreviouslyprescribeddosemaybeconsidered.Subsequently,thephysicianmaycontinuedecreasingthe

dose,butatamoregradualrate.

4.3Contraindications

Hypersensitivitytocitalopramortoanyoftheexcipients.

MAOIs(monoamineoxidaseinhibitors)

Somecasespresentedwithfeaturesresemblingserotoninsyndrome.

CitalopramshouldnotbegiventopatientsreceivingMonoamineOxidaseInhibitors(MAOIs)includingselegiline

indailydosesexceeding10mg/day.Citalopramshouldnotbegivenforfourteendaysafterdiscontinuationofan

irreversibleMAOIorforthetimespecifiedafterdiscontinuationofareversibleMAOI(RIMA)asstatedinthe

prescribingtextoftheRIMA.MAOIsshouldnotbeintroducedforsevendaysafterdiscontinuationofcitalopram

(seesection4.5).

Citalopramiscontraindicatedinthecombinationwithlinezolidunlesstherearefacilitiesforcloseobservationand

monitoringofbloodpressure(seesection4.5).

Concomitanttreatmentwithpimozide(seesection4.5).

4.4Specialwarningsandprecautionsforuse

Treatmentofelderlypatientsandpatientswithreducedkidneyandliverfunction,seesection4.2.

Useinchildrenandadolescentsunder18yearsofage

Citalopramshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years.Suicide-related

behaviours(suicideattemptandsuicidalthoughts),andhostility(predominantlyaggression,oppositionalbehaviourand

anger)weremorefrequentlyobservedinclinicaltrialsamongchildrenandadolescentstreatedwithantidepressants

comparedtothosetreatedwithplacebo.If,basedonclinicalneed,adecisiontotreatisneverthelesstaken,thepatient

shouldbecarefullymonitoredfortheappearanceofsuicidalsymptoms.Inaddition,long-termsafetydatainchildren

andadolescentsconcerninggrowth,maturationandcognitiveandbehaviouraldevelopmentarelacking.

Paradoxicalanxiety

Somepatientswithpanicdisordermayexperienceintensifiedanxietysymptomsatthestartoftreatmentwith

antidepressants.Thisparadoxicalreactionusuallysubsideswithinthefirsttwoweeksofstartingtreatment.Alow

startingdoseisadvisedtoreducethelikelihoodofaparadoxicalanxiogeniceffect(seesection4.2).

Hyponatraemia

Hyponatraemia,probablyduetoinappropriateantidiuretichormonesecretion(SIADH),hasbeenreportedasarare

adversereactionwiththeuseofSSRIsandgenerallyreverseondiscontinuationoftherapy.Elderlyfemalepatients

seemtobeatparticularlyhighrisk.

Suicide/suicidalthoughtsorclinicalworsening

Depressionisassociatedwithanincreasedriskofsuicidalthoughts,selfharmandsuicide(suicide-relatedevents).This

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treatment,patientsshouldbecloselymonitoreduntilsuchimprovementoccurs.Itisgeneralclinicalexperiencethatthe

riskofsuicidemayincreaseintheearlystageofrecovery.

Patientswithahistoryofsuicide-relatedevents,orthoseexhibitingasignificantdegreeofsuicidalideationpriorto

commencementoftreatmentareknowntobeatgreaterriskofsuicidalthoughtsorsuicideattempts,andshouldreceive

carefulmonitoringduringtreatment.Ameta-analysisofplacebo-controlledclinicaltrialsofantidepressantdrugsin

adultpatientswithpsychiatricdisordersshowedanincreasedriskofsuicidalbehaviourwithantidepressantscompared

toplaceboinpatientslessthan25yearsold.Closesupervisionofpatientsandinparticularthoseathighriskshould

accompanydrugtherapyespeciallyinearlytreatmentandfollowingdosechanges.Patients(andcaregiversofpatients)

shouldbealertedabouttheneedtomonitorforanyclinicalworsening,suicidalbehaviourorthoughtsandunusual

changesinbehaviourandtoseekmedicaladviceimmediatelyifthesesymptomspresent.

Akathisia/psychomotorrestlessness:

TheuseofSSRIs/SNRIshasbeenassociatedwiththedevelopmentofakathisia,characterisedbyasubjectively

unpleasantordistressingrestlessnessandneedtomoveoftenaccompaniedbyaninabilitytositorstandstill.Thisis

mostlikelytooccurwithinthefirstfewweeksoftreatment.Inpatientswhodevelopthesesymptoms,increasingthe

dosemaybedetrimental.

Mania

Citalopramshouldbeusedwithcautioninpatientswithahistoryofmania/hypomania.Citalopramshouldbe

discontinuedinanypatiententeringamanicphase.

Seizures

Seizuresareapotentialriskwithantidepressantdrugs.

Citalopramshouldbediscontinuedinanypatientwhodevelopsseizures.Citalopramshouldbeavoidedinpatientswith

unstableepilepsyandpatientswithcontrolledepilepsyshouldbecarefullymonitored.Citalopramshouldbe

discontinuedifthereisanincreaseinseizurefrequency.

Diabetes

Inpatientswithdiabetes,treatmentwithanSSRImayalterglycaemiccontrol.Insulinand/ororalhypoglycaemic

dosagemayneedtobeadjusted.

Serotoninsyndrome

InrarecasesaserotoninsyndromehasbeenreportedinpatientsusingSSRIs.Acombinationofsymptoms,suchas

agitation,tremor,myoclonusandhyperthermiamayindicatethedevelopmentofthiscondition.Treatmentwith

citalopramshouldbediscontinuedimmediatelyandsymptomatictreatmentinitiated.

Serotonergicmedicines

Citalopramshouldnotbeusedconcomitantlywithmedicinalproductswithserotonergiceffectssuchassumatriptanor

othertriptans,tramadol,oxitriptanandtryptophan.

Haemorrhage

Therehavebeenreportsofprolongedbleedingtimeand/orbleedingabnormalitiessuchasecchymosis,gynaecological

haemorrhages,gastrointestinalbleedingsandothercutaneousormucousbleedingswithSSRIs(seeSection4.8).

CautionisadvisedinpatientstakingSSRIs,particularlyinconcomitantusewithactivesubstancesknowntoaffect

plateletfunctionorotheractivesubstancesthatcanincreasetheriskofhaemorrhageaswellasinpatientswitha

historyofbleedingdisorders(seeSection4.5).

ElectroconvulsiveTherapy(ECT)

Thereislittleclinicalexperienceofconcurrentadministrationofcitalopramandelectro-convulsivetherapy,therefore

cautionisadvisable.

Reversible,selectiveMAO -Ainhibitors

ThecombinationofcitalopramwithMAO -Ainhibitorsisgenerallynotrecommendedduetotheriskofonsetofa

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Forinformationonconcomitanttreatmentwithnon-selective,irreversibleMAO-inhibitorsseesection4.5.

StJohn´swort(Hypericumperforatum)

UndesirableeffectsmaybemorecommonduringconcomitantuseofcitalopramandherbalpreparationscontainingSt

John'swort(Hypericumperforatum).ThereforecitalopramandStJohn'swortpreparationsshouldnotbetaken

concomitantly(seeSection4.5).

Withdrawalsymptomsseenondiscontinuation

Withdrawalsymptomswhentreatmentisdiscontinuedarecommon,particularlyifdiscontinuationisabrupt(see

section4.8).

Theriskofwithdrawalsymptomsmaybedependentonseveralfactorsincludingthedurationanddoseoftherapyand

therateofdosereduction.Dizziness,sensorydisturbances(includingparaesthesia,sleepdisturbances(including

insomniaandintensedreams),agitationoranxiety,nauseaand/orvomiting,tremorandheadachearethemost

commonlyreportedreactions.Generallythesesymptomsaremildtomoderate;however,insomepatientstheymaybe

severeinintensity.Theyusuallyoccurwithinthefirstfewdaysofdiscontinuingtreatment,buttherehavebeenvery

rarereportsofsuchsymptomsinpatientswhohaveinadvertentlymissedadose.Generallythesesymptomsareself-

limitingandusuallyresolvewithin2weeks,thoughinsomeindividualstheymaybeprolonged(2-3monthsormore).

ItisthereforeadvisedthatCitalopramshouldbegraduallytaperedwhendiscontinuingtreatmentoveraperiodof

severalweeksormonths,accordingtothepatient’sneeds(see"WithdrawalSymptomsSeenonDiscontinuation",

Section4.2).”

Psychosis

Treatmentofpsychoticpatientswithdepressiveepisodesmayincreasepsychoticsymptoms.

QTprolongation

Increasedlevelsofasidemetaboliteofcitalopram(didemethylcitalopram)cantheoreticallyprolongtheQTintervalin

patientspredisposed,patientswithcongenitalprolongedQT-syndromeorinpatientswith

hypokalaemia/hypomagnesaemia.ECGmonitoringof2500patientsinclinicaltrials,including277patientswithpre-

existingcardiacconditionsdidnotrevealclinicallysignificantchanges.However,ECGmonitoringmaybeadvisablein

caseofoverdoseorconditionsofalteredmetabolismwithincreasedpeaklevels,e.g.liverimpairment.

Renalimpairment

Theuseofcitalopraminpatientswithsevererenalimpairment(creatinineclearancelessthan30ml/min.)isnot

recommendedasnoinformationisavailableonuseinthesepatients.(seeSection4.2).

Hepaticimpairment

Incasesofimpairedhepaticfunctiondosereductionisrecommended(seeSection4.2)andliverfunctionhastobe

closelymonitored.

Dosetitration

Atthebeginningofthetreatment,insomniaandagitationcanoccur.Adosetitrationmaybehelpful.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Pharmacodynamicinteractions

Atthepharmacodynamiclevelcasesofserotoninsyndromewithcitalopramandmoclobemideandbuspironehave

beenreported.

Contraindicatedcombinations

MAO-inhibitors

ThesimultaneoususeofcitalopramandMAO-inhibitorscanresultinsevereundesirableeffects,includingthe

serotoninsyndrome(seeSection4.3).

CasesofseriousandsometimesfatalreactionshavebeenreportedinpatientsreceivinganSSRIincombinationwitha

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moclobemideandinpatientswhohaverecentlydiscontinuedanSSRIandhavebeenstartedonaMAOI.

Somecasespresentedwithfeaturesresemblingserotoninsyndrome.Symptomsofanactivesubstanceinteractionwith

aMAOIinclude:hyperthermia,rigidity,myoclonus,autonomicinstabilitywithpossiblerapidfluctuationsofvital

signs,mentalstatuschangesthatincludeconfusion,irritabilityandextremeagitationprogressingtodeliriumandcoma

(Seesection4.3).

Pimozide

Concomitantadministrationofasingledoseof2mgpimozidetohealthyvolunteers,whoweretreatedwithcitalopram

40mg/dayfor11days,causedonlyaminorincreaseintheAUCandCmaxofpimozideofapproximately10%,not

beingstatisticallysignificant.Despitetheminorincreaseinplasmapimozidelevels,theQTcintervalwasmore

prolongedafterconcomitantadministrationofcitalopramandpimozide(onaverage10ms)ascomparedto

administrationofasingledoseofpimozidealone(onaverage2ms).Sincethisinteractionwasalreadyobservedafter

administrationofasingledoseofpimozide,concomitanttreatmentwithcitalopramandpimozideiscontra-indicated.

Combinationsrequiringprecautionforuse

Selegiline(selectiveMAO -Binhibitor)

Apharmacokinetic/pharmacodynamicinteractionstudywithconcomitantlyadministeredcitalopram(20mgdaily)and

selegiline(10mgdaily)(aselectiveMAO -Binhibitor)demonstratednoclinicallyrelevantinteractions.Theconcomitant

useofcitalopramandselegiline(indosesabove10mgdaily)isnotrecommended.

Serotonergicmedicinalproducts

Lithiumandtryptophan

Thereisnopharmacokineticinteractionbetweenlithiumandcitalopram.However,therehavebeenreportsofenhanced

serotonergiceffectswhenSSRIswereadministeredincombinationwithlithiumortryptophan.Cautionisadvised

duringsimultaneoususeofcitalopramwiththeseactivesubstances.Routinemonitoringoflithiumlevelsshouldbe

continuedasusual.

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

associatedeffects.

Untilfurtherinformationisavailable,thesimultaneoususeofcitalopramand5-HTagonists,suchassumatriptanand

othertriptans,isnotrecommended(seeSection4.4).

St.John’sWort

DynamicinteractionsbetweenSSRIsandherbalremedyStJohn’swort(Hypericumperforatum)canoccur,resultingin

anincreaseinundesirableeffects(seesection4.4).Pharmacokineticinteractionshavenotbeeninvestigated.

Haemorrhage

Cautioniswarrantedforpatientswhoarebeingtreatedsimultaneouslywithanticoagulants,medicinalproductsthat

affectthefunctionofthrombocytes,suchasnonsteroidalanti-inflammatorydrugs(NSAIDs),acetylsalicylicacid,

dipyridamol,andticlopidineorothermedicines(e.g.atypicalantipsychotics,phenothiazines,tricyclicdepressants)that

canincreasetheriskofhaemorrhage(seeSection4.4).

ECT(electroconvusivetherapy)

Therearenoclinicalstudiesestablishingtherisksorbenefitsofthecombineduseofelectroconvulsivetherapy(ECT)and

citalopram(seesection4.4).

Alcohol

Nopharmacodynamicorpharmacokineticinteractionshavebeendemonstratedbetweencitalopramandalcohol.

However,thecombinationofcitalopramandalcoholisnotadvisable.

MedicinalproductsinducingQTprolongationorhypokalaemia/hypomagnesaemia

CautioniswarrantedforconcomitantuseofotherQTintervalprolongingmedicinesor

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Medicinalproductsloweringtheseizurethreshold

SSRIscanlowertheseizurethreshold.Cautionisadvisedwhenconcomitantlyusingothermedicinalproductscapable

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

andbutyrophenones),mefloquin,bupropionandtramadol).

Desipramine,imipramine

Inapharmacokineticstudynoeffectwasdemonstratedoneithercitalopramorimipraminelevels,althoughthelevelof

desipramine,theprimarymetaboliteofimipraminewasincreased.Whendesipramineiscombinedwithcitalopram,an

increaseofthedesipramineplasmaconcentrationhasbeenobserved.Areductionofthedesipraminedosemaybe

needed

Neuroleptics

Experiencewithcitalopramhasnotrevealedanyclinicallyrelevantinteractionswithneuroleptics.However,aswith

otherSSRIs,thepossibilityofapharmacodynamicinteractioncannotbeexcluded.

Pharmacokineticinteractions

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

andCYP2D6(approx.31%)isozymesofthecytochromeP450system.Thefactthatcitalopramismetabolisedbymore

thanoneCYPmeansthatinhibitionofitsbiotransformationislesslikelyasinhibitionofoneenzymemaybecompensated

byanother.Thereforeco-administrationofcitalopramwithothermedicinalproductsinclinicalpracticehasverylow

likelihoodofproducingpharmacokineticmedicinalproductinteractions.

Food

Theabsorptionandotherpharmacokineticpropertiesofcitalopramhavenotbeenreportedtobeaffectedbyfood.

Influenceofothermedicinalproductsonthepharmacokineticsofcitalopram

Co-administrationwithketoconazole(potentCYP3A4inhibitor)didnotchangethepharmacokineticsofcitalopram.

Apharmacokineticinteractionstudyoflithiumandcitalopramdidnotrevealanypharmacokineticinteractions(seealso

above).

Cimetidine

Cimetidine,aknownenzyme-inhibitor,causedaslightriseintheaveragesteady-statecitalopramlevels.Cautionis

thereforerecommendedwhenadministeringhighdosesofcitalopramincombinationwithhighdosesofcimetidine.

Co-administrationofescitalopramwithomeprazole30mgoncedaily(aCYP2C19inhibitor)resultedinmoderate

(approximately50%)increaseintheplasmaconcentrationsofescitalopram.

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

fluvoxamine,lansoprazole,ticlopidine)orcimetidine.Areductioninthedoseofescitaloprammaybenecessarybased

onmonitoringofundesirableeffectsduringconcomitanttreatment.

Metoprolol

Escitalopram(theactiveenantiomerofcitalopram)isaninhibitoroftheenzymeCYP2D6.Cautionisrecommended

whenescitalopramisco-administeredwithmedicinalproductsthataremainlymetabolisedbythisenzyme,andthat

haveanarrowtherapeuticindex,e.g.flecainide,propafenoneandmetoprolol(whenusedincardiacfailure),orsome

CNSactingmedicinalproductsthataremainlymetabolisedbyCYP2D6,e.g.antidepressantssuchasdesipramine,

clomipramineandnortryptylineorantipsychoticslikerisperidone,thioridazineandhaloperidol.Dosageadjustment

maybewarranted.Co-administrationwithmetoprololresultedinatwofoldincreaseintheplasmalevelsofmetoprolol,

butdidnotstatisticallysignificantincreasetheeffectofmetoprololonthebloodpressureandcardiacrhythm.

Effectsofcitalopramonothermedicinalproducts

Apharmacokinetic/pharmacodynamicinteractionstudywithconcomitantadministrationofcitalopramandmetoprolol(a

CYP2D6substrate)showedatwofoldincreaseinmetoprololconcentrations,butnostatisticallysignificantincreaseinthe

effectofmetoprololonbloodpressureandheartrateinhealthyvolunteers.

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ofCYP1A2,CYP2C19andCYP2D6ascomparedtootherSSRIsestablishedassignificantinhibitors.

Levomepromazine,digoxin,carbamazepine

Thusnochangeoronlyverysmallchangesofnoclinicalimportancewereobservedwhencitalopramwasgivenwith

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

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

carbamazepineepoxid)andtriazolam).

Nopharmacokineticinteractionwasobservedbetweencitalopramandlevomepromazine,ordigoxin,(indicatingthat

citalopramneitherinducenorinhibitP-glycoprotein).

4.6Fertility,pregnancyandlactation

Pregnancy

Alargeamountofdataonpregnantwomen(morethan2500exposedoutcomes)indicatenomalformativefeto/

neonataltoxicity.Citalopramcanbeusedduringpregnancyifclinicallyneeded,takingintoaccounttheaspects

mentionedbelow.

EpidemiologicaldatahavesuggestedthattheuseofSSRIsinpregnancy,particularinlatepregnancy,mayincreasethe

riskofpersistentpulmonaryhypertensioninthenewborn(PPHN).Theobservedriskwasapproximately5casesper

1000pregnancies.Inthegeneralpopulation1to2casesofPPHNper1000pregnanciesoccur.

CasesofwithdrawalsymptomsinthenewbornchildhavebeendescribedaftertheuseofSSRIattheendofpregnancy.

Neonatesshouldbeobservedifmaternaluseofcitalopramcontinuesintothelaterstagesofpregnancyparticularinthe

thirdtrimester.

Abruptdiscontinuationshouldbeavoidedduringpregnancy.

ThefollowingsymptomsmayalsooccurintheneonateaftermaternalSSRI/SNRIuseinlaterstagesofpregnancy:

respiratorydistress,cyanosis,apnoea,seizures,temperatureinstability,feedingdifficulty,vomiting,hypoglycaemia,

hypertonia,hypotonia,hyperreflexia,tremor,jitteriness,irritability,lethargy,constantcrying,somnolenceand

difficultysleeping.Thesesymptomscouldbeduetoeitherserotonergiceffectsordiscontinuationsymptoms.Ina

majorityofinstancesthecomplicationsbeginimmediatelyorsoon(<24hours)afterdelivery

Lactation

Citalopramisexcretedintobreastmilk.Itisestimatedthatthesucklinginfantwillreceiveabout5%oftheweight

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

existinginformationisinsufficientforassessmentoftherisktothechild.Cautionisrecommended.

4.7Effectsonabilitytodriveandusemachines

Citalopramhasminorormoderateinfluenceontheabilitytodriveandusemachines.

Psychoactivemedicinalproductscanreducetheabilitytomakejudgementsandtoreacttoemergencies.Patients

shouldbeinformedoftheseeffectsandbewarnedthattheirabilitytodriveacaroroperatemachinerycouldbe

affected.

4.8Undesirableeffects

Adverseeffectsobservedwithcitalopramareingeneralmildandtransient.Theyaremostfrequentduringthefirstone

ortwoweeksoftreatmentandusuallyattenuatesubsequently.TheadversereactionsarepresentedattheMedDRA

PreferredTermLevel.

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

diarrhoea,nauseaandfatigue.

ThetableshowsthepercentageofadversedrugreactionsassociatedwithSSRIsand/orcitalopramseenineither 1%

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

(1/10000),notknown(cannotbeestimatedfromavailabledata).

Verycommon

(>1/10) Common

(>1/100to

<

1/10) Uncommon

(>1/1,000to

<

1/100) Rare

(>1/10,000to

<1/1,000) Veryrare

(<1/10,000) notknown

(cannotbe

estimatedfrom

theavailable

data)

Bloodand

lymphatic

system

disorders Thrombocytopenia

Immunesystem

disorders allergicreactions anaphylactic

reactions Hyper-

sensitivity,

Endocrine

disorders Thesyndrome

ofinappropriate

anti-diuretic

hormone

secretion

(SIADH)have

beenreported,

predominantly

intheelderly

(seeSection

4.4).

Metabolismand

nutrition

disorders weight

decrease,

weight

increase,

appetite

decreased,

increased

appetite,

anorexia Hyponatriaemia

havebeen

reported,

predominantly

intheelderly

(seeSection

4.4). Hypokalaemia

Psychiatric

disorders agitation,

nervousness sleepdisorders,

impaired

concentration,

abnormal

dreaming,

amnesia,

anxiety,

decreased

libido,apathy,

confusional

state,abnormal

orgasm

euphoria,

increasedlibido,

aggression,

depersonalization,

hallucination,

mania panicattacks

(these

symptomsmay

beduetothe

underlying

disease) Suicidalideation

andsuicidal

behaviours*

bruxism,

restlessness

Nervoussystem

disorders somnolence,

insomnia,

headache,

tremor,

dizziness migraine,taste

abnormalities,

paraesthesia,

disturbancein

attention extrapyramidal

disorders,

convulsions,

syncope serotonine

syndromehas

beenreported

inpatients

usingSSRIs,

convulsion

grandmal Psychomotor

restlessness/akathisia

(seesection4.4),

movement

disorder

Eyedisorders abnormal

accommodation abnormalities

ofvision Mydriasis

Earand

labyrinth

disorders tinnitus

Cardiac

disorders palpitations tachycardia Bradycardia, supraventricular

andventricular

arrhytmia QT-prolongation 1

Vascular

disorders postural

hypotension, Haemorrhage

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CasesofQT-prolongationhavebeenreportedduringthepost-marketingperiod,predominantlyinpatientswithpre-

existingcardiacdisease

*Casesofsuicidalideationandsuicidalbehaviourshavebeenreportedduringcitalopramtherapyorearlyafter

treatmentdiscontinuation(seesection4.4).

Classeffects

Epidemiologicalstudies,mainlyconductedinpatients50yearsofageandolder,showanincreasedriskofbone

fracturesinpatientsreceivingSSRIsandTCAs.Themechanismleadingtothisriskisunknown.

Withdrawalsymptomsseenondiscontinuation

DiscontinuationofSSRIs/SNRIs(particularlywhenabrupt)commonlyleadstowithdrawalsymptoms.Dizziness,

sensorydisturbances(includingparaesthesiaandelectricshocksensations),sleepdisturbances(includinginsomniaand

intensedreams),agitationoranxiety,nauseaand/orvomiting,tremor,confusion,sweating,headache,diarrhoea,

palpitations,emotionalinstability,irritability,andvisualdisturbancesarethemostcommonlyreportedreactions.

Generallytheseeventsaremildtomoderateandareself-limiting;however,insomepatientstheymaybesevereand/or

hypotension,

hypertension gynaecological

haemorrhage,

gastrointestinal

haemorrhage,

rectal

haemorrhage,

ecchymosisand

otherformsof

skin

haemorrhageor

bleedinginthe

mucous

membranes)

Respiratory,

thoracicand

mediastinal

disorders rhinitis,

sinusitis,

yawning, coughing Epistaxis

Gastrointestinal

disorders nausea,dry

mouth,

constipation,

diarrhoea dyspepsia,

vomiting,

abdominal

pain,flatulence,

increased

salivation

Hepatobiliary

disorders increasedliver

enzymevalues Hepatitis Liverfunction

testabnormal

Skinand

subcutaneous

tissuedisorders increased

sweating rash,pruritus Photosensitivity

reaction,urticaria,

alopecia,purpura angiodema Ecchymosis

Musculoskeletal

andconnective

tissuedisorders Myalgia,

athralgia

Renaland

urinary

disorders micturition

disorder,

polyuria Urinaryretention

Reproductive

systemand

breastdisorders ejaculation

failure,

ejaculation

disorder,

female:

menorrhagia,

dysmenorrhoea,

impotence galactorrhea Female:

Metrorrhagia

Male:Priapism

General

disordersand

administration

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bydosetaperingshouldbecarriedout(seesection4.2and4.4).

4.9Overdose

Toxicity

Comprehensiveclinicaldataoncitalopramoverdosearelimitedandmanycasesinvolveconcomitantoverdosesof

otherdrugs/alcohol.Fatalcasesofcitalopramoverdosehavebeenreportedwithcitalopramalone;however,the

majorityoffatalcaseshaveinvolvedoverdosewithconcomitantmedications.

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

Pharmacotherapeuticgroup

Pharmacotherapeuticgroup:Antidepressant,Selectiveserotoninreuptakeinhibitors

ATCcode:N06AB04

Mechanismofactionandpharmacodynamiceffects

Tolerancetotheinhibitoryeffectofcitalopramon5-HTuptakedoesnotoccurduringlong-termtreatment.

Theantidepressanteffectisprobablyconnectedwiththespecificinhibitionofserotoninuptakeinthebrainneurons.

Citalopramhasalmostnoeffectontheneuronaluptakeofnoradrenaline,dopamineandgamma-aminobutyricacid.

Citalopramshowsnoaffinity,oronlyverylittle,forcholinergic,histaminergicandavarietyofadrenergic,serotonergic

anddopaminergicreceptors.

Citalopramisabi-cyclicisobenzophurane-derivativethatischemicallynotrelatedtotricyclicandtetracyclic

antidepressantsorotheravailableantidepressants.Themainmetabolitesofcitalopramarealsoselectiveserotonin

uptakeinhibitors,thoughtoalesserdegree.Themetabolitesarenotreportedtocontributetotheoverallantidepressant

effect.

5.2Pharmacokineticproperties

Generalcharacteristicsoftheactivesubstance

Absorption

Citalopramisrapidlyabsorbedfollowingoraladministration:themaximumplasmaconcentrationisreachedon

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

Distribution:

Theapparentdistributionvolumeis12-17l/kg.Theplasma-proteinbindingofcitalopramanditsmetabolitesisbelow

80%.

Bio-transformation:

Citalopramismetabolisedintodemethylcitalopram,didemethylcitalopram,citalopram-N-oxideandthedeaminated

propionicacid-derivative.Thepropionicacid-derivativeispharmacologicallyinactive.Demethylcitalopram,

didemethylcitalopramandcitalopram-N-oxideareselectiveserotoninuptakeinhibitors,althoughweakerthanthe

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Invivoresearchhasdemonstratedthattheplasmalevelsofcitalopramanditsmetabolitesdependonthe

sparteine/debrisoquinephenotypeandthemephenytoinphenotype.However,itisnotnecessarytodoseindividually

accordingtothesephenotypes.

Elimination:

Theplasmahalf-lifeisapproximately1½days.Aftersystemicadministration,theplasmaclearanceisapproximately

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

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

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

andrenalclearanceis0.05-0.08l/min.

Steady-stateconcentrationsarereachedafter1-2weeks.Alinearrelationshiphasbeendemonstratedbetweenthe

steady-stateplasmalevelandthedoseadministered.Atadoseof40mgperday,anaverageplasmaconcentrationof

approximately300nmol/lisreached.Thereisnoclearrelationshipbetweencitalopramplasmalevelsandtherapeutic

responseorsideeffects.

Characteristicsrelatingtopatients

Elderlypatients(65years)

Longerhalf-livesanddecreasedclearancevaluesduetoareducedrateofmetabolismhavebeendemonstratedin

elderlypatients.

Reducedhepaticfunction

Citalopramiseliminatedmoreslowlyinpatientswithreducedhepaticfunction.Thehalf-lifeofcitalopramisabout

twiceaslongandsteadystatecitalopramconcentrationsatagivendosewillbeabouttwiceashighasinpatientswith

normalliverfunction.

Reducedrenalfunction

Inpatientswithamildlytomoderatelyreducedrenalfunctionalongerhalf-lifeandasmallincreaseintheexposureof

citalopramhasbeenobserved.Citalopramiseliminatedmoreslowly,withoutanimportanteffectonthe

pharmacokineticsofcitalopram.

5.3Preclinicalsafetydata

Preclinicaldatarevealednospecialhazardforhumansbasedonconventionalstudiesofsafetypharmacology,

genotoxicityandcarcinogenicpotential.

Phospholipidosishasbeenobservedinseveralorgansfollowingmultipleadministrationinrats.Theeffectwas

reversibleatdiscontinuation.Accumulationofphospholipidshasbeenobservedinlongtermanimalstudieswithmany

cation-amphophilicdrugs.Theclinicalrelevanceoftheseresultsisnotclear.

Reproductiontoxicitystudiesinratshavedemonstratedskeletalanomaliesintheoffspring,butnoincreasedfrequency

ofmalformations.Theeffectsmayberelatedtothepharmacologicalactivityormaybeaconsequenceofmaternal

toxicity.Peri-andpostnatalstudieshaverevealedreducedsurvivalinoffspringduringthelactationperiod.The

potentialriskforhumansisunknown.”

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Core:

Mannitol

Microcrystallinecellulose

Colloidalsilica,anhydrous

Magnesiumstearate

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Hypromellose

Macrogol6000

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

PVC/PVDC/ALblister:5years.

HDPE-tabletcontainer:3years.

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

Citalopram40mgtablets,packedinPVC/PVDC/Alblistersareavailableinpacksizesof10,14,20,28,30,50,56,98

and100tabletsperbox,100x1unitdoseblister.

HDPEtabletcontainerwithaLDPEtamperevidentcapcontaining250,500tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

ClonmelHealthcareLtd

WaterfordRoad

Clonmel

Co.Tipperary

8MARKETINGAUTHORISATIONNUMBER

PA126/131/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:17November2004

Dateoflastrenewal:18February2009

10DATEOFREVISIONOFTHETEXT

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