CIPRAMIL 20MG FILM-COATED TABLETS

Main information

  • Trade name:
  • CIPRAMIL 20MG FILM-COATED TABLETS
  • Dosage:
  • 20 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CIPRAMIL 20MG FILM-COATED TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA0465/068/002A
  • Authorization date:
  • 24-08-2001
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cipramil20mgFilm-CoatedTablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontainscitalopramhydrobromideequivalentto20mgcitalopram.

Excipients:lactosemonohydrate.

Forfulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

ProductimportedfromSpain,UnitedKingdom,France,Hungary,TheNetherlandsandItaly:

White,oval-shapedtabletsplainononesideandwithabreaklineontheotherside.‘C’isembossedtotheleftofthe

breaklineand‘N’isembossedtotherightofthebreakline.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofdepressiveillnessintheinitialphaseandasmaintenanceagainstpotentialrelapse/recurrence.

Cipramilisalsoindicatedinthetreatmentofpanicdisorderwithorwithoutagoraphobia.

4.2Posologyandmethodofadministration

Depression

Adults:

Cipramilshouldbeadministeredasasingleoraldoseof20mgdaily.

Dependentonindividualpatientresponse,thedosemaybeincreasedtoamaximumof40mgdaily.Thedosemaybe

giveninthemorningorevening.

Atreatmentperiodofatleast6monthsisusuallynecessarytoprovideadequatemaintenanceagainstthepotentialfor

relapse.

PanicDisorder

Adults:

Incommonwithotherpharmacotherapyusedinthispatientgroup,alowstartingdoseisadvisedtoreducethe

likelihoodofaparadoxicalinitialanxiogeniceffect.Asingledoseof10mgdailyisrecommendedforthefirstweek

beforeincreasingthedoseto20mgdaily.Dependentofindividualpatientresponse,thedosemaybeincreasedtoa

maximumof40mgdaily.

Maximumeffectivenessofcitalopramintreatingpanicdisorderisreachedafterabout3monthsandtheresponseis

maintainedduringcontinuedtreatment.Dependentonindividualpatientresponseitmaybenecessarytocontinue

treatmentforseveralmonths.

OCD

Adults:

Aninitialdoseof20mgdailyisrecommended.

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Elderlypatient(>65yearsofage)

Forelderlypatientsthedoseshouldbedecreasedtohalfoftherecommendeddose,e.g.10-20mgdaily.The

recommendedmaximumdosefortheelderlyis20mgdaily.

Childrenandadolescents(under18years):Notrecommended,assafelyandefficacyhavenotbeenestablishedinthis

population.

Reducedhepaticfunction:

Aninitialdoseof10mgdailyforthefirsttwoweeksoftreatmentisrecommendedinpatientswithmildormoderate

hepaticimpairment.Dependingonindividualpatientresponse,thedosemaybeincreasedtoamaximumof20mg

daily.Cautionandextracarefuldosetitrationisadvisedinpatientswithseverelyreducedhepaticfunction(seesection

5.2).

Reducedrenalfunction:

Dosageadjustmentisnotnecessaryincasesofmildormoderaterenalimpairment.Noinformationisavailableincases

ofsevererenalimpairment(creatinineclearance<20ml/min)

PoormetabolisersofCYP2C19

Aninitialdoseof10mgdailyduringthefirsttwoweeksoftreatmentisrecommendedfor

patientswhoareknowntobepoormetaboliserswithrespecttoCYP2C19.Thedosemaybe

increasedtoamaximumof20mgdailydependingonindividualpatientresponse,(seesection5.2).

CitalopramTabletsareadministeredasasingledailydoseandcanbetakenatanytimeofthedaywithoutregardto

foodintake.

4.3Contraindications

Hypersensitivitytocitalopram.Sumatriptan'sserotonergiceffectsaresuspectedtobeenhancedbySSRIs.Until

furtherevidenceisavailableitisadvisednottousecitalopramsimultaneouslywith5-HTagonistseg.sumatriptan.

Concomitanttreatmentwithpimozide(seesection4.5,Interactionwithothermedicinalproductsandotherformsof

interaction)

CitalopramiscontraindicatedinpatientswithknownQT-intervalprolongationorcongenitallongQTsyndrome.

CitalopramiscontraindicatedtogetherwithmedicinalproductsthatareknowntoprolongtheQT-interval(seesection

4.5).

4.4Specialwarningsandprecautionsforuse

Suicide/suicidalthoughtorclinicalworsenings:Depressionisassociatedwithanincreasedriskofsuicidalthoughts,

selfharmandsuicide(suicide-relatedevents).Thisriskpersistsuntilsignificantremissionoccurs.Asimprovement

maynotoccurduringthefirstfewweeksormoreoftreatment,patientsshouldbecloselymonitoreduntilsuch

improvementoccursItisgeneralclinicalexperiencethattheriskofsuicidemayincreaseintheearlystagesof

recovery.

OtherpsychiatricconditionsforwhichCipramilisprescribedcanalsobeassociatedwithanincreasedriskofsuicide-

relatedevents.Inaddition,theseconditionsmaybeco-morbidwithmajordepressivedisorder.Thesameprecautions

observedwhentreatingpatientswithmajordepressivedisordershouldthereforebeobservedwhentreatingpatients

withotherpsychiatricdisorders.

Patientswithahistoryofsuicide-relatedevents,thoseexhibitingasignificantdegreeofsuicidalideationpriorto

commencementoftreatmentareknowntobeatgreaterriskofsuicidalthoughtsorsuicideattempts,andshould

receivecarefulmonitoringduringtreatment.Inaddition,thereisapossibilityofanincreasedriskofsuicidalbehaviour

inyoungadults.Ameta-analysisofplacebo-controlledclinicaltrialsofantidepressantdrugsinadultpatientswith

psychiatricdisordersshowedanincreasedriskofsuicidalbehaviourwithantidepressantscomparedtoplaceboin

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Closesupervisionofpatientsandinparticularthoseathighriskshouldaccompanydrugtherapyespeciallyinearly

treatmentandfollowingdosechanges.Patients(andcaregiversofpatients)shouldbealertedabouttheneedtomonitor

fortheemergenceofsucheventsandtoseekmedicaladviceimmediatelyifthesesymptomspresent.Anyclinical

worsening,suicidalbehaviourorthoughtsandunusualchangesinbehaviourandtoseekmedicaladviceimmediatelyif

thesesymptomspresent

Useinchildren&adolescentsundertheageof18:

Cipramilshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years.Suicide-related

behaviours(suicidalattemptandsuicidalthoughts),andhostility(predominantlyaggression,oppositionalbehaviours

andanger)weremorefrequentlyobservedinclinicaltrialsamongchildrenandadolescentstreatedwithantidepressants

comparedtothosetreatedwithplacebo.If,basedonclinicalneed,adecisiontotreatisneverthelesstaken,thepatient

shouldbecarefullymonitoredfortheappearanceofsuicidalsymptoms.Inaddition,long-termsafetydatainchildren

andadolescentsconcerninggrowth,maturationandcognitiveandbehaviouraldevelopmentarelacking.

AswithotherSSRIs,citalopramshouldnotbegiventopatientsreceivingMonoamineOxidaseInhibitors(MAOIs),or

for14daysaftertheirdiscontinuation.MAOIsshouldnotbeintroducedforsevendaysafterdiscontinuationof

citalopram.Rarely,theoccurrenceof‘serotoninsyndrome’hasbeenreportedinpatientsreceivingSSRIs.A

combinationofsymptoms,possiblyincludingagitation,tremor,myoclonusandhyperthermia,mayindicatethe

developmentofthiscondition.

SSRIsshouldbeadministeredwithcautioninpatientstreatedconcomitantlywithanticoagulants,drugswhichhavean

effectonplateletfunction(e.g.NSAIDS,acetylsalicylicacid,aspirinandticlopidine)orotherdrugsthatmayincrease

theriskofbleeding.

Cautionshouldbeexercisedinpatientswithahistoryofbleedingabnormalities.

Experiencewithcitalopramhasnotrevealedanyclinicallyrelevantinteractionswithneuroleptics.However,aswith

otherSSRIs,thepossibilityofapharmacodynamicinteractioncannotbeexcluded.

Considerationshouldbegiventofactorswhichmayaffectthedispositionofaminormetaboliteofcitalopram

(didemethylcitalopram)sinceincreasedlevelsofthismetabolitecouldtheoreticallyprolongtheQTcintervalin

susceptibleindividuals.However,inECGmonitoringof2500patientsinclinicaltrials,including277patientswith

pre-existingcardiacconditions,noclinicallysignificantchangeswerenoted.

Undesirableeffectsmaybemorecommonduringconcomitantuseofserotoninre-uptakeinhibitorsandherbal

preparationscontainingStJohnsWort(Hypericumperforatum).

Aswithmostantidepressants,citalopramshouldbediscontinuedifthepatiententersamanicphase.Thereislittle

clinicalexperienceofconcurrentuseofcitalopramandECT.

Somepatientswithpanicdisorderexperienceaninitialanxiogeniceffectwhenstartingpharmacotherapy.Alow

startingdose(seePosology)reducesthelikelihoodofthiseffect.

Asimprovementofthedepressivestatemaynotoccurduringthefirstfewweeksormoreoftreatment,patientsshould

becloselymonitoredduringthisperiod.Itisgeneralclinicalexperiencewithallanti-depressantsthattheriskof

suicidemayincreaseintheearlystagesofrecovery.

Thepossibilityofsuicideattemptisinherentindepressionandmaypersistuntilsignificantremissionoccurs.

Potentiallysuicidalpatientsshouldnothaveaccesstolargequantitiesofdrugs.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

QTintervalprolongation

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prolongationandventriculararrhythmiaincludingtorsadedepointeshavebeenreportedduringthepost-marketing

period,predominantlyinpatientsoffemalegender,withhypokalemia,orwithpre-existingQTprolongationorother

cardiacdiseases(seesections4.3,4.5,4.8,4.9and5.1).

Cautionisadvisedinpatientswithsignificantbradycardia;orinpatientswithrecentacutemyocardialinfarctionor

uncompensatedheartfailure.

Electrolytedisturbancessuchashypokalaemiaandhypomagnesaemiaincreasetheriskformalignantarrhythmiasand

shouldbecorrectedbeforetreatmentwithcitalopramisstarted.

Ifpatientswithstablecardiacdiseasearetreated,anECGreviewshouldbeconsideredbeforetreatmentisstarted.

Ifsignsofcardiacarrhythmiaoccurduringtreatmentwithcitalopram,thetreatmentshouldbewithdrawnandanECG

shouldbeperformed.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Pharmacodynamicinteractions

Atthepharmacodynamicleveltherehaveonlybeenfewdocumentedcasesofserotoninsyndromewithcitalopramand

moclobemideandbuspirone.

Contraindicatedcombinations

MAOIs(non-selectiveaswellasselectiveA(moclobemide)-riskof“serotoninsyndrome”(seesection4.3

Contraindications).

Pimozide

Coadministrationofasingledoseofpimozide2mgtosubjectstreatedwithracemiccitalopram40mg/dayfor11days

causedanincreaseinAUCandC

ofpimozide,althoughnotconsistentlythroughoutthestudy.Theco-

administrationofpimozideandcitalopramresultedinameanincreaseintheQTcintervalofapproximately10msec.

Duetotheinteractionnotedatalowdoseofpimozide,concomitantadministrationofcitalopramandpimozideis

contraindicated.

Combinationsrequiringprecautionforuse

Selegiline(selectiveMAO-Binhibitor)

Apharmacokinetic/pharmacodynamicinteractionstudywithconcomitantlyadministeredcitalopram(20mgdaily)

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

toleratedtheselegiline-citalopramcombinationwell.

Serotonergicmedicinalproducts

Lithiumandtryptophan

Nopharmacodynamicinteractionshavebeenfoundinclinicalstudiesinwhichcitalopramhasbeengiven

concomitantlywithlithium.HowevertherehavebeenreportsofenhancedeffectswhenSSRIshavebeengivenwith

lithiumortryptophanandthereforetheconcomitantuseofcitalopramwiththesemedicinalproductsshouldbe

undertakenwithcaution.

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

associatedeffects.

St.John'sWort

DynamicinteractionsbetweenSSRIsandherbalremedyStJohn'swort(Hypericumperforatum)canoccur,resultingin

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Haemorrhage

TherehavebeenreportsofcutaneousbleedingabnormalitiessuchasecchymosesandpurpurawithSSRIs.Cautionis

advisedinpatientstakingSSRIs,particularlywithconcomitantuseoforalanticoagulants;medicinalproductsknownto

affectplateletfunction(e.g.atypicalantipsychoticsandphenothiazines,mosttricyclicantidepressants,acetylsalicyclic

acidandnon-steroidalanti-inflammatorymedicinalproducts(NSAIDs),ticlopidineanddipyridamole)aswellasin

patientswithahistoryofbleedingdisorders(seesection4.4SpecialWarningsandPrecautionsforUse).

ECT(electroconvulsivetherapy)

Therearenoclinicalstudiesestablishingtherisksorbenefitsofthecombineduseofelectroconvulsivetherapy(ECT)

andcitalopram(seesection4.4SpecialWarningsandPrecautionsforUse).

Alcohol

ThecombinationofSSRIsandalcoholisnotadvisable.However,clinicalstudieshaverevealednoadverse

Pharmacodynamicinteractionsbetweencitalopramandalcohol.

Pharmacokineticinteractions

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

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

morethanoneCYPmeansthatinhibitionofitsbiotransformationislesslikelyandco-administrationofcitalopram

withothermedicinalproductsinclinicalpracticehasverylowlikelihoodofproducingpharmacokineticmedicinal

productinteractions

Influenceofothermedicinalproductsonthepharmacokineticsofcitalopram

Co-administrationwithketoconazole(potentCYP3A4inhibitor)didnotchangethepharmacokineticsofcitalopram.A

pharmacokineticinteractionstudyoflithiumandcitalopramdidnotrevealanypharmacokineticinteractions.

Cimetidine(potentCYP2D6,3A4and1A2inhibitor)causedamoderateincreaseintheaveragesteadystatelevelsof

citalopram.Nogeneraldosereductionforcitalopramisrecommendedduringco-administrationwithcimetidine.

Effectsofcitalopramonothermedicinalproducts

Apharmacokinetic/pharmacodynamicinteractionstudywithconcomitantadministrationofcitalopramandmetoprolol

(aCYP2D6substrate)showedatwofoldincreaseinmetoprololconcentrations,butnostatisticallysignificantincrease

intheeffectofmetoprololonbloodpressureandheartrateinhealthyvolunteers.

CitalopramanddemethylcitalopramarenegligibleinhibitorsofCYP2C9,CYP2E1andCYP3A4,andonlyweak

inhibitorsofCYP1A2,CYP2C19andCYP2D6ascomparedtootherSSRIsestablishedassignificantinhibitors.

Thusnochangeinpharmacokineticsoronlyverysmallchangesofnoclinicalimportancewereobservedwhen

citalopramwasgivenwithCYP1A2substrates(clozapineandtheophylline),CYP2C9(warfarin),CYP2C19

(imipramineandmephenytoin),CYP2D6(sparteine,imipramine,amitriptyline,risperidone)andCYP3A4(warfarin,

carbamazepineandtriazolam).

Inapharmacokineticinteractionstudycitalopramdidnotcauseanychangesinthepharmacokineticsofdigoxin

meaningthatcitalopramneitherinducesnorinhibitsP-glycoprotein.

Contraindicatedcombinations

QTintervalprolongation

PharmacokineticandpharmacodynamicstudiesbetweencitalopramandothermedicinalproductsthatprolongtheQT

intervalhavenotbeenperformed.Anadditiveeffectofcitalopramandthesemedicinalproductscannotbeexcluded.

Therefore,co-administrationofcitalopramwithmedicinalproductsthatprolongtheQTinterval,suchasClassIAand

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CitalopramandriskofQTprolongationOctober2011Page2/10certainantimicrobialagents(e.g.sparfloxacin,

moxifloxacin,erythromycinIV,pentamidine,antimalariantreatmentparticularlyhalofantrine),certainantihistamines

(astemizole,mizolastine)etc.,iscontraindicated.

Influenceofothermedicinalproductsonthepharmacokineticsofcitalopram

Cimetidine(potentCYP2D6,3A4and1A2inhibitor)causedamoderateincreaseintheaveragesteadystatelevelsof

citalopram.Cautionisadvisedwhenadministeringcitalopramincombinationwithcimetidine.Doseadjustmentmaybe

warranted.

4.6Fertility,pregnancyandlactation

CategoryBl

Animalstudieshavenotshownanyevidenceofteratogenicpotentialandcitalopramdoesnotaffectreproductionor

perinatalconditions.Citalopramappearsinmilkinverylowconcentrations.

Duetolimitedhumandatacitalopramshouldonlybeusedinpregnancyifconsiderednecessaryandundertheclose

supervisionofaphysician.Innursingmothers,cautionisrecommendedasitisnotknownwhethercitalopramexcreted

inmilkmayaffecttheinfant.

NeonatesshouldbeobservedifmaternaluseofCipramilcontinuesintothelaterstagesofpregnancy,particularinthe

thirdtrimester.Abruptdiscontinuationshouldbeavoidedduringpregnancy.

ThefollowingsymptomsmayoccurintheneonatesaftermaternalSSRI/SNRIuseinlaterstagesofpregnancy:

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

hypertonia,hypotonia,hyperreflexia,tremor,jitteriness,irrability,lethargy,constantcrying,somnolenceanddifficulty

sleeping.Thesesymptomscouldbeduetoeitherserotonergiceffectsordiscontinuationsymptoms.Inamajorityof

instancesthecomplicationsbeginimmediatelyorsoon(<24hours)afterdelivery.

4.7Effectsonabilitytodriveandusemachines

Citalopramdoesnotimpairintellectualfunctionandpsychomotorperformance.However,patientswhoareprescribed

psychotropicmedicationmaybeexpectedtohavesomeimpairmentofgeneralattentionandconcentrationeitherdueto

theillnessitself,themedicationorbothandshouldbecautionedabouttheirabilitytodriveacarandoperate

machinery.

4.8Undesirableeffects

CasesofsuicidalideationandsuicidalbehaviourshavebeenreportedduringCipramiltherapyorearlyaftertreatment

discontinuation(seesection4.4)

Adverseeffectsobservedwithcitalopramareingeneralmildandtransient.Theyaremostprominentduringthefirst

oneortwoweeksoftreatmentandusuallyattenuateasthedepressivestateimproves.

Themostcommonlyobservedadverseeventsassociatedwiththeuseofcitalopramandnotseenatanequalincidence

amongplacebo-treatedpatientswere:nausea,somnolence,mouthdry,sweatingincreasedandtremor.Theincidence

ofeachinexcessoverplaceboislow(<10%).

Incomparativeclinicaltrialswithtricyclicantidepressantstheincidenceofadverseeventsoccurringwithcitalopram

wasfoundtobelowerinallcases.

Treatmentemergentadverseeventsreportedinclinicaltrials(N=2985):

Frequent:(5-20%)

Skinandappendagesdisorders:Sweatingincreased(13%)

Centralandperipheralnervoussystemdisorders:Headache(19%),tremor(12%),dizziness(8%).

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Psychiatricdisorders:Somnolence(17%),insomnia(12%),agitation(6%),nervousness(6%).

Gastro-intestinalsystemdisorders:Nausea(20%),mouthdry(18%),constipation(10%),diarrhoea(7%).

Heartrateandrhythmdisorders:Palpitation(6%).

Bodyasawhole:Asthenia(11%).

Lessfrequent:(1-5%)

Skinandappendagesdisorders:Rash,pruritis.

Centralandperipheralnervoussystemdisorders:Paraesthesia,migraine.

Visiondisorders:Visionabnormal.

Specialsensesother,disorder:Tasteperversion.

Psychiatricdisorders:Sleepdisorder,libidodecreased,concentrationimpaired,dreamingabnormal,amnesia,anxiety,

appetiteincreased,anorexia,apathy,impotence,suicideattempt,confusion,yawning.

Gastrointestinalsystemdisorders:Dyspepsia,vomiting,abdominalpain,flatulence,salivaincreased.

Metabolicandnutritionaldisorders:Weightdecrease,weightincrease.

Cardiovasculardisorders,general:Hypotensionpostural.

Heartrateandrhythmdisorders:Tachycardia.

Respiratorysystemdisorders:Rhinitis.

Urinarysystemdisorders:Micturitiondisorder,polyuria.

Reproductivedisorders,male:Ejaculationfailure.

Reproductivedisorders,female:Anorgasmiafemale.

Bodyasawhole:Fatigue.

Rare:(<1%)

Musculo-skeletalsystemdisorder:Myalgia.

Centralandperipheralnervoussystemdisorders:ExtrapyramidalDisorder,convulsions.

Hearingandvestibulardisorders:Tinnitus.

Psychiatricdisorders:Euphoria,libidoincreased,suicideattempt

Respiratorysystemdisorder:Coughing.

Bodyasawhole:Malaise.

Frequencyunknown:

Ventriculararrhythmiaincludingtorsadedepointe

CasesofQT-prolongationandventriculararrhythmiaincludingtorsadedepointeshavebeenreportedduringthepost-

marketingperiod,predominantlyinpatientsoffemalegender,withhypokalemia,orwithpre-existingQT

prolongationorothercardiacdiseases(seesections4.3,4.4,4.5,4.9and5.1).

Hyponatraemia,sometimesassociatedwiththesyndromeofinappropriateantidiuretichormonesecretion(SIADH),has

beenreportedwiththeuseofSSRIsandotherantidepressants.

TreatmentwithSSRIshasoccasionallybeenassociatedwithsymptomssuggestiveofposturalhypotension,

hypotension,hypertensionand

tachycardia.Therehavealsobeenrarereportsofsupraventricularandventriculararrhythmias.Todatecausalityhas

notbeenestablished.

Rarelytherehavebeenreportsofbleedingabnormalitiessuchasecchymosis,purpura,gastrointestinal,gynaecological,

mucosalandcutaneousbleedingwithSSRIs(seeSection4.4SpecialWarningsandPrecautionsforUse).

SideeffectinDiscontinuation:Withdrawalreactionshavebeenreportedinassociationwithselectiveserotoninre-

uptakeinhibitors(SSRIs),includingCipramil.Commonsymptomsincludedizziness,parasthesia,headache,anxiety

andnausea.AbruptdiscontinuationoftreatmentwithCipramilshouldbeavoided.Themajorityofsymptoms

experiencedonwithdrawalofSSRIsarenon-seriousandself-limiting.

4.9Overdose

Citalopramisgiventopatientsatpotentialriskofsuicideandsomereportsofattemptedsuicidehavebeenreceived.

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Symptoms:Experiencefrom8casesconsideredduetocitalopramalonehasrecordedthefollowingsymptoms/signs:

somnolence,coma,stiffenedexpression,episodeofgrandmalconvulsion,sinustachycardia,occasionalnodalrhythm,

sweating,nausea,vomiting,cyanosis,hyperventilation.Nocasewasfatal.Theclinicalpicturewasinconsistent,no

observationbeingmadeinmorethantwoindividuals.

Sixfatalitieshavebeenreported.Inoneoverdosewassuspected;highpostmortemplasmalevelswereseenalthoughit

isnottechnicallypossibletointerpretthesewithconfidence.

Intheremainingfiveacombinationwithotherdrugshadbeentaken.Theclinicalsyndromeobservedpriortodeathin

threeofthesecaseswherecitalopramwastakenwithmoclobemidewasinterpretedasthatofserotoninsyndrome.No

clinicaldetailsareavailableontheothertwo.

Treatment:Thereisnospecificantidote.Treatmentissymptomaticandsupportive.Gastriclavageshouldbecarried

outassoonaspossibleafteroralingestion.Medicalsurveillanceisadvisable.

ECGmonitoringisadvisableincaseofoverdoseinpatientswithcongestiveheartfailure/bradyarrhythmias,inpatients

usingconcomitantmedicationsthatprolongtheQTinterval,orinpatientswithalteredmetabolism,e.g.liver

impairment.

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

seriesofreceptorsincluding

5-HT

,5-HT

,DAD

andD

receptors,

-,-adrenoreceptors,histamineH

,muscarinecholinergic,

benzodiazepineandopioidreceptors.Aseriesoffunctionalinvitrotestsinisolatedorgansaswellasfunctionalinvivo

testshaveconfirmedthelackofreceptoraffinity.Thisabsenceofeffectsonreceptorsonreceptorscouldexplainwhy

citalopramproducesfewerofthetraditionalsideeffectssuchasdrymouth,bladderandgutdisturbance,blurredvision,

sedation,cardiotoxicityandorthostatichypotension.

Suppressionofrapideyemovement(REM)sleepisconsideredapredictorofantidepressantactivity.Liketricyclic

antidepressants,otherSSRIsandMAOinhibitors,citalopramsuppressesREM-sleepandincreasesdeepslow-wave

sleep.

Althoughcitalopramdoesnotbindtoopioidreceptorsitpotentiatestheanti-noiceptiveeffectofcommonlyusedopioid

analgesics.Therewaspotentiationofd-amphetamine-inducedhyperactivityfollowingadministrationofcitalopram.

ThemainmetabolitesofcitalopramareallSSRIsalthoughtheirpotencyandselectivityratiosarelowerthanthoseof

citalopram.However,theselectivityratiosofthemetabolitesarehigherthanthoseofmanyofthenewerSSRIs.The

metabolitesdonotcontributetotheoverallantidepressanteffect.

Inhumanscitalopramdoesnotimpaircognitive(intellectualfunction)andpsychomotorperformanceandhasnoor

minimalsedativeproperties,eitheraloneorincombinationwithalcohol.

Citalopramdidnotreducesalivaflowinasingledosestudyinhumanvolunteersandinnoneofthestudiesinhealthy

volunteersdidcitalopramhavesignificantinfluenceoncardiovascularparameters.Citalopramhasnoeffectonthe

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Inadouble-blind,placebo-controlledECGstudyinhealthysubjects,thechangefrombaselineinQTc(Fridericia-

correction)was7.5(90%CI5.9-9.1)msecatthe20mg/daydoseand16.7(90%CI15.0-18.4)msecatthe60mg

day/dose(seesections4.3,4.4,4.5,4.8and4.9).

5.2Pharmacokineticproperties

Absorption:Absorptionisalmostcompleteandindependentoffoodintake(T

average/mean3.8hours).Oral

bioavailabilityisabout80%.

Distribution:Theapparentvolumeofdistribution(V

)isabout12.3L/kg.Theplasmaproteinbindingisbelow80%

forcitalopramanditsmainmetabolites.

Biotransformation:Citalopramismetabolisedtotheactivedemethylcitalopram,didemethylcitalopram,citalopram-N-

oxideandaninactivedeaminatedpropionicacidderivative.AlltheactivemetabolitesarealsoSSRIs,althoughweaker

thantheparentcompound.Unchangedcitalopramisthepredominantcompoundinplasma.

Elimination:Theeliminationhalf-life(T

)isabout1.5daysandthesystemiccitalopramplasmaclearance(Cl

)is

about0.33L/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

levelsandtherapeuticresponseorsideeffects.

ElderlyPatients(65years):

Longerhalf-livesanddecreasedclearancevaluesduetoareducedrateofmetabolismhavebeendemonstratedin

elderlypatients.

Reducedhepaticfunction:Citalopramiseliminatedmoreslowlyinpatientswithreducedhepaticfunction.Thehalf-

lifeofcitalopramisabouttwiceaslongandsteadystatecitalopramconcentrationsatagivendosewillbeabouttwice

ashighasinpatientswithnormalliverfunction.

Reducedrenalfunction:Citalopramiseliminatedmoreslowlyinpatientswithmildtomoderatereductionofrenal

function,withoutanymajorimpactonthepharmacokineticsofcitalopram.Atpresentnoinformationisavailablefor

treatmentofpatientswithseverelyreducedrenalfunction(creatinineclearance<20ml/min).

5.3Preclinicalsafetydata

Citalopramhaslowacutetoxicity.Inchronictoxicitystudiestherewerenofindingsofconcernforthetherapeuticuse

ofcitalopram.Basedondatafromreproductiontoxicitystudies(segmentI,IIandIII)thereisnoreasontohave

specialconcernfortheuseofcitalopraminwomenofchild-bearingpotential.Citalopramhasnomutagenicor

carcinogenicpotential.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Maizestarch

Lactosemonohydrate

Microcrystallinecellulose

Irish Medicines Board

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Date Printed 27/03/2012 CRN 2110110 page number: 9

Glycerol(85%)(E422)

Croscarmellosesodium

Magnesiumstearate

Hypromellose

Macrogol400

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelflifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25 °

Storeintheoriginalpackageinordertoprotectfromlight.

6.5Natureandcontentsofcontainer

Blisterpacksof28tabletsinacardboardoutercartonoranoverlabelledoutercarton.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

PCOManufacturing

Unit10,AshbourneBusinessPark

Rath

Ashbourne

Co.Meath

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA0465/068/002

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:24August2001

Dateoflastrenewal:24August2006

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 27/03/2012 CRN 2110110 page number: 10