CIPRAMIL

Main information

  • Trade name:
  • CIPRAMIL Film Coated Tablet 10 Base Milligrams
  • Dosage:
  • 10 Base Milligrams
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CIPRAMIL Film Coated Tablet 10 Base Milligrams
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1659/022/001
  • Authorization date:
  • 21-12-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cipramil10mgfilm-coatedtablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains10mgcitalopram(as12.49mgcitalopramhydrobromide).

Excipients:Lactosemonohydrate

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

ProductimportedfromtheUnitedKingdom:

10mg:White,round,film-coatedtabletsmarked'CL'ononeside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofdepressiveillnessintheinitialphaseandasmaintenanceagainstpotentialrelapse/recurrence.

Cipramilisalsoindicatedinthetreatmentofpanicdisorderwithorwithoutagoraphobia.

4.2Posologyandmethodofadministration

Adults

TreatingDepression

Citalopramshouldbeadministeredasasingleoraldoseof20mgdaily.Dependentonindividualpatientresponseand

severityofdepressionthedosemaybeincreasedtoamaximumof60mgdaily.

TreatingPanicDisorder

Asingleoraldoseof10mgisrecommendedforthefirstweekbeforeincreasingthedoseto20mgdaily.Thedose

maybefurtherincreased,uptoamaximumof60mgdailydependentonindividualpatientresponse.

Elderlypatients(>65yearsofage)

Inelderlypatientsthedosemaybeincreasedtoamaximumof40mgdaily.

Children&Adolescents(<18years)

Cipramilshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years(seesection4.4.

Specialwarningsandprecautionsforuse).

Reducedrenalfunction

Dosageadjustmentisnotnecessaryinpatientswithmildormoderaterenalimpairment.Noinformationisavailableon

treatmentofpatientswithseverelyreducedrenalfunction(creatinineclearance<20ml/min).

Reducedhepaticfunction

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MethodofAdministration

Citalopramtabletsareadministeredasasingledailydoseandcanbetakenatanytimeofthedaywithoutregardto

foodintake.

Durationoftreatment

Theantidepressanteffectusuallysetsinafter2to4weeks.Treatmentwithantidepressantsissymptomaticandmust

thereforebecontinuedforanappropriatelengthoftime,usuallyupto6monthsafterrecoveryinordertoprevent

relapse.Inpatientswithrecurrentdepression(unipolar)maintenancetherapymayneedtobecontinuedforanumber

ofyearstopreventnewepisodes.

Maximumeffectivenessofcitalopramintreatingpanicdisorderisreachedafterabout3monthsandtheresponseis

maintainedduringcontinuedtreatment.

WithdrawalsymptomsseenondiscontinuationofSSRI.

Abruptdiscontinuationshouldbeavoided.Whenstoppingtreatmentwithcitalopramthedoseshouldbegradually

reducedoveraperiodofatleastoneortwoweeksinordertoreducetheriskofwithdrawalreactions(seesection4.4

andsection4.8).Ifintolerablesymptomsoccurfollowingadecreaseinthedoseorupondiscontinuationoftreatment,

thenresumingthepreviouslyprescribeddosemaybeconsidered.Subsequentlythephysicianmaycontinuedecreasing

thedose,butatamoregradualrate.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients(seesection6.1).

MAOIs(monoamineoxidaseinhibitors)

CasesofseriousandsometimesfatalreactionshavebeenreportedinpatientsreceivinganSSRIincombinationwith

monoamineoxidaseinhibitor(MAOI),includingtheselectiveMAO-BinhibitorselegilineandthereversibleMAOI

(RIMA),moclobemideandinpatientswhohaverecentlydiscontinuedanSSRIandhavebeenstartedonaMAOI.

Somecasespresentedwithfeaturesresemblingserotoninsyndrome.

CitaloprammustnotbeusedincombinationwithaMAOIincludingselegilineindosesabove10mgdaily.

Treatmentwithcitaloprammaybeinstituted14daysafterdiscontinuationofnon-selectiveMAOIsandminimumone

dayafterdiscontinuationofmoclobemide.TreatmentwithMAOIsmaybeintroduced7daysafterdiscontinuationof

citalopram(seesection4.5Interactionwithothermedicinalproductsandotherformsofinteraction).

Concomitanttreatmentwithpimozide.

4.4Specialwarningsandprecautionsforuse

Treatmentofelderlypatientsandpatientswithreducedkidneyandliverfunction,seesection4.2.

Useinchildrenandadolescentsunder18yearsofage

Antidepressantsshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years.Suicide

relatedbehaviours(suicideattemptandsuicidalthoughts),andhostility(predominantlyaggression,oppositional

behaviourandanger)weremorefrequentlyobservedinclinicaltrialsamongchildrenandadolescentstreatedwith

antidepressantscomparedtothosetreatedwithplacebo.If,basedonclinicalneed,adecisiontotreatisnevertheless

taken,thepatientshouldbecarefullymonitoredfortheappearanceofsuicidalsymptoms.

Paradoxicalanxiety

Somepatientswithpanicdisordermayexperienceintensifiedanxietysymptomsatthestartoftreatmentwith

antidepressants.Thisparadoxicalreactionusuallysubsideswithinthefirsttwoweeksofstartingtreatment.Alow

startingdoseisadvisedtoreducethelikelihoodofaparadoxicalanxiogeniceffect(seesection4.2Posologyand

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Hyponatraemia

Hyponatraemia,probablyduetoinappropriateantidiuretichormonesecretion(SIADH),hasbeenreportedasarare

adversereactionwiththeuseofSSRIs.Elderlyfemalepatientsespeciallyseemtobeariskgroup.

Suicide/suicidalthoughtsorclinicalworsening

Depressionisassociatedwithanincreasedriskofsuicidalthoughts,selfharmandsuicide(suicide-relatedevents).This

riskpersistsuntilsignificantremissionoccurs.

Asimprovementmaynotoccurduringthefirstfewweeksormoreoftreatment,patientsshouldbecloselymonitored

untilsuchimprovementoccurs.Itisgeneralclinicalexperiencethattheriskofsuicidemayincreaseintheearlystages

ofrecovery.

Otherpsychiatricconditionsforwhichcitalopramisprescribedcanalsobeassociatedwithanincreasedriskofsuicide-

relatedevents.Inaddition,theseconditionsmaybeco-morbidwithmajordepressivedisorder.Thesameprecautions

observedwhentreatingpatientswithmajordepressivedisordershouldthereforebeobservedwhentreatingpatients

withotherpsychiatricdisorders.

Patientswithahistoryofsuicide-relatedevents,orthoseexhibitingasignificantdegreeofsuicidalideationpriorto

commencementoftreatment,areatgreaterriskofsuicidalthoughtsorsuicideattempts,andshouldreceivecareful

monitoringduringtreatment.Ameta-analysisofplacebo-controlledclinicaltrialsofantidepressantdrugsinadult

patientswithpsychiatricdisordersshowedanincreasedriskofsuicidalbehaviourwithantidepressantscomparedto

placeboinpatientslessthan25yearsold.

Closesupervisionofpatientsandinparticularthoseathighriskshouldaccompanydrugtherapyespeciallyinearly

treatmentandfollowingdosechanges.Patients(andcaregiversofpatients)shouldbealertedabouttheneedtomonitor

foranyclinicalworsening,suicidalbehaviourorthoughtsandunusualchangesinbehaviourandtoseekmedicaladvice

immediatelyifthesesymptomspresent.

Akathisia/psychomotorrestlessness

TheuseofSSRIs/SNRIshasbeenassociatedwiththedevelopmentofakathisia,characterisedbyasubjectively

unpleasantordistressingrestlessnessandneedtomoveoftenaccompaniedbyaninabilitytositorstandstill.Thisis

mostlikelytooccurwithinthefirstfewweeksoftreatment.Inpatientswhodevelopthesesymptoms,increasingthe

dosemaybedetrimental.

Mania

Inpatientswithmanic-depressiveillnessachangetowardsthemanicphasemayoccur.Shouldthepatiententera

manicphasecitalopramshouldbediscontinued.

Seizures

Althoughanimalexperimentshaveshownthatcitalopramhasnoepileptogenicpotentialitshould,likeother

antidepressants,beusedwithcautioninpatientswithahistoryofseizures.

Diabetes

Asdescribedforotherpsychotropicscitaloprammaymodifyinsulinandglucoseresponsescallingforadjustmentof

theantidiabetictherapyindiabeticpatients;inadditionthedepressiveillnessitselfmayaffectpatients´glucose

balance.

Serotoninsyndrome

Ifcitalopramisusedconcomitantlywithmedicinalproductswithserotonergiceffectssuchassumatriptanorother

triptans,tramadolandtryptophan , cautionisadvisable .

Rarely,theoccurrenceof“serotoninsyndrome”hasbeenreportedinpatientsreceivingSSRIs.Acombinationof

symptoms,possiblyincludingagitation,confusion,tremor,myoclonusandhyperthermia,mayindicatethe

developmentofthiscondition(seesection4.5Interactionwithothermedicinalproductsandotherformsof

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Haemorrhage

TherehavebeenreportsofcutaneousbleedingabnormalitiessuchasecchymosesandpurpurawithSSRIs.Cautionis

advisedinpatientstakingSSRIs,particularlywithconcomitantuseoforalanticoagulants;medicinalproductsknownto

affectplateletfunction(e.g.atypicalantipsychoticsandphenothiazines,mosttricyclicantidepressants,acetylsalicyclic

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

patientswithahistoryofbleedingdisorders(seesection4.5Interactionwithothermedicinalproductsandotherforms

ofinteraction)

ECT(electroconvulsivetherapy)

ThereislimitedclinicalexperienceofconcurrentadministrationofSSRIsandECT;thereforecautionisadvisable.

Reversible,selectiveMAO-Ainhibitors

ThecombinationofcitalopramwithMAO-Ainhibitorsisgenerallynotrecommendedduetotheriskofonsetofa

serotoninsyndrome(seesection4.5Interactionswithothermedicinalproductsandotherformsofinteraction)

Forinformationonconcomitanttreatmentwithnon-selective,irreversibleMAO-inhibitors,seesection4.5.

StJohn’sWort

ConcomitantuseofSSRIsandherbalremediescontainingStJohn’sWort(Hypericumperforatum)mayresultinan

increasedincidenceofadversereactions(seesection4.5Interactionwithothermedicinalproductsandotherformsof

interaction).

WithdrawalsymptomsseenondiscontinuationofSSRItreatment

Withdrawalsymptomswhentreatmentisdiscontinuedarecommon,particularlyifdiscontinuationisabrupt(see

section4.8UndesirableEffects).Inarecurrencepreventionclinicaltrialwithcitalopram,adverseeventsafter

discontinuationofactivetreatmentwereseenis40%ofpatientsversus20%inpatientscontinuingcitalopram.

Theriskofwithdrawalsymptomsmaybedependentonseveralfactorsincludingthedurationanddoseoftherapyand

therateofdosereduction.Dizziness,sensorydisturbances(includingparaesthesia),sleepdisturbances(including

insomniaandintensedreams),agitationoranxiety,nauseaand/orvomiting,tremor,confusion,sweating,headache,

diarrhoea,palipitations,emotionalinstability,irritabilityandvisualdisturbancesarethemostcommonlyreported

reactions.Generallythesesymptomsaremildtomoderate,however,insomepatientstheymaybesevereinintensity.

Theyusuallyoccurwithinthefirstfewdaysofdiscontinuingtreatment,buttherehavebeenveryrarereportsofsuch

symptomsinpatientswhohaveinadvertentlymissedadose.

Generallythesesymptomsareself-limitingandusuallyresolvewithin2weeks,thoughinsomeindividualstheymay

beprolonged(2-3monthsormore).Itisthereforeadvisedthatcitalopramshouldbegraduallytaperedwhen

discontinuingtreatmentoveraperiodofseveralweeksormonths,accordingtothepatient’sneeds(seesection4.2

Posologyandmethodofadministration)

Excipients

Thetabletscontainlactosemonohydrate.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Pharmacodynamicinteractions

Atthepharmacodynamicleveltherehaveonlybeenfewdocumentedcasesofserotoninsyndromewithcitalopramand

moclobemideandbuspirone.

Contraindicatedcombinations

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

Contraindications)

Pimzode

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

anincreaseinundesirableeffects(seesection4.4SpecialWarningsandPrecautionsforUse)

Haemorrhage

TherehavebeenreportsofcutaneousbleedingabnormalitiessuchasecchymosesandpurpurawithSSRIs.Cautionis

advisedinpatientstakingSSRIs,particularlywithconcomitantuseoforalanticoagulants;medicinalproductsknownto

affectplateletfunction(e.g.atypicalantipsychoticsandphenothiazines,mosttricyclicantidepressants,acetylsalicyclic

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

patientswithahistoryofbleedingdisorders(seesection4.4SpecialWarningsandPrecautionsforUse).

ECT(electroconvusivetherapy)

Therearenoclinicalstudiesestablishingtherisksorbenefitsofthecombineduseofelectroconvulsivetherapy(ECT)

andcitalopram(seesection4.4SpecialWarningsandPrecautionsforUse)

Alcohol

ThecombinationofSSRIsandalcoholisnotadvisable.However,clinicalstudieshaverevealednoadverse

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Pharmacokineticinteractions

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

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

bymorethanoneCYPmeansthatinhibitionofitsbiotransformationislesslikelyandco-administrationofcitalopram

withothermedicinalproductsinclinicalpracticehasverylowlikelihoodofproducingpharmacokineticmedicinal

productinteractions.

Influenceofothermedicinalproductsonthepharmacokineticsofcitalopram

Co-administrationwithketoconazole(potentCYP3A4inhibitor)didnotchangethepharmacokineticsofcitalopram.

Apharmacokineticinteractionstudyoflithiumandcitalopramdidnotrevealanypharmacokineticinteractions.

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.

4.6Fertility,pregnancyandlactation

Pregnancy

Clinicalexperienceofuseinpregnantwomenislimitedbutnoreports,whichmaycauseconcernhavebeenreceived.

Basedondatafromreproductiontoxicitystudies(segmentI,IIandIII)thereisnoreasontohavespecialconcernfor

theuseofcitalopraminwomenofchildbearingpotential.

NeonatesshouldbeobservedifmaternaluseofCipramilcontinuesintothelaterstagesofpregnancy,particularinthe

thirdtrimester.Abruptdiscontinuationshouldbeavoidedduringpregnancy.

ThefollowingsymptomsmayoccurintheneonatesaftermaternalSSRI/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.

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4.7Effectsonabilitytodriveandusemachines

Citalopramdoesnotimpairintellectualfunctionandpsychomotorperformance.However,patientswhoareprescribed

psychotropicmedicationmaybeexpectedtohavesomeimpairmentofgeneralattentionandconcentrationeitherdueto

theillnessitself,themedicationorbothandshouldbecautionedabouttheirabilitytodriveacarandoperate

machinery.

4.8Undesirableeffects

Adverseeffectsobservedwithcitalopramareingeneralmildandtransient.Theyaremostfrequentduringthefirstone

ortwoweeksoftreatmentandusuallyattenuatesubsequently.TheadversereactionsarepresentedattheMedDRA

PreferredTermLevel.

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

diarrhoea,nauseaandfatigue.

ThetableshowsthepercentageofadversedrugreactionsassociatedwithSSRIsand/orcitalopramseenineither ≥1%

ofpatientsindouble-blindplacebo-controlledtrialsorinthepost-marketingperiod.Frequenciesaredefinedas:very

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

(<1/10000),notknown(cannotbeestimatedfromavailabledata).

MedDRASOC Frequency Preferredterm

Bloodandlymphatic

disorders NotKnown Thrombocytopenia

Immunesystem

disorders NotKnown Hypersensitivity,

Anaphylacticreaction

Endocrinedisorders NotKnown InappropriateADH

secretion

Metabolismand

nutritiondisorders Common Appetitedecreased

Uncommon Increasedappetite

Rare Hyponatraemia

Psychiatricdisorders Common Agitation,libido

decreased,anxiety,

nervousness,

confusionalstate,

abnormalorgasm

(female)

Uncommon Aggression,

depersonalization,

hallucination,mania

NotKnown Panicattack,

bruxism,restlessness,

Suicide-related

events(seesection

4.4)

Nervoussystem Verycommon Somnolence,

insomnia

Common Tremor,paraesthesia

Uncommon Syncope

Rare Convulsiongrand

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disorders

NotKnown Convulsions,

serotoninsyndrome,

extrapyramidal

disorder,akathisia,

movementdisorder

Eyedisorders Uncommon Mydriasis

NotKnown Visualdisturbance

Earandlabyrinth

disorders Common Tinnitus

Cardiacdisorders Uncommon Bradycardia,

tachycardia

Vasculardisorders NotKnown Orthostatic

hypotension

Respiratorythoracic

andmediastinal

disorders Common Yawning

NotKnown Epistaxis

Gastrointestinal

disorders Verycommon Drymouth,Nausea

Common Diarrhoea,vomiting

NotKnown Gastrointestinal

haemorrhage

(includingrectal

haemorrhage)

Hepatobiliary

disorders Rare Hepatitis

Skinand

subcutaneoustissue

disorders Verycommon Sweatingincreased

Common Pruritus

Uncommon Urticaria,alopecia,

rash,purpura

NotKnown Ecchymosis,

angioedemas

Musculoskeletal,

connectivetissueand

bonedisorders Common Myalgia,arthralgia

Renalandurinary

disorders Uncommon Urinaryretention

Reproductivesystem

andbreastdisorders Common Impotence,

ejaculationdisorder,

ejaculationfailure

Uncommon Female:Menorrhagia

NotKnown Female:Metrorrhagia

Male:Priapism,

galactorrhoea

Generaldisorders

andadministration

siteconditions Common Fatigue

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Numberofpatients:Citalopram/placebo=1346/545

CasesofQT-prolongationhavebeenreportedduringthepost-marketingperiod,predominantlyinpatientswithpre-

existingcardiacdisease.

WithdrawalsymptomsseenondiscontinuationofSSRItreatment

DiscontinuationofCitalopram(particularlywhenabrupt)commonlyleadstowithdrawalsymptoms.Dizziness,sensory

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

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

irritability,andvisualdisturbancesarethemostcommonlyreportedreactions.Generallytheseeventsaremildto

moderateandareself-limiting,however,insomepatientstheymaybesevereand/orprolonged.Itisthereforeadvised

thatwhencitalopramtreatmentisnolongerrequired,gradualdiscontinuationbydosetaperingshouldbecarriedout

(seesection4.2andsection4.4).

4.9Overdose

Toxicity

Comprehensiveclinicaldataoncitalopramoverdosearelimitedandmanycasesinvolveconcomitantoverdosesof

otherdrugs/alcohol.Fatalcasesofcitalopramoverdosehavebeenreportedwithcitalopramalone;however,the

majorityoffatalcaseshaveinvolvedoverdosewithconcomitantmedications.

Symptoms

Thefollowingsymptomshavebeenseeninreportedoverdoseofcitalopram:convulsion,tachycardia,somnolence,

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

bradycardia,dizziness,bundlebranchblock,QRSprolongation,hypertension,andmydriasis.

Treatment

Thereisnospecificantidote.Establishandmaintainanairway,ensureadequateoxygenationandrespiratoryfunction.

Gastriclavageandtheuseofactivatedcharcoalmightbeconsidered.Gastriclavageshouldbecarriedoutassoonas

possibleafteroralingestion.Cardiacandvitalsignsmonitoringarerecommendedalongwithgeneralsymptomatic

supportivemeasures.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATC-code:N06AB04

MechanismofAction

Biochemicalandbehaviouralstudieshaveshownthatcitalopramisapotentinhibitorofserotonin(5-HT)-uptake.

Tolerancetotheinhibitionof5-HT-uptakeisnotinducedbylong-termtreatmentwithcitalopram.

CitalopramisaverySelectiveSerotoninReuptakeInhibitor(SSRI)withno,orminimal,effectonnoradrenaline(NA),

Investigations Common Weightdecreased

Uncommon Weightincreased

NotKnown Liverfunctiontest

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IncontrasttomanytricyclicantidepressantsandsomeofthenewerSSRIs,citalopramhasnoorverylowaffinityfora

seriesofreceptorsincluding5-HT

5-HT

,DAD

andD

receptors,

-adrenoceptors,histamineH

muscarinecholinergic,benzodiazepine,andopioidreceptors.Aseriesoffunctionalinvitrotestsinisolatedorgansas

wellasfunctionalinvivotestshaveconfirmedthelackofreceptoraffinity.Thisabsenceofeffectsonreceptorscould

explainwhycitalopramproducesfewerofthetraditionalside-effectssuchasdrymouth,bladderandgutdisturbance,

blurredvision,sedation,cardiotoxicityandorthostatichypotension.

ThemainmetabolitesofcitalopramareallSSRIsalthoughtheirpotencyandselectivityratiosarelowerthanthoseof

citalopram.However,theselectivityratiosofthemetabolitesarehigherthanthoseofmanyofthenewerSSRIs.The

metabolitesdonotcontributetotheoverallantidepressanteffect.

Pharmacodynamiceffects

Suppressionofrapideyemovement(REM)sleepisconsideredapredictorofantidepressantactivity.Liketricyclic

antidepressants,otherSSRIsandMAOinhibitors,citalopramsuppressesREM-sleepandincreasesdeepslow-wave

sleep.

Althoughcitalopramdoesnotbindtoopioidreceptorsitpotentiatestheanti-nociceptiveeffectofcommonlyused

opioidanalgesics.

Inhumans,citalopramdoesnotimpaircognitive(intellectualfunction)andpsychomotorperformanceandhasnoor

minimalsedativeproperties,eitheraloneorincombinationwithalcohol.

Citalopramdidnotreducesalivaflowinasingledosestudyinhumanvolunteersandinnoneofthestudiesinhealthy

volunteersdidcitalopramhavesignificantinfluenceoncardiovascularparameters.Citalopramhasnoeffectonthe

serumlevelsofgrowthhormone.CitalopramlikeotherSSRIsmayincreaseplasmaprolactin,aneffectsecondarytothe

prolactinstimulatingroleofserotoninandofnoclinicalimportance.

5.2Pharmacokineticproperties

Absorption

Absorptionisalmostcompleteandindependentoffoodintake(T

mean3hours).Oralbioavailabilityisabout80%.

Distribution

Theapparentvolumeofdistribution(V

isabout12-17L/kg.Theplasmaproteinbindingisbelow80%for

citalopramanditsmainmetabolites.

Biotransformation

Citalopramismetabolisedtotheactivedemethylcitalopram,didemethylcitalopram,citalopram-N-oxideandaninactive

deaminatedpropionicacidderivative.AlltheactivemetabolitesarealsoSSRIs,althoughweakerthantheparent

compound.Unchangedcitalopramisthepredominantcompoundinplasma.Theconcentrationsofdemethylcitalopram

anddidemethylcitalopramareusually30-50%and5-10%ofthecitalopramconcentration,respectively.The

biotransformationofcitalopramtodemethylcitalopramismediatedbyCYP2C19(approx.38%),CYP3A4(approx.

31%)andCYP2D6(approx.31%).

Elimination

Theeliminationhalf-life(T

)isabout1.5daysandthesystemiccitalopramplasmaclearance(Cl

)isabout0.3-0.4

L/min,andoralplasmaclearance(Cl

oral )isabout0.4L/min.

Citalopramisexcretedmainlyviatheliver(85%)andtheremainder(15%)viathekidneys;12%-23%ofthedaily

doseisexcretedinurineasunchangedcitalopram.Hepatic(residual)clearanceisabout0.3L/minandrenalclearance

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Linearity

Thekineticsarelinear.Steadystateplasmalevelsareachievedin1-2weeks.Averageconcentrationsof300nmol/L

(165-405nmol/L)areachievedatadailydoseof40mg.

Elderlypatients(>65years)

Longerhalf-lives(1.5-3.75days)anddecreasedclearancevalues(0.08-0.3L/min)duetoareducedrateofmetabolism

havebeendemonstratedinelderlypatients.Steadystatevalueswereabouttwiceashighintheelderlyasinyounger

patientstreatedwiththesamedose.

Reducedhepaticfunction

Citalopramiseliminatedmoreslowlyinpatientswithreducedhepaticfunction.Thehalf-lifeofcitalopramisabout

twiceaslongandsteadystatecitalopramconcentrationsatagivendosewillbeabouttwiceashighasinpatientswith

normalliverfunction.

Reducedrenalfunction

Citalopramiseliminatedmoreslowlyinpatientswithmildtomoderatereductionofrenalfunction,withoutanymajor

impactonthepharmacokineticsofcitalopram.Atpresentnoinformationisavailablefortreatmentofpatientswith

severelyreducedrenalfunction(creatinineclearance<20mL/min).

Polymorphism

Invivoinvestigationshaveshownthatthemetabolismofcitalopramexhibitsnoclinicallyimportantpolymorphismof

thesparteine/debrisoquineoxidation(CYP2D6).ForCYP2C19,asaprecaution,aninitialdoseof10mgshouldbe

consideredforknownpoormetabolisers(seesection4.2).

Pharmacokinetic/pharmacodynamicrelationship

Thereisnoclearrelationshipbetweencitalopramplasmalevelsandtherapeuticresponseorsideeffects.The

metabolitesdonotcontributetotheoverallantidepressanteffect.

5.3Preclinicalsafetydata

Acutetoxicity

Citalopramhaslowacutetoxicity.

Chronictoxicity

Inchronictoxicitystudiestherewerenofindingsofconcernforthetherapeuticuseofcitalopram.

Reproductionstudies

Basedondatafromreproductiontoxicitystudies(segmentI,IIandIII)thereisnoreasontohavespecialconcernfor

theuseofcitalopraminwomenofchildbearingpotential.

Citalopramappearsinmilkinlowconcentrations.

Embryotoxicitystudiesinratswithdosesof56mg/kg/day,whichcausematernaltoxicityshowedboneanomaliesin

theregionofthevertebralcolumnandribs.Thematernalplasmalevelwasthen2-3timesthetherapeuticconcentration

inman.Inratscitalopramdidnothaveanyeffectonfertility,pregnancyandpostnataldevelopmentbutdiminishedthe

birthweightofthepups.Citalopramanditsmetabolitesreachfoetalconcentrations,whichare10-15timesthematernal

plasmalevel.Clinicalexperienceofuseinpregnantwomenandduringlactationislimited.

Mutagenicandcarcinogenicpotential

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Maizestarch

Lactosemonohydrate

Microcrystalline-cellulose

Copovidone

Glycerol

CroscarmelloseSodium

Magnesiumstearate

Methylhydroxypropyl-cellulose

Macrogol

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductshallbethedateshownontheblisterstripsandouterpackageoftheproduct

onthemarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Storebelow25°C.

6.5Natureandcontentsofcontainer

Pressthroughpacks(UPVC/PVdCwithaluminiumclosure)containing28tabletsinanover-labelledcarton.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

IPSHealthcareLimited

SterlingHouse,

501MiddletonRoad

Chadderton,Oldham,

Lancashire

OL99LY

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8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1659/22/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:21stDecember2010

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Date Printed 21/12/2010 CRN 2088164 page number: 13