CIPRAMIL

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1500/051/001
  • Authorization date:
  • 05-02-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cipramil20mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains20mgcitalopramascitalopramhydrobromide

Excipients:Lactose

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Film-coatedtablet

ProductimportedfromtheNetherlandsandItaly

White,oval,scoredtabletmarked“C”and“N”symmetricallyaroundthescore.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofdepressiveillnessintheinitialphaseandasmaintenanceagainstpotentialrelapse/recurrence.

Cipramilisalsoindicatedinthetreatmentofpanicdisorderwithorwithoutagoraphobia.

4.2Posologyandmethodofadministration

Depression

Adults

Citalopramshouldbeadministeredasasingleoraldoseof20mgdaily.Dependentonindividualpatientresponse,the

dosemaybeincreasedtoamaximumof40mgdaily.

PanicDisorder

Adults

Asingleoraldoseof10mgisrecommendedforthefirstweekbeforeincreasingthedoseto20mgdaily.Dependenton

individualpatientresponse,thedosemayincreasedtoamaximumof40mgdaily.

Adults

Aninitialdoseof20mgdailyisrecommended.Dependentonindividualpatientresponse,thedosemaybeincreasedto

amaximumof40mgdaily.

Elderlypatients(>65yearsofage)

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

recommendedmaximumdosefortheelderlyis20mgdaily.

Reducedhepaticfunction

Aninitialdoseof10mgdailyforthefirsttwoweeksoftreatmentisrecommendedinpatientswithmildormoderate

hepaticimpairment.Dependingonindividualpatientresponse,thedosemaybeincreasedtoamaximumof20mg

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5.2).

PoormetabolisersofCYP2C19

Aninitialdoseof10mgdailyduringthefirsttwoweeksoftreatmentisrecommendedforpatientswhoareknownto

bepoormetaboliserswithrespecttoCYP2C19.Thedosemaybeincreasedtoamaximumof20mgdailydependingon

individualpatientresponse,(seesection5.2).

MethodofAdministration

Citalopramtabletsareadministeredasasingledailydoseandcanbetakenatanytimeofthedaywithoutregardto

foodintake.

Durationoftreatment

Theantidepressanteffectusuallysetsinafter2to4weeks.Treatmentwithantidepressantsissymptomaticandmust

thereforebecontinuedforanappropriatelengthoftime,usuallyupto6monthsafterrecoveryinordertoprevent

relapse.Inpatientswithrecurrentdepression(unipolar)maintenancetherapymayneedtobecontinuedforanumberof

yearstopreventnewepisodes.

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),includingtheselectiveMAOBinhibitorselegilineandthereversibleMAOI

(RIMA),moclobemideandinpatientswhohaverecentlydiscontinuedanSSRIandhavebeenstartedonaMAOI.

Somecasespresentedwithfeaturesresemblingserotoninsyndrome.

CitaloprammustnotbeusedincombinationwithaMAOIincludingselegilineindosesabove10mgdaily.

Treatmentwithcitaloprammaybeinstituted14daysafterdiscontinuationofnon-selectiveMAOIsandminimumone

dayafterdiscontinuationofmoclobemide.TreatmentwithMAOIsmaybeintroduced7daysafterdiscontinuationof

citalopram(seesection4.5Interactionwithothermedicinalproductsandotherformsofinteraction).

Concomitanttreatmentwithpimozide.

CitalopramiscontraindicatedinpatientswithknownQT-intervalprolongationorcongenitallongQTsyndrome.

CitalopramiscontraindicatedtogetherwithmedicinalproductsthatareknowntoprolongtheQT-interval(seesection

4.5).

4.4Specialwarningsandprecautionsforuse

Treatmentofelderlypatientsandpatientswithreducedkidneyandliverfunction,seesection4.2.

Useinchildrenandadolescentsunder18yearsofage

Antidepressantsshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years.Suicide

relatedbehaviours(suicideattemptandsuicidalthoughts),andhostility(predominantlyaggression,oppositional

behaviourandanger)weremorefrequentlyobservedinclinicaltrialsamongchildrenandadolescentstreatedwith

antidepressantscomparedtothosetreatedwithplacebo.If,basedonclinicalneed,adecisiontotreatisnevertheless

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Paradoxicalanxiety

Somepatientswithpanicdisordermayexperienceintensifiedanxietysymptomsatthestartoftreatmentwith

antidepressants.Thisparadoxicalreactionusuallysubsideswithinthefirsttwoweeksofstartingtreatment.Alowstarting

doseisadvisedtoreducethelikelihoodofaparadoxicalanxiogeniceffect(seesection4.2PosologyandMethodof

Administration).

Hyponatraemia

Hyponatraemia,probablyduetoinappropriateantidiuretichormonesecretion(SIADH),hasbeenreportedasarareadverse

reactionwiththeuseofSSRIs.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,characterisedbyasubjectivelyunpleasant

ordistressingrestlessnessandneedtomoveoftenaccompaniedbyaninabilitytositorstandstill.Thisismostlikelyto

occurwithinthefirstfewweeksoftreatment.Inpatientswhodevelopthesesymptoms,increasingthedosemaybe

detrimental.

Mania

Inpatientswithmanic-depressiveillnessachangetowardsthemanicphasemayoccur.Shouldthepatiententeramanic

phasecitalopramshouldbediscontinued.

Seizures

Althoughanimalexperimentshaveshownthatcitalopramhasnoepileptogenicpotentialitshould,likeother

antidepressants,beusedwithcautioninpatientswithahistoryofseizures.

Diabetes

Asdescribedforotherpsychotropicscitaloprammaymodifyinsulinandglucoseresponsescallingforadjustmentofthe

antidiabetictherapyindiabeticpatients;inadditionthedepressiveillnessitselfmayaffectpatients´glucosebalance.

Serotoninsyndrome

Ifcitalopramisusedconcomitantlywithmedicinalproductswithserotonergiceffectssuchassumatriptanorothertriptans,

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Rarely,theoccurrenceof“serotoninsyndrome”hasbeenreportedinpatientsreceivingSSRIs.Acombinationof

symptoms,possiblyincludingagitation,confusion,tremor,myoclonusandhyperthermia,mayindicatethe

developmentofthiscondition(seesection4.5Interactionwithothermedicinalproductsandotherformsof

interactions).

Haemorrhage

TherehavebeenreportsofcutaneousbleedingabnormalitiessuchasecchymosesandpurpurawithSSRIs.Cautionis

advisedinpatientstakingSSRIs,particularlywithconcomitantuseoforalanticoagulants;medicinalproductsknownto

affectplateletfunction(e.g.atypicalantipsychoticsandphenothiazines,mosttricyclicantidepressants,acetylsalicyclicacid

andnon-sterodialanti-inflammatorymedicinalproducts(NSAIDs),ticlopidineanddipyridamole)aswellasinpatients

withahistoryofbleedingdisorders(seesection4.5Interactionwithothermedicinalproductsandotherformsof

interaction)

ECT(electroconvulsivetherapy)

ThereislimitedclinicalexperienceofconcurrentadministrationofSSRIsandECT;thereforecautionisadvisable.

Reversible,selectiveMAO-Ainhibitors

ThecombinationofcitalopramwithMAO-Ainhibitorsisgenerallynotrecommendedduetotheriskofonsetofa

serotoninsyndrome(seesection4.5

Interactionswithothermedicinalproductsandotherformsofinteraction)

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

StJohn’sWort

ConcomitantuseofSSRIsandherbalremediescontainingStJohn’sWort(Hypericumperforatum)mayresultinan

increasedincidenceofadversereactions(seesection4.5Interactionwithothermedicinalproductsandotherformsof

interaction).

QTintervalprolongation

Citalopramhasbeenfoundtocauseadose-dependentprolongationoftheQT-interval.CasesofQTinterval

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.

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

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Posologyandmethodofadministration)

Excipients

Thetabletscontainlactosemonohydrate.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnotreceivethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Pharmacodynamicinteractions

Atthepharmacodynamicleveltherehaveonlybeenfewdocumentedcasesofserotoninsyndromewithcitalopramand

moclobemideandbuspirone.

Contraindicatedcombinations

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

Contraindications)

QTintervalprolongation

PharmacokineticandpharmacodynamicstudiesbetweencitalopramandothermedicinalproductsthatprolongtheQT

intervalhavenotbeenperformed.Anadditiveeffectofcitalopramandthesemedicinalproductscannotbeexcluded.

Therefore,co-administrationofcitalopramwithmedicinalproductsthatprolongtheQTinterval,suchasClassIAandIII

antiarrhythmics,antipsycotics(e.g.fentiazinederviatives,pimozide,haloperidol),tricyclicantidepressants,certain

antimicrobialagents(e.g.sparfloxacin,moxifloxacin,erythromycinIV,pentamidine,anti-malariantreatmentparticularly

halofantrine),certainantihistamines(astemizole,mizolastine)etc.,iscontraindicated.

Pimozide

Coadministrationofasingledoseofpimozide2mgtosubjectstreatedwithracemiccitalopram40mg/dayfor11days

causedanincreaseinAUCandC

ofpimozide,althoughnotconsistentlythroughoutthestudy.Theco-

administrationofpimozideandcitalopramresultedinameanincreaseintheQTcintervalofapproximately10msec.

Duetotheinteractionnotedatalowdoseofpimozide,concomitantadministrationofcitalopramandpimozideis

contraindicated.

Combinationsrequiringprecautionforuse

Selegiline(selectiveMAO -Binhibitor)

Apharmacokinetic/pharmacodynamicinteractionstudywithconcomitantlyadministeredcitalopram(20mgdaily)and

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

theselegiline-citalopramcombinationwell.

Serotonergicmedicinalproducts

Lithiumandtryptophan

Nopharmacodynamicinteractionshavebeenfoundinclinicalstudiesinwhichcitalopramhasbeengivenconcomitantly

withlithium.HowevertherehavebeenreportsofenhancedeffectswhenSSRIshavebeengivenwithlithiumor

tryptophanandthereforetheconcomitantuseofcitalopramwiththesemedicinalproductsshouldbeundertakenwith

caution.

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

associatedeffects.

St.John’sWort

DynamicinteractionsbetweenSSRIsandherbalremedyStJohn’swort(Hypericumperforatum)canoccur,resultingin

anincreaseinundesirableeffects(seesection4.4SpecialWarningsandPrecautionsforUse)

Haemorrhage

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advisedinpatientstakingSSRIs,particularlywithconcomitantuseoforalanticoagulants;medicinalproductsknownto

affectplateletfunction(e.g.atypicalantipsychoticsandphenothiazines,mosttricyclicantidepressants,acetylsalicyclic

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

patientswithahistoryofbleedingdisorders(seesection4.4SpecialWarningsandPrecautionsforUse)

ECT(electroconvusivetherapy)

Therearenoclinicalstudiesestablishingtherisksorbenefitsofthecombineduseofelectroconvulsivetherapy(ECT)and

citalopram(seesection4.4SpecialWarningsandPrecautionsforUse)

Alcohol

ThecombinationofSSRIsandalcoholisnotadvisable.However,clinicalstudieshaverevealednoadverse

pharmacodynamicinteractionsbetweencitalopramandalcohol.

Pharmacokineticinteractions

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

andCYP2D6(approx.31%)isozymesofthecytochromeP450system.Thefactthatcitalopramismetabolisedbymore

thanoneCYPmeansthatinhibitionofitsbiotransformationislesslikelyandco-administrationofcitalopramwithother

medicinalproductsinclinicalpracticehasverylowlikelihoodofproducingpharmacokineticmedicinalproduct

interactions.

Influenceofothermedicinalproductsonthepharmacokineticsofcitalopram

Cimetidine(potentCYP2D6,3A4and1A2inhibitor)causedamoderateincreaseintheaveragesteadystatelevelsof

citalopram.Cautionisadvisedwhenadministeringcitalopramincombinationwithcimetidine.Doseadjustmentmaybe

warranted.

Effectsofcitalopramonothermedicinalproducts

Apharmacokinetic/pharmacodynamicinteractionstudywithconcomitantadministrationofcitalopramandmetoprolol(a

CYP2D6substrate)showedatwofoldincreaseinmetoprololconcentrations,butnostatisticallysignificantincreaseinthe

effectofmetoprololonbloodpressureandheartrateinhealthyvolunteers.

CitalopramanddemethylcitalopramarenegligibleinhibitorsofCYP2C9,CYP2E1andCYP3A4,andonlyweakinhibitors

ofCYP1A2,CYP2C19andCYP2D6ascomparedtootherSSRIsestablishedassignificantinhibitors.

Thusnochangeinpharmacokineticsoronlyverysmallchangesofnoclinicalimportancewereobservedwhencitalopram

wasgivenwithCYP1A2substrates(clozapineandtheophylline),CYP2C9(warfarin),CYP2C19(imipramineand

mephenytoin),CYP2D6(sparteine,imipramine,amitriptyline,risperidone)andCYP3A4(warfarin,carbamazepineand

triazolam).

Inapharmacokineticinteractionstudycitalopramdidnotcauseanychangesinthepharmacokineticsofdigoxinmeaning

thatcitalopramneitherinducesnorinhibitsP-glycoprotein.

4.6Fertility,pregnancyandlactation

Pregnancy

Clinicalexperienceofuseinpregnantwomenislimitedbutnoreports,whichmaycauseconcernhavebeenreceived.

Basedondatafromreproductiontoxicitystudies(segmentI,IIandIII)thereisnoreasontohavespecialconcernforthe

useofcitalopraminwomenofchildbearingpotential.

NeonatesshouldbeobservedifmaternaluseofCipramilcontinuesintothelaterstagesofpregnancy,particularinthe

thirdtrimester.Abruptdiscontinuationshouldbeavoidedduringpregnancy.

ThefollowingsymptomsmayoccurintheneonatesaftermaternalSSRI/SNRIuseinlaterstagesofpregnancy:

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

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difficultysleeping.Thesesymptomscouldbeduetoeitherserotonergiceffectsordiscontinuationsymptoms.Ina

majorityofinstancesthecomplicationsbeginimmediatelyorsoon(<24hours)afterdelivery.

Lactation

Citalopramisexcretedintobreastmilk.Itisestimatedthatthesucklinginfantwillreceiveabout5%oftheweight

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

existinginformationisinsufficientforassessmentoftherisktothechild.

Cautionisrecommended.

4.7Effectsonabilitytodriveandusemachines

Citalopramdoesnotimpairintellectualfunctionandpsychomotorperformance.However,patientswhoareprescribed

psychotropicmedicationmaybeexpectedtohavesomeimpairmentofgeneralattentionandconcentrationeitherdueto

theillnessitself,themedicationorbothandshouldbecautionedabouttheirabilitytodriveacarandoperate

machinery.

4.8Undesirableeffects

Adverseeffectsobservedwithcitalopramareingeneralmildandtransient.Theyaremostfrequentduringthefirstoneor

twoweeksoftreatmentandusuallyattenuatesubsequently.TheadversereactionsarepresentedattheMedDRA

PreferredTermLevel

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

diarrhoea,nauseaandfatigue.

ThetableshowsthepercentageofadversedrugreactionsassociatedwithSSRIsand/orcitalopramseenineither 1%of

patientsindouble-blindplacebo-controlledtrialsorinthepost-marketingperiod.Frequenciesaredefinedas:verycommon

(1/10);common(1/100,<1/10);uncommon(1/1000,<1/100);rare(1/10000,<1/1000);veryrare(<1/10000),not

known(cannotbeestimatedfromavailabledata).

MedDRASOC Frequency Preferredterm

Bloodandlymphatic

disorders NotKnown Thrombocytopenia

Immunesystemdisorders NotKnown HypersensitivityNOS

Anaphylacticreaction

Endocrinedisorders NotKnown InappropriateADHsecretion

Metabolismandnutrition

disorders Common AppetitedecreasedNOS 1

Uncommon increasedappetite

Rare Hyponatremia,

Psychiatricdisorders Common Agitation,libidodecreased,

anxiety,nervousness,

confusionalstate,abnormalorgasm

(female)

Uncommon Aggression,depersonalization,

hallucination,mania

Rare Suicide-relatedevents(seesection4.4)

NotKnown Panicattack,bruxism,restlessness

Verycommon Somnolence,insomniaNEC 2

Common Tremor,paraesthesiaNEC

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Numberofpatients:Citalopram/placebo=1346/545

NOS=Nototherwisespecified

Nervoussystemdisorders Rare Convulsiongrandmal,dyskinesia

NotKnown ConvulsionsNOS,serotonin

syndrome,extrapyramidaldisorder

NEC,akathisia,movementdisorder

Eyedisorders Uncommon Mydriasis

NotKnown Visualdisturbance

Earandlabyrinthdisorders Common Tinnitus

Cardiacdisorders Uncommon Bradycardia,tachycardia

Frequencyunknown Ventriculararrhythmiaincluding

torsadedepointes

Vasculardisorders NotKnown Orthostatichypotension

Respiratorythoracicand

mediastinaldisorders Common Yawning

NotKnown Epistaxis

Gastrointestinaldisorders Verycommon Drymouth,Nausea

Common DiarrhoeaNOS 1

,vomiting

NotKnown Gastrointestinalhaemorrhage

(includingrectalhaemorrhage)

Hepatobiliarydisorders Rare Hepatitis

Skinandsubcutaneous

tissuedisorders Verycommon Sweatingincreased

Common Pruritus

Uncommon Urticaria,alopecia,rash,purpuraNOS

NotKnown Ecchymosis,angioedemas

Musculoskeletal,

connectivetissueandbone

disorders Common Myalgia,arthralgia

Renalandurinary

disorders Uncommon Urinaryretention

Reproductivesystemand

breastdisorders Common Impotence,ejaculationdisorderNOS

ejaculationfailure

Uncommon Female:Menorrhagia

NotKnown Female:Metrorrhagia

Male:Priapism,galactorrhoea

Generaldisordersand

administrationsite

conditions Common Fatigue

Uncommon Oedema

Investigations Common Weightdecreased

Uncommon Weightincreased

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CasesofQT-prolongationandventriculararrhythmiaincludingtorsadedepointeshavebeenreportedduringthepost-

marketingperiod,predominantlyinpatientsoffemalegender,withhypokalemia,orwithpre-existingQTprolongation

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

WithdrawalsymptomsseenondiscontinuationofSSRItreatment

DiscontinuationofCitalopram(particularlywhenabrupt)commonlyleadstowithdrawalsymptoms.Dizziness,sensory

disturbances(including

paraesthesia),sleepdisturbances(includinginsomniaandintensedreams),agitationoranxiety,nauseaand/orvomiting,

tremor,confusion,sweating,headache,diarrhoea,palpitations,emotionalinstability,irritability,andvisualdisturbances

arethemostcommonlyreportedreactions.Generallytheseeventsaremildtomoderateandareself-limiting,however,

insomepatientstheymaybesevereand/orprolonged.Itisthereforeadvisedthatwhencitalopramtreatmentisno

longerrequired,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),

dopamine(DA)andgammaaminobutyricacid(GABA)uptake.

IncontrasttomanytricyclicantidepressantsandsomeofthenewerSSRIs,citalopramhasnoorverylowaffinityfora

seriesofreceptorsincluding5-HT

5-HT

,DAD

andD

receptors,

-adrenoceptors,histamineH

muscarinecholinergic,benzodiazepine,andopioidreceptors.Aseriesoffunctionalinvitrotestsinisolatedorgansas

wellasfunctionalinvivotestshaveconfirmedthelackofreceptoraffinity.Thisabsenceofeffectsonreceptorscould

explainwhycitalopramproducesfewerofthetraditionalside-effectssuchasdrymouth,bladderandgutdisturbance,

blurredvision,sedation,cardiotoxicityandorthostatichypotension.

ThemainmetabolitesofcitalopramareallSSRIsalthoughtheirpotencyandselectivityratiosarelowerthanthoseof

citalopram.However,theselectivityratiosofthemetabolitesarehigherthanthoseofmanyofthenewerSSRIs.The

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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

about0.05-0.08L/min.

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

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Reducedrenalfunction

Citalopramiseliminatedmoreslowlyinpatientswithmildtomoderatereductionofrenalfunction,withoutanymajor

impactonthepharmacokineticsofcitalopram.Atpresentnoinformationisavailablefortreatmentofpatientswith

severelyreducedrenalfunction(creatinineclearance<20mL/min).

Polymorphism

Invivoinvestigationshaveshownthatthemetabolismofcitalopramexhibitsnoclinicallyimportantpolymorphismofthe

sparteine/debrisoquineoxidation(CYP2D6).ForCYP2C19,asaprecaution,aninitialdoseof10mgshouldbeconsidered

forknownpoormetabolisers(seesection4.2).

Pharmacokinetic/pharmacodynamicrelationship

Thereisnoclearrelationshipbetweencitalopramplasmalevelsandtherapeuticresponseorsideeffects.Themetabolites

donotcontributetotheoverallantidepressanteffect.

5.3Preclinicalsafetydata

Acutetoxicity

Citalopramhasalowacutetoxicity.

Chronictoxicity

Inchronicstudiestherewerenofindingsofconcernforthetherapeuticuseofcitalopram.

Reproductionstudies

Basedondatafromreproductiontoxicitystudies(segmentI,IIandIII)thereisnoreasontohavespecialconcernfor

theuseofcitalopraminwomenofchildbearingpotential.

Citalopramappearsinmilkinlowconcentrations.

Embryotoxicitystudiesinratswithdosesof56mg/kg/day,whichcausematernaltoxicityshowedboneanomaliesin

theregionofthevertebralcolumnandribs.Thematernalplasmalevelwasthen2-3timesthetherapeuticconcentration

inman.Inratscitalopramdidnothaveanyeffectonfertility,pregnancyandpostnataldevelopmentbutdiminishedthe

birthweightofthepups.Citalopramanditsmetabolitesreachfoetalconcentrations,whichare10-15timesthematernal

plasmalevel.Clinicalexperienceofuseinpregnantwomenandduringlactationislimited.

Mutagenicandcarcinogenicpotential

Citalopramhasnomutagenicorcarcinogenicpotential.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Maizestarch

Lactose

Microcrystallinecellulose

Copovidone

Glycerol

Croscarmellosesodium

Magnesiumstearate

Hypromellose

Macrogol

Titaniumdioxide(E171)

6.2Incompatibilities

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6.3Shelflife

Theshelflifeexpirydateofthisproductisthedateshownontheblisterstripsandoutercartonoftheproductas

marketedinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25˚C.Keepintheoriginalcontainerinordertoprotectfromlight.

6.5Natureandcontentsofcontainer

Anover-labelledcardboardcartoncontainingtwoblisters.Eachblistercontains14tablets.

Anover-labelledcardboardcartoncontainingoneblisterwhichcontains28tablets.

Packsize:28tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements

7PARALLELPRODUCTAUTHORISATIONHOLDER

ProfindWholesaleLtd

Unit625,KilshaneAvenue

NorthwestBusinessPark

Dublin15

Ireland

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1500/51/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:5 th

February2010

10DATEOFREVISIONOFTHETEXT

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