CIPRAMIL

Main information

  • Trade name:
  • CIPRAMIL Tablets 10 Milligram
  • Dosage:
  • 10 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CIPRAMIL Tablets 10 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1328/021/001
  • Authorization date:
  • 25-08-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cipramil10mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains10mgCitalopram(ashydrobromide).

Excipients:Lactose

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedTablet.

ProductimportedfromtheUK:

Round,whitetabletmarked‘CL’ononeside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofdepressiveillnessintheinitialphaseandasmaintenanceagainstpotentialrelapse/recurrence.

Cipramilisalsoindicatedinthetreatmentofpanicdisorderwithorwithoutagoraphobia.

4.2Posologyandmethodofadministration

Adults

TreatingDepression

Citalopramshouldbeadministeredasasingleoraldoseof20mgdaily.Dependentonindividualpatientresponseand

severityofdepressionthedosemaybeincreasedtoamaximumof60mgdaily.

TreatingPanicDisorder

Asingleoraldoseof10mgisrecommendedforthefirstweekbeforeincreasingthedoseto20mgdaily.Thedosemay

befurtherincreased,uptoamaximumof60mgdailydependentonindividualpatientresponse.

Elderlypatients(>65yearsofage)

Inelderlypatientsthedosemaybeincreasedtoamaximumof40mgdaily.

Children&Adolescents(<18years)

Cipramilshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years(seesection4.4.

Specialwarningsandprecautionsforuse).

Reducedrenalfunction

Dosageadjustmentisnotnecessaryinpatientswithmildormoderaterenalimpairment.Noinformationisavailableon

treatmentofpatientswithseverelyreducedrenalfunction(creatinineclearance<20ml/min).

Reducedhepaticfunction

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/09/2010 CRN 2081859 page number: 1

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)

○CasesofseriousandsometimesfatalreactionshavebeenreportedinpatientsreceivinganSSRIincombination

withmonoamineoxidaseinhibitor(MAOI),includingtheselectiveMAO-Binhibitorselegilineandthereversible

MAOI

○(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

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/09/2010 CRN 2081859 page number: 2

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

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/09/2010 CRN 2081859 page number: 3

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

lactasedeficiencyorglucose-galactosemalabsorptionshouldnotreceivethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Pharmacodynamicinteractions

Atthepharmacodynamicleveltherehaveonlybeenfewdocumentedcasesofserotoninsyndromewithcitalopramand

moclobemideandbuspirone.

Contraindicatedcombinations

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

Contraindications)

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/09/2010 CRN 2081859 page number: 4

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

pharmacodynamicinteractionsbetweencitalopramandalcohol.

Pharmacokineticinteractions

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

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

bymorethanoneCYPmeansthatinhibitionofitsbiotransformationislesslikelyandco-administrationofcitalopram

withothermedicinalproductsinclinicalpracticehasverylowlikelihoodofproducingpharmacokineticmedicinal

productinteractions.

Influenceofothermedicinalproductsonthepharmacokineticsofcitalopram

Co-administrationwithketoconazole(potentCYP3A4inhibitor)didnotchangethepharmacokineticsofcitalopram.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/09/2010 CRN 2081859 page number: 5

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.

4.6Pregnancyandlactation

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.

EpidemiologicaldatahavesuggestedthattheuseofSSRIsinpregnancy,particularinlatepregnancy,mayincreasethe

riskofpersistentpulmonaryhypertensioninthenewborn(PPHN).Theobservedriskwasapproximately5casesper

1000pregnancies.Inthegeneralpopulation1to2casesofPPHNper1000pregnanciesoccur.

Lactation

Citalopramisexcretedintobreastmilk.Itisestimatedthatthesucklinginfantwillreceiveabout5%oftheweight

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

existinginformationisinsufficientforassessmentoftherisktothechild.

Cautionisrecommended.

4.7Effectsonabilitytodriveandusemachines

Citalopramdoesnotimpairintellectualfunctionandpsychomotorperformance.However,patientswhoareprescribed

psychotropicmedicationmaybeexpectedtohavesomeimpairmentofgeneralattentionandconcentrationeitherdueto

theillnessitself,themedicationorbothandshouldbecautionedabouttheirabilitytodriveacarandoperate

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/09/2010 CRN 2081859 page number: 6

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 HypersensitivityNOS

Anaphylacticreaction

Endocrinedisorders

NotKnown InappropriateADHsecretion

Metabolismand

nutritiondisorders Common AppetitedecreasedNOS 1

Uncommon increasedappetite

Rare Hyponatremia,

Psychiatricdisorders

Common Agitation,libidodecreased,

anxiety,nervousness,

confusionalstate,abnormal

orgasm(female)

Uncommon Aggression,depersonalization,

hallucination,mania

Rare Suicide-relatedevents(see

section4.4)

NotKnown Panicattack,bruxism,

restlessness

Nervoussystem

disorders Verycommon Somnolence,insomniaNEC 2

Common Tremor,paraesthesiaNEC

Uncommon Syncope

Rare Convulsiongrandmal,

dyskinesia

NotKnown ConvulsionsNOS,serotonin

syndrome,extrapyramidal

disorder

NEC,akathisia,movement

disorder

Eyedisorders

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/09/2010 CRN 2081859 page number: 7

NotKnown Visualdisturbance

Earandlabyrinth

disorders Common Tinnitus

Cardiacdisorders

Uncommon Bradycardia,tachycardia

Vasculardisorders

NotKnown Orthostatichypotension

Respiratorythoracic

andmediastinal

disorders Common Yawning

NotKnown Epistaxis

Gastrointestinal

disorders Verycommon Drymouth,Nausea

Common

DiarrhoeaNOS 1

,vomiting

NotKnown Gastrointestinalhaemorrhage

(includingrectalhaemorrhage)

Hepatobiliary

disorders Rare Hepatitis

Skinandsubcutaneous

tissuedisorders 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

Generaldisordersand

administrationsite

conditions Common Fatigue

Uncommon Oedema

Investigations

Common Weightdecreased

Uncommon Weightincreased

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/09/2010 CRN 2081859 page number: 8

Numberofpatients:Citalopram/placebo=1346/545

NOS=Nototherwisespecified

NEC=Notelsewhereclassified

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).

Classeffects

Epidemiologicalstudies,mainlyinpatients50yearsofageandolder,showanincreasedriskofbonefracturesin

patientsreceivingSSRIsandTCAs.Themechanismleadingtothisriskisunknown.

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

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/09/2010 CRN 2081859 page number: 9

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

about0.05-0.08L/min.

Linearity

Thekineticsarelinear.Steadystateplasmalevelsareachievedin1-2weeks.Averageconcentrationsof300nmol/L

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/09/2010 CRN 2081859 page number: 10

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,whichare10-15timesthematernalplasmalevel.Clinical

experienceofuseinpregnantwomenandduringlactationislimited.

Mutagenicandcarcinogenicpotential

Citalopramhasnomutagenicorcarcinogenicpotential.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Maizestarch

LactoseMonohydrate

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/09/2010 CRN 2081859 page number: 11

Copovidone

Glycerol

CroscarmelloseSodium

Magnesiumstearate

Hypromellose

Macrogol400

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductisthedateshownonthecontainerandouterpackageoftheproductonthe

marketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

6.5Natureandcontentsofcontainer

PressthroughpacksconsistingofaluminiumfoilandUPVC/PVdCfoilincartonscontaining28tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

B&SHealthcare

Unit4

BradfieldRoad

Ruislip

Middlesex

HA40NU

UnitedKingdom

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1328/021/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:25August2006

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/09/2010 CRN 2081859 page number: 12