CIPRAMIL

Main information

  • Trade name:
  • CIPRAMIL Oral Drops Solution 40 Mg/Ml
  • Dosage:
  • 40 Mg/Ml
  • Pharmaceutical form:
  • Oral Drops Solution
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CIPRAMIL Oral Drops Solution 40 Mg/Ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1659/022/002
  • Authorization date:
  • 21-12-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cipramil40mg/mlOraldrops,solution.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

1mlcontains40mgcitalopram(as44.48mgcitalopramhydrochloride)

1ml=20drops.1drop=2mgcitalopram

Excipients

Methylparahydroxybenzoate(E218)

Propylparahydroxybenzoate(E216)

Ethanollessthan100mginalldoses

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Oraldrops,solution.

ProductimportedfromUnitedKingdom:

Clear,nearlycolourlesstoyellowishsolutionwithabittertaste.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofdepressiveillnessintheinitialphaseandasmaintenanceagainstpotentialrelapse/recurrence.

Cipramilisalsoindicatedinthetreatmentofpanicdisorderwithorwithoutagoraphobia.

4.2Posologyandmethodofadministration

Adults

TreatingDepression

Citalopramdropsshouldbeadministeredasasingleoraldoseof16mg(8drops)daily.Dependentonindividual

patientresponseandseverityofdepressionthedosemaybeincreasedtoamaximumof48mg(24drops)daily.

TreatingPanicDisorder

Asingleoraldoseof8mg(4drops)dailyisrecommendedforthefirstweekbeforeincreasingthedoseto16mg(8

drops)daily.Thedosemaybefurtherincreased,uptoamaximumof48mg(24drops)daily,dependentonindividual

patientresponse.

Elderlypatients(>65yearsofage)

Inelderlypatientsthedosemaybeincreasedtoamaximumof32mg(16drops)daily.

Children&Adolescents(<18years)

Cipramilshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18years,seesection4.4

Reducedrenalfunction

Dosageadjustmentisnotnecessaryinpatientswithmildormoderaterenalimpairment.Noinformationisavailableon

treatmentofpatientswithseverelyreducedrenalfunction(creatinineclearance <

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/12/2010 CRN 2088164 page number: 1

Reducedhepaticfunction

Patientswithreducedhepaticfunctionshouldreceivedosagesofnomorethan24mg/day(12drops/day)

Methodofadministration

Citalopramoraldrops,solutionisadministeredasasingledailydose.

Citalopramoraldrops,solutioncanbetakenanytimeofthedaywithoutregardtofoodintake.

Citalopramoraldrops,solutioncanbemixedwithwater,orangejuiceorapplejuice.

Citalopramoraldrops,solutionhaveanapproximately25%higherbioavailabilitycomparedtotablets.Consequently

dosesoftabletscorrespondtodosesofdropsasfollows:

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(seesection4.5InteractionswithotherMedicamentsandotherformsofInteractions)

Tablets Drops

10mg 8mg(4drops)

20mg 16mg(8drops)

30mg 24mg(12drops)

40mg 32mg(16drops)

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/12/2010 CRN 2088164 page number: 2

4.4Specialwarningsandprecautionsforuse

Treatmentofelderlypatientsandpatientswithreducedkidneyandliverfunction,(seesection4.2Posologyand

methodofadministration).

Useinchildrenandadolescentsunder18yearsofage

Antidepressantsshouldnotbeusedinthetreatmentofchildrenandadolescentsunderageof18years.Suiciderelated

behaviours(suicideattemptandsuicidalthoughts),andhostility(predominantlyaggression,oppositionalbehaviourand

anger)weremorefrequentlyobservedinclinicaltrialsamongchildrenandadolescentstreatedwithantidepressants

comparedtothosetreatedwithplacebo.If,basedonclinicalneed,adecisiontotreatisneverthelesstaken,thepatient

shouldbecarefullymonitoredfortheappearanceofsuicidalsymptoms.

Paradoxicalanxiety

Somepatientswithpanicdisordermayexperienceintensifiedanxietysymptomsatthestartoftreatmentwith

antidepressants.Thisparadoxicalreactionusuallysubsideswithinthefirsttwoweeksofstartingtreatment.Alow

startingdoseisadvisedtoreducethelikelihoodofaparadoxicalanxiogeniceffect(seesection4.2Posologyand

methodofadministration).

Hyponatraemia

Hyponatraemia,probablyduetoinappropriateantidiuretichormonesecretion(SIADH),hasbeenreportedasarare

adversereactionwiththeuseofSSRIs.Elderlyfemalepatientsespeciallyseemtobeariskgroup.

Suicide/suicidalthoughtsorclinicalworsening

Depressionisassociatedwithanincreasedriskofsuicidalthoughts,selfharmandsuicide(suicide-

relatedevents).Thisriskpersistsuntilsignificantremissionoccurs.Asimprovementmaynotoccurduringthefirstfew

weeksormoreoftreatment,patientsshouldbecloselymonitoreduntilsuchimprovementoccurs.Itisgeneralclinical

experiencethattheriskofsuicidemayincreaseintheearlystagesofrecovery.

Otherpsychiatricconditionsforwhichcitalopramisprescribedcanalsobeassociatedwithanincreasedriskofsuicide-

relatedevents.Inaddition,theseconditionsmaybeco-morbidwithmajordepressivedisorder.Thesameprecautions

observedwhentreatingpatientswithmajorwhentreatingpatientswithotherpsychiatricdisorders.

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

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/12/2010 CRN 2088164 page number: 3

Seizures

Althoughanimalexperimentshaveshownthatcitalopramhasnoepileptogenicpotentialitshould,

likeotherantidepressants,beusedwithcautionin

patientswithahistoryofseizures.

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

interactions).

Haemorrhage

TherehavebeenreportsofcutaneousbleedingabnormalitiessuchasecchymosesandpurpurawithSSRIs.Cautionis

advisedinpatientstakingSSRIs,particularlywithconcomitantuseoforalanticoagulants;medicinalproductsknownto

affectplateletfunction(e.g.atypicalantipsychoticsandphenothiazines,mosttricyclicantidepressants,phenothiazines,

mosttricyclicantidepressants,acetylsalicyclicacidandnon-sterodialanti-inflammatorymedicinalproducts(NSAIDs),

ticlopidineanddipyridamole)aswellasinpatientswithahistoryofbleedingdisorders(seesection4.5Interaction

withothermedicinalproductsandotherformsofinteractions).

ECT(electroconvulsivetherapy)

ThereislimitedclinicalexperienceofconcurrentadministrationofSSRIsandECT;thereforecautionisadvisable.

Reversible,selectiveMAO-Ainhibitors

ThecombinationofcitalopramwithMAO-Ainhibitorsisgenerallynotrecommendedduetotheriskofonsetofa

serotoninsyndrome(seesection4.5).

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

Interactionwithothermedicinalproductsandotherformsofinteractions).

StJohn’sWort

ConcomitantuseofSSRIsandherbalremediescontainingStJohn’sWort(Hypericumperforatum)mayresultinan

increasedincidenceofadversereactions(seesection4.5Interactionwithothermedicinalproductsandotherformsof

interactions).

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,palpitations,emotionalinstability,irritability,andvisualdisturbancesarethemostcommonlyreported

reactions.Generallythesesymptomsaremildtomoderate,however,insomepatientstheymaybesevereinintensity.

Theyusuallyoccurwithinthefirstfewdaysofdiscontinuingtreatment,buttherehavebeenvery

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/12/2010 CRN 2088164 page number: 4

Generallythesesymptomsareself-limitingandusuallyresolvewithin2weeks,thoughinsome

individualstheymaybeprolonged(2-3monthsormore).Itisthereforeadvisedthatcitalopramshould

begraduallytaperedwhendiscontinuingtreatmentoveraperiodofseveralweeksormonths,accordingtothepatient’s

needs(seesection4.2Posologyandmethodofadministration).

Excipients

Theoralsolutioncontainssmallamountsofethanol,lessthan100mginalldoses.

ThesolutionalsocontainsMethylparahydroxybenzoate(E218)andpropylparahydroxybenzoate(E216)whichmay

causeallergicreactions(possiblydelayed).

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

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/12/2010 CRN 2088164 page number: 5

Haemorrhage

TherehavebeenreportsofcutaneousbleedingabnormalitiessuchasecchymosesandpurpurawithSSRIs.Cautionis

advisedinpatientstakingSSRIs,particularlywithconcomitantuseoforalanticoagulants;medicinalproductsknownto

affectplateletfunction(e.g.atypicalantipsychoticsandphenothiazines,mosttricyclicantidepressants,acetylsalicyclic

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

patientswithahistoryofbleedingdisorders(seesection4.4Specialwarningsandspecialprecautionsforuse)

ECT(electroconvusivetherapy)

Therearenoclinicalstudiesestablishingtherisksorbenefitsofthecombineduseofelectroconvulsivetherapy(ECT)

andcitalopram(seesection4.4Specialwarningsandspecialprecautionsforuse)

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.

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

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/12/2010 CRN 2088164 page number: 6

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.

Cautionisrecommended.

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 HypersensitivityNOS

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/12/2010 CRN 2088164 page number: 7

Endocrinedisorders NotKnown InappropriateADH

secretion

Metabolismand

nutritiondisorders Common Appetitedecreased

Uncommon increasedappetite

Rare Hyponatremia,

Psychiatricdisorders Common Agitation,libido

decreased,

anxiety,nervousness,

confusionalstate,

abnormalorgasm

(female)

Uncommon Aggression,

depersonalization,

hallucination,mania

Rare Suicide-relatedevents

(seesection4.4)

NotKnown Panicattack,bruxism,

restlessness

Nervoussystem

disorders Verycommon Somnolence,insomnia

Common Tremor,paraesthesia

Uncommon Syncope

Rare Convulsiongrandmal,

dyskinesia

NotKnown ConvulsionsNOS,

serotonin

syndrome,

extrapyramidal

disorder

NEC,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

Verycommon Drymouth,Nausea

Common

DiarrhoeaNOS 1

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/12/2010 CRN 2088164 page number: 8

Numberofpatients:Citalopram/placebo=1346/545

NOS=Nototherwisespecified

NEC=Notelsewhereclassified

CasesofQT-prolongationhavebeenreportedduringthepost-marketingperiod,predominantlyinpatientswithpre-

existingcardiacdisease.

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,

Gastrointestinal

disorders vomiting

NotKnown Gastrointestinal

haemorrhage

(includingrectal

haemorrhage)

Hepatobiliary

disorders Rare Hepatitis

Skinandsubcutaneous

tissuedisorders Verycommon Sweatingincreased

Common Pruritus

Uncommon Urticaria,alopecia,

rash,purpuraNOS

NotKnown Ecchymosis,

angioedemas

Musculoskeletal,

connectivetissueand

bonedisorders Common Myalgia,arthralgia

Renalandurinary

disorders Uncommon Urinaryretention

Reproductivesystem

andbreastdisorders Common Impotence,ejaculation

disorderNOS 1

ejaculationfailure

Uncommon Female:Menorrhagia

NotKnown Female:Metrorrhagia

Male:Priapism,

galactorrhoea

Generaldisordersand

administrationsite

conditions Common Fatigue

Uncommon Oedema

Investigations Common Weightdecreased

Uncommon Weightincreased

NotKnown Liverfunctiontest

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/12/2010 CRN 2088164 page number: 9

Itisthereforeadvisedthatwhencitalopramtreatmentisnolongerrequired,gradualdiscontinuationbydosetapering

shouldbecarriedout(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.Establishandmaintain

anairway,ensureadequateoxygenationandrespiratoryfunction.Gastriclavageandtheuseofactivatedcharcoal

mightbeconsidered.Gastriclavageshouldbecarriedoutassoonaspossibleafteroralingestion.Cardiacandvital

signsmonitoringarerecommendedalongwithgeneralsymptomaticsupportivemeasures.

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

explainwhycitalopramproducesfewerofthetraditionalsideeffectssuchasdrymouth,bladderandgutdisturbance,

blurredvision,sedation,cardiotoxicityandorthostatichypotension.

ThemainmetabolitesofcitalopramareallSSRIsalthoughtheirpotencyandselectivityratiosarelowerthanthoseof

citalopram.However,theselectivityratiosofthemetabolitesarehigherthanthoseofmanyofthenewerSSRIs.The

metabolitesdonotcontributetotheoverallantidepressanteffect.

Pharmacodynamiceffects

Suppressionofrapideyemovement(REM)sleepisconsideredapredictorofantidepressantactivity.Liketricyclic

antidepressants,otherSSRIsandMAOinhibitors,citalopramsuppressesREM-sleepandincreasesdeepslow-wave

sleep.

Althoughcitalopramdoesnotbindtoopioidreceptorsitpotentiatestheanti-nociceptiveeffectofcommonlyused

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/12/2010 CRN 2088164 page number: 10

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

Citalopramismetabolizedtotheactivedemethylcitalopram,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%ofthedailydose

isexcretedinurineasunchangedcitalopram.Hepatic(residual)clearanceisabout0.3L/minandrenalclearanceabout

0.05-0.08L/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

normalliverfunction.

Reducedrenalfunction

Citalopramiseliminatedmoreslowlyinpatientswithmildtomoderatereductionofrenalfunction,withoutanymajor

impactonthepharmacokineticsofcitalopram.Atpresentnoinformationisavailablefortreatmentofpatientswith

severelyreducedrenalfunction(creatinineclearance <

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/12/2010 CRN 2088164 page number: 11

Polymorphism

Invivoinvestigationshaveshownthatthemetabolismofcitalopramexhibitsnoclinicallyimportantpolymorphismof

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

consideredforknownpoormetabolisers(seesection4.2).

Pharmacokinetic/pharmacodynamicrelationship

Thereisnoclearrelationshipbetweencitalopramplasmalevelsandtherapeuticresponseorsideeffects.

Themetabolitesdonotcontributetotheoverallantidepressanteffect.

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

Citalopramhasnomutagenicorcarcinogenicpotential.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Methylparahydroxybenzoate(E218)

Propylparahydroxybenzoate(E216)

Ethanol

Hydroxyethylcellulose

Purifiedwater

6.2Incompatibilities

CipramilDropsshouldonlybemixedwithwater,orangejuiceorapplejuice.

6.3ShelfLife

Unopened:Theshelf-lifeexpirydateofthisproductshallbethedateshownontheblisterandouterpackageofthe

productonthemarketinthecountryoforigin.

Abottlemaybeusedfor16weeksafterfirstopening,ifstoredbelow25°Cinthedark.

6.4Specialprecautionsforstorage

Irish Medicines Board

______________________________________________________________________________________________________________________

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

6.5Natureandcontentsofcontainer

Brownglassbottlecontaining15mlwithscrewcapandpolyethylenedropper.Onebottlepercartoninanover-labelled

carton

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

IPSHealthcareLimited

SterlingHouse,

501MiddletonRoad

Chadderton,Oldham,

Lancashire

OL99LY,

UnitedKingdom.

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1659/22/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:21stDecember2010

Irish Medicines Board

______________________________________________________________________________________________________________________

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