CIPRAPINE

Main information

  • Trade name:
  • CIPRAPINE Film Coated Tablet 40 Milligram
  • Dosage:
  • 40 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CIPRAPINE Film Coated Tablet 40 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0281/117/003
  • Authorization date:
  • 18-06-2004
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Ciprapine40mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains40mgcitalopramascitalopramhydrobromide.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

Round,white,biconvextabletswithadiameterof10mm.

Thetabletscanbedividedintoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofmajordepressiveepisodes.

4.2Posologyandmethodofadministration

Citalopramshouldbeadministeredasasingleoraldose,eitherinthemorningorintheevening.Thetabletscanbe

takenwithorwithoutfood,butwithfluid.

Followingtreatmentinitiation,anantidepressanteffectshouldnotbeexpectedforatleasttwoweeks.Treatmentshould

continueuntilthepatienthasbeenfreeofsymptomsfor4-6months.Citalopramshouldbewithdrawnslowly,itis

advisedthatthedoseisgraduallyreducedover1-2weekperiods.

Adults:

Therecommendedstartingdoseis20mgperday.Ifnecessary,thedosecanbeincreasedupto40mgperday,

dependingontheindividualresponseofthepatient.Themaximumdoseis60mgperday.

Elderlypatients(>65yearsofage):

Forelderlypatientsthedoseshouldbedecreasedtohalfoftherecommendeddose,e.g10-20mgperday.Depending

ontheindividualresponseofthepatient,thedosecanbeincreased.

Childrenandadolescentsundertheageof18:

Notrecommended,assafetyandefficacyhavenotbeenestablishedinthispopulation.

Reducedrenalfunction:

Dosageadjustmentisnotrequiredifthepatienthasmildtomoderaterenalimpairment.Noinformationisavailableon

treatmentofpatientswithsevererenalimpairment(creatinineclearancelessthan20ml/min)(seeSection4.4Special

warningsandspecialprecautionsforuse).

Reducedhepaticfunction:

Patientswithhepaticimpairmentshouldreceiveastartingdoseof10mgperday.Thedoseshouldnotexceed30mg

perday.Thesepatientsshouldbeclinicallymonitored(seeSection4.4Specialwarningsandspecialprecautionsfor

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4.3Contraindications

Hypersensitivitytocitalopramortoanyoftheexcipients.

CitalopramshouldnotbegiventopatientsreceivingMonoamineOxidaseInhibitors(MAOIs)including

selegilineindailydosesexceeding10mg/day.Citalopramshouldnotbegivenforfourteendaysafter

discontinuationofanirreversibleMAOIorforthetimespecifiedafterdiscontinuationofareversibleMAOI

(RIMA)asstatedintheprescribingtextoftheRIMA.MAOIsshouldnotbeintroducedforsevendaysafter

discontinuationofcitalopram.

CasesofseriousandsometimesfatalreactionshavebeenreportedinpatientsreceivinganSSRIincombinationwitha

monoamineoxidaseinhibitor(MAOI),includingtheselectiveMAOIselegilineandthereversibleMAOI(RIMA),

moclobemideandinpatientswhohaverecentlydiscontinuedanSSRIandhavebeenstartedonaMAOI.

Somecasespresentedwithfeaturesresemblingserotoninsyndrome.Symptomsofanactivesubstanceinteractionwith

aMAOIinclude:hyperthermia,rigidity,myoclonus,autonomicinstabilitywithpossiblerapidfluctuationsofvital

signs,mentalstatuschangesthatincludeconfusion,irritabilityandextremeagitationprogressingtodeliriumandcoma.

4.4Specialwarningsandprecautionsforuse

Citalopramshouldbeprescribedinthesmallestquantityoftabletsinordertoreducetheriskofoverdose.

Citalopramshouldnotbeusedconcomitantlywithmedicinalproductswithserotonergiceffectssuchassumatriptanor

othertriptans,tramadol,oxitriptanandtryptophan.

Inpatientswithdiabetes,treatmentwithanSSRImayalterglycaemiccontrol.Insulinand/ororalhypoglycaemic

dosagemayneedtobeadjusted.

Citalopramshouldbediscontinuedinanypatientwhodevelopsseizures.Citalopramshouldbeavoidedinpatientswith

unstableepilepsyandpatientswithcontrolledepilepsyshouldbecarefullymonitored.Citalopramshouldbe

discontinuedifthereisanincreaseinseizurefrequency.

Thereislittleclinicalexperienceofconcurrentadministrationofcitalopramandelectro-convulsivetherapy,therefore

cautionisadvisable.

Citalopramshouldbeusedwithcautioninpatientswithahistoryofmania/hypomania.Citalopramshouldbe

discontinuedinanypatiententeringamanicphase.

Therehavebeenreportsofprolongedbleedingtimeand/orbleedingabnormalitiessuchasecchymosis,gynaecological

haemorrhages,gastrointestinalbleedingsandothercutaneousormucousbleedingswithSSRIs(seeSection4.8

Undesirableeffects).CautionisadvisedinpatientstakingSSRIs,particularlyinconcomitantusewithactivesubstances

knowntoaffectplateletfunctionorotheractivesubstancesthatcanincreasetheriskofhaemorrhageaswellasin

patientswithahistoryofbleedingdisorders(seeSection4.5Interactions).

InrarecasesaserotoninsyndromehasbeenreportedinpatientsusingSSRIs.Acombinationofsymptoms,suchas

agitation,tremor,myoclonusandhyperthermiamayindicatethedevelopmentofthiscondition.Treatmentwith

citalopramshouldbediscontinuedimmediatelyandsymptomatictreatmentinitiated.

Treatmentofpsychoticpatientswithdepressiveepisodesmayincreasepsychoticsymptoms.

Suicide/suicidalthoughtsorclinicalworsening:

Depressionisassociatedwithanincreasedriskofsuicidalthoughts,selfharmandsuicide(suicide-relatedevents).This

riskpersistsuntilsignificantremissionoccurs.Asimprovementmaynotoccurduringthefirstfewweeksormoreof

treatment,patientsshouldbecloselymonitoreduntilsuchimprovementoccurs.Itisgeneralclinicalexperiencethatthe

riskofsuicidemayincreaseintheearlystagesofrecovery.

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commencementoftreatmentareknowntobeatgreaterriskofsuicidalthoughtsorsuicideattempts,andshouldreceive

carefulmonitoringduringtreatment.

Ameta -analysisofplacebo-controlledclinicaltrialsofantidepressantdrugsinadultpatientswithpsychiatricdisorders

showedanincreasedriskofsuicidalbehaviourwithantidepressantscomparedtoplaceboinpatientslessthan25years

old.

Closesupervisionofpatientsandinparticularthoseathighriskshouldaccompanydrugtherapyespeciallyinearly

treatmentandfollowingdosechanges.Patients(andcaregiversofpatients)shouldbealertedabouttheneedtomonitor

foranyclinicalworsening,suicidalbehaviourorthoughtsandunusualchangesinbehaviourandtoseekmedicaladvice

immediatelyifthesesymptomspresent.

Useinchildrenandadolescentsunder18yearsofage

Ciprapine40mgfilm-coatedtabletsshouldnotbeusedinthetreatmentofchildrenandadolescentsundertheageof18

years.Suicide-relatedbehaviours(suicideattemptandsuicidalthoughts),andhostility(predominantlyaggression,

oppositionalbehaviourandanger)weremorefrequentlyobservedinclinicaltrialsamongchildrenandadolescents

treatedwithantidepressantscomparedtothosetreatedwithplacebo.If,basedonclinicalneed,adecisiontotreatis

neverthelesstaken,thepatientshouldbecarefullymonitoredfortheappearanceofsuicidalsymptoms.Inaddition,

long-termsafetydatainchildrenandadolescentsconcerninggrowth,maturationandcognitiveandbehavioural

developmentarelacking.

Theuseofcitalopraminpatientswithsevererenalimpairment(creatinineclearancelessthan20ml/min.)isnot

recommendedasnoinformationisavailableonuseinthesepatients.(seeSection4.2Posologyandmethodof

administration).

Incasesofimpairedhepaticfunctiondosereductionisrecommended(seeSection4.2Posologyandmethodof

administration)andliverfunctionhastobecloselymonitored.

Hyponatraemiaandthesyndromeofinappropriateanti-diuretichormonesecretion(SIADH)hasbeenreportedrarely,

predominantlyintheelderly,andgenerallyreversesondiscontinuationoftherapy.

UndesirableeffectsmaybemorecommonduringconcomitantuseofcitalopramandherbalpreparationscontainingSt

John'swort(Hypericumperforatum).ThereforecitalopramandStJohn'swortpreparationsshouldnotbetaken

concomitantly(seeSection4.5Interactions).

Atthebeginningofthetreatment,insomniaandagitationcanoccur.Adosetitrationmaybehelpful.

Increasedlevelsofaminormetaboliteofcitalopram(didemethylcitalopram)couldtheoreticallyprolongtheQTc

intervalinsusceptibleindividuals.ECGmonitoringof2500patientsinclinicaltrials,including277patientswithpre-

existingcardiacconditionsdidnotrevealclinicallysignificantchanges.However,ECGmonitoringmaybeadvisable

incaseofoverdoseorconditionsofalteredmetabolismwithincreasedpeaklevels,e.g.liverimpairment.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Pharmacodynamicinteractions

ThesimultaneoususeofcitalopramandMAO-inhibitorscanresultinseveresideeffects,includingtheserotonin

syndrome(seeSection4.3Contraindications).

Theserotonergiceffectofsumatriptanmaybepotentiatedbyselectiveserotoninre-uptakeinhibitors(SSRIs).Until

furtherinformationisavailable,thesimultaneoususeofcitalopramand5-HTagonists,suchassumatriptanandother

triptans,isnotrecommended(seeSection4.4Specialwarningsandspecialprecautionsforuse).

Cautioniswarrantedforpatientswhoarebeingtreatedsimultaneouslywithanticoagulants,medicinalproductsthat

affectthefunctionofthrombocytes,suchasNSAIDs,acetylsalicylicacid,dipyridamol,andticlopidineorother

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(seeSection4.4Specialwarningsandspecialprecautionsforuse).

Experiencewithcitalopramhasnotrevealedanyclinicallyrelevantinteractionswithneuroleptics.However,aswith

otherSSRIs,thepossibilityofapharmacodynamicinteractioncannotbeexcluded.

Undesirableeffectsmaybemorecommonduringconcomitantuseofcitalopramandherbalpreparations

containingStJohn'swort(Hypericumperforatum)(seeSection4.4Specialwarningsandspecialprecautionsfor

use).

Nopharmacodynamicorpharmacokineticinteractionshavebeendemonstratedbetweencitalopramandalcohol.

However,thecombinationofcitalopramandalcoholisnotadvisable.

Pharmacokineticinteractions

Pharmacokineticinteractionsbasedonplasma-proteinbindingshouldnotbeexpected.Citalopramisaweakinhibitor

ofCYP2D6.Althoughclinicallyrelevantmedicinalinteractionswithcitalopramareunusual,aninteractioncannotbe

excludedifcitalopramisadministeredsimultaneouslywithanothermedicinalproductthatismetabolisedbyCYP2D6.

Co-administrationofcitalopramandmetoprolol(CYP2D6substrate)resultedinatwo-foldincreaseintheplasma

levelsofmetoprolol.Noclinicallysignificanteffectsonbloodpressureorheartratewereobserved.

Cimetidine,aknownenzyme-inhibitor,causedaslightriseintheaveragesteady-statecitalopramlevels.Cautionis

thereforerecommendedwhenadministeringhighdosesofcitalopramincombinationwithhighdosesofcimetidine.

Thereisnopharmacokineticinteractionbetweenlithiumandcitalopram.However,therehavebeenreportsofenhanced

serotonergiceffectswhenSSRIswereadministeredincombinationwithlithiumortryptophan.Cautionisadvised

duringsimultaneoususeofcitalopramwiththeseactivesubstances.Routinemonitoringoflithiumlevelsshouldbe

continuedasusual.

Inapharmacokineticstudynoeffectwasdemonstratedoneithercitalopramorimipraminelevels,althoughthe

levelofdesipramine,theprimarymetaboliteofimipraminewasincreased.Whendesipramineiscombinedwith

citalopram,anincreaseofthedesipramineplasmaconcentrationhasbeenobserved.Areductionofthe

desipraminedosemaybeneeded.

Nopharmacokineticinteractionwasobservedbetweencitalopramandlevomepromazine,digoxinorcarbamazepine

anditsmetabolitecarbamazepine-epoxide.

Theabsorptionandotherpharmacokineticpropertiesofcitalopramhavenotbeenreportedtobeaffectedbyfood.

4.6Fertility,pregnancyandlactation

Pregnancy:

TherearelimiteddatafromtheuseofCitalopraminpregnantwomen.Epidemiologicaldatahavesuggestedthatthe

useofSSRIsinpregnancy,particularlyinlatepregnancy,mayincreasetheriskofpersistentpulmonaryhypertension

inthenewborn(PPHN).Theobservedriskwasapproximately5casesper1000pregnancies.Inthegeneralpopulation

1to2casesofPPHNper1000pregnanciesoccur.

Studiesinratshaveshownteratogeniceffectsathighdoseswhichcausedmaternaltoxicity(seeSection5.3Preclinical

safetydata).Thepotentialriskforhumansisunknown.Citalopramshouldonlybeusedinpregnancyifconsidered

clearlynecessary.

Withdrawalsymptomsmayoccurintheneonateaftermaternalcitalopramusenearterm.Casesofwithdrawal

symptomsinthenewbornchildhavebeendescribedaftertheuseofSSRIattheendofpregnancy.

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Citalopramisexcretedinmilkinsmallquantities.Theadvantagesofbreastfeedingshouldout-weighthepotential

adverseeffectsforthechild .

4.7Effectsonabilitytodriveandusemachines

Citalopramhasminorormoderateinfluenceontheabilitytodriveandusemachines.

Psychoactivemedicinalproductscanreducetheabilitytomakejudgementsandtoreacttoemergencies.Patients

shouldbeinformedoftheseeffectsandbewarnedthattheirabilitytodriveacaroroperatemachinerycouldbe

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4.8Undesirableeffects

Adversereactionsobservedwithcitalopramareingeneralmildandtransient.Theyaremostprominentduring

thefirstweeksoftreatmentandusuallyattenuateasthedepressivestateimproves.

Treatmentemergentadverseeventsreportedinclinicaltrials:

verycommon

(>10%) common

(>1%,<10%) uncommon

(>0,1%,<1%) veryrare

(<0,01%,

includingisolated

reports)

Psychiatric

disorders somnolence,

insomnia,

agitation,

nervousness sleepdisorders,

impaired

concentration,

abnormal

dreaming,

amnesia,anxiety,

decreasedlibido,

increasedappetite,

anorexia,apathy,

suicideattempt,

euphoria,

increasedlibido hallucinations,

mania,

depersonalisation,

panicattack(these

symptomsmaybe

duetothe

underlying

disease)

Nervous

system

disorders headache,tremor,

dizziness migraine,

paraesthesia extrapyramidal

disorder,

convulsions

Cardiac

disorders palpitations tachycardia bradycardia supraventricular

andventricular

arrhythmia

Vascular

Disorders postural

hypotension,

hypotension,

hypertension

Gastrointestinal

disorders nausea,dry

mouth,

constipation,

diarrhoea dyspepsia,

vomiting,

abdominalpain,

flatulence,

increased

salivation

Renalandurinary

disorders micturition

disorder,polyuria

Metabolismand

nutrition

Disorders weightdecrease,

weightincrease

Hepato-biliary

disorders increasedliver

enzymevalues

Respiratory

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Rare(>0,01%,<0.1%)

Haemorrhage(forexample,gynaecologicalhaemorrhage,gastrointestinalhaemorrhage,ecchymosisandotherformsof

skinhaemorrhageorbleedinginthemucousmembranes)canoccuronrareoccasions.

InrarecasesaserotoninsyndromehasbeenreportedinpatientsusingSSRIs.Hyponatraemiaandthesyndromeof

inappropriateanti-diuretichormonesecretion(SIADH)hasbeenreportedrarely,predominantlyintheelderly(see

Section4.4“Specialwarningsandspecialprecautionsforuse”).

FrequencyNotKnown:

Casesofsuicidalideationandsuicidalbehaviourshavebeenreportedduringcitalopramtherapyorearlyaftertreatment

discontinuation(seesection4.4).

Withdrawalreactions

Withdrawalreactionsmayoccurwhentreatmentisstopped,althoughthepreclinicalandclinicaldatadonotsuggest

thatcitalopramcausesdependency.Withdrawalreactionsinclude:dizziness,paraesthesia,headache,nauseaand

anxiety.Mostofthewithdrawalreactionsaremildandself-limitinginnature.Iftreatmentisbeingstopped,itis

advisedthatthedoseisgraduallyreducedover1-2weekperiods.

Classeffects

Epidemiologicalstudies,mainlyinpatients50yearsofageandolder,showanincreasedriskofbonefracturesin

patientsreceivingSSRI'sandTCA's.Themechanismleadingtothisriskisunknown.

4.9Overdose

Symptomsofoverdose

Eightcasesareknownofacutecitalopramoverdose,atdosesofupto2000mg.Thefollowingsymptomswere

observed:somnolence,coma,stupor,seizure,sinustachycardia,transpiration,nausea,retching,cyanosis,

Reproductive

system

disorders ejaculationfailure,

female

anorgasmia,

dysmenorrhoea,

impotence galactorrhoea

Skindisorders increased

sweating rash,pruritus photosensitivity angiodema

Eyedisorders abnormal

accommodation abnormalities

ofvision

Specialsenses

disorders tasteabnormalities

Earand

labyrinth

disorders tinnitus

Musculoskeletal

disorders myalgia arthralgia

General

disorders asthenia fatigue,yawning allergicreactions,

syncope,malaise anaphylactoid

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Sixfatalcasesareknown,mainlyaftercombinationwithothermedicinalproducts.

Treatmentofanoverdose

Thereisnoknownspecificantidotetocitalopram.Treatmentshouldbesymptomaticandsup-portive.

Ifpossible,thepatientshouldbemadetovomit,afterwhichactivatedcarbonandanosmoticallyworkinglaxative

(suchassodiumsulfate)shouldbegiven.Stomachevacuationshouldbecon-sidered.Ifconsciousnessisimpairedthe

patientshouldbeintubated.Monitoringofcardiacandvitalsignsisrecommendedtogetherwithgeneralsymptomatic

supportivemeasures.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:

Antidepressant,Selectiveserotoninreuptakeinhibitors

ATCcode:N06AB04

Mechanismofactionandpharmacodynamiceffects

Tolerancetotheinhibitoryeffectofcitalopramon5-HTuptakedoesnotoccurduringlong-termtreatment.

Theantidepressanteffectisprobablyconnectedwiththespecificinhibitionofserotoninuptakeinthebrainneurons.

Citalopramhasalmostnoeffectontheneuronaluptakeofnoradrenaline,dopamineandgamma-aminobutyricacid.

Citalopramshowsnoaffinity,oronlyverylittle,forcholinergic,histaminergicandavarietyofadrenergic,serotonergic

anddopaminergicreceptors.

Citalopramisabi-cyclicisobenzophurane-derivativethatischemicallynotrelatedtotricyclicandtetracyclic

antidepressantsorotheravailableantidepressants.Themainmetabolitesofcitalopramarealsoselectiveserotonin

uptakeinhibitors,thoughtoalesserdegree.Themetabolitesarenotreportedtocontributetotheoverallantidepressant

effect.

5.2Pharmacokineticproperties

Generalcharacteristicsoftheactivesubstance

Absorption:

Citalopramisrapidlyabsorbedfollowingoraladministration:themaximumplasmaconcentrationisreachedon

averageafter4(1-7)hours.Absorptionisindependentoffoodintake.Oralbioavailabilityisapproximately80%.

Distribution:

Theapparentdistributionvolumeis12-17l/kg.Theplasma-proteinbindingofcitalopramanditsmetabolitesisbelow

80%.

Bio-transformation:

Citalopramismetabolisedintodemethylcitalopram,didemethylcitalopram,citalopram-N-oxideandthedeaminated

propionicacid-derivative.Thepropionicacid-derivativeispharmacologicallyinactive.Demethylcitalopram,

didemethylcitalopramandcitalopram-N-oxideareselectiveserotoninuptakeinhibitors,althoughweakerthanthe

parentcompound.

Invivoresearchhasdemonstratedthattheplasmalevelsofcitalopramanditsmetabolitesdependonthe

sparteine/debrisoquinephenotypeandthemephenytoinphenotype.However,itisnotnecessarytodoseindividually

accordingtothesephenotypes.

Elimination:

Theplasmahalf-lifeisapproximately1½days.Aftersystemicadministration,theplasmaclearanceisapproximately

0.3-0.4l/minandafteroraladministrationtheplasmaclearanceisapproximately0.4l/min.

Citalopramismainlyeliminatedviatheliver(85%),butalsopartly(15%)viathekidneys.Ofthequantityof

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andrenalclearanceis0.05-0.08l/min.

Steady-stateconcentrationsarereachedafter1-2weeks.Alinearrelationshiphasbeendemonstratedbetweenthe

steady-stateplasmalevelandthedoseadministered.Atadoseof40mgperday,anaverageplasmaconcentrationof

approximately300nmol/lisreached.Thereisnoclearrelationshipbetweencitalopramplasmalevelsandtherapeutic

responseorsideeffects.

Characteristicsrelatingtopatients

Longerplasmahalf-lifevaluesandasmallerclearancehavebeenfoundinolderpatientsduetoareducedmetabolism.

Theeliminationofcitalopramprogressesmoreslowlyinpatientswithreducedliverfunction.Theplasmahalf-lifeof

citalopramisapproximatelytwiceaslongandthesteady-stateplasmaconcentrationapproximatelytwiceashighin

comparisonwithpatientswithanormalliverfunction.

Theeliminationofcitalopramprogressesmoreslowlyinpatientswithamildtomoderaterenalfunctiondisorder,

withoutanymajorimpactonthepharmacokineticsofcitalopram.Noinformationisavailableontreatmentofpatients

withsevererenalimpairment(creatinineclearancelessthan20ml/min)(seeSection4.4Specialwarningsandspecial

precautionsforuse).

5.3Preclinicalsafetydata

Inlaboratoryanimalsnoevidenceforaspecialhazardforhumanswasfound.Thisisbasedonconventionalstudiesof

safetypharmacology,repeateddosetoxicity,genotoxicityandcarcinogenicpotential.Phospholipidosisinseveral

organswasobservedinrepeateddosetoxicitystudiesinrats.Thisreversibleeffectisknownforseverallipophilic

aminesandwasnotconnectedwithmorphologicalandfunctionaleffects.Theclinicalrelevanceisnotclear.

Embryotoxicitystudiesinratshaveshownskeletalanomaliesathighmaternaltoxicdoses.Theeffectscouldpossibly

berelatedtothepharmacologicalactivityorcouldbeanindirecteffectrelatedtomaternaltoxicity.Thepotentialrisk

forhumansisunknown.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Core:

Mannitol

Microcrystallinecellulose

Colloidalsilica,anhydrous

Magnesiumstearate

Coating:

Hypromellose

Macrogol6000

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

3years.

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

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Ciprapine40mgfilm-coatedtablets;packedinPVC/PVDC/Alblistersareavailableinpacksizesof10,14,20,28,30,

50,56,98and100tabletsperbox,100x1unitdoseblister.

HDPEtabletcontainerwithaLDPEtamperevidentcapcontaining250,500tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialrequirements

7MARKETINGAUTHORISATIONHOLDER

PinewoodLaboratoriesLimited

Ballymacarbry

Clonmel

Co.Tipperary

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA281/117/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:18June2004

Dateoflastrenewal:18February2009

10DATEOFREVISIONOFTHETEXT

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