CIPROFLOXACIN PFIZER

Main information

  • Trade name:
  • CIPROFLOXACIN PFIZER
  • Dosage:
  • 2 Mg/ Ml
  • Pharmaceutical form:
  • Solution for Infusion
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CIPROFLOXACIN PFIZER
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0822/028/004
  • Authorization date:
  • 16-03-2012
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

CiprofloxacinPfizer2mg/mlSolutionforinfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

EachpresentationofCiprofloxacinPfizer2mg/mlinfusioncontainsthefollowing:

CiprofloxacinPfizer100mg/50mlSolutionforinfusion

1mlofsolutionforinfusioncontains2mgciprofloxacinas2.544mgciprofloxacinlactate.

Each50mlvialcontains100mgciprofloxacin(asciprofloxacinlactate).

Excipient:Each50mlcontains7.7mmol(177mg)sodium.

CiprofloxacinPfizer200mg/100mlSolutionforinfusion

1mlofsolutionforinfusioncontains2mgciprofloxacinas2.544mgciprofloxacinlactate.

Each100mlbottlecontains200mgciprofloxacin(asciprofloxacinlactate).

Excipient:Each100mlcontains15.4mmol(354mg)sodium.

CiprofloxacinPfizer400mg/200mlSolutionforinfusion

1mlofsolutionforinfusioncontains2mgciprofloxacinas2.544mgciprofloxacinlactate.

Each200mlbottlecontains400mgciprofloxacin(asciprofloxacinlactate).

Excipient:Each200mlcontains30.8mmol(708mg)sodium.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Solutionforinfusion(IV).

Clear,colourlesstoslightlyyellowsolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

CiprofloxacinPfizer2mg/mlSolutionforinfusionisindicatedforthetreatmentofthefollowinginfections(see

sections4.4and5.1).Specialattentionshouldbepaidtoavailableinformationonresistancetociprofloxacinbefore

commencingtherapy.

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantibacterialagents.

Adults

LowerrespiratorytractinfectionsduetoGram-negativebacteria.

-exacerbationsofchronicobstructivepulmonarydisease.

-broncho-pulmonaryinfectionsincysticfibrosisorinbronchiectasis.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2012 CRN 2074402 page number: 1

Chronicsuppurativeotitismedia

AcuteexacerbationofchronicsinusitisespeciallyifthesearecausedbyGram-negative bacteria

Urinarytractinfections

Epididymo-orchitisincludingcasesduetoNeisseriagonorrhoeae.

PelvicinflammatorydiseaseincludingcasesduetoNeisseriagonorrhoeae.

IntheabovegenitaltractinfectionswhenthoughtorknowntobeduetoNeisseriagonorrhoeaeitisparticularly

importanttoobtainlocalinformationontheprevalenceofresistancetociprofloxacinandtoconfirmsusceptibility

basedonlaboratorytesting.

Infectionsofthegastro-intestinaltract(e.g.travellers`diarrhoea)

Intra-abdominalinfections

InfectionsoftheskinandsofttissuecausedbyGram-negativebacteria

Malignantexternalotitis

Infectionsofthebonesandjoints

Treatmentofinfectionsinneutropenicpatients

Prophylaxisofinfectionsinneutropenicpatients

Inhalationanthrax(post-exposureprophylaxisandcurativetreatment)

Childrenandadolescents

Broncho-pulmonaryinfectionsincysticfibrosiscausedbyPseudomonasaeruginosa.

Complicatedurinarytractinfectionsandpyelonephritis.

Inhalationanthrax(post-exposureprophylaxisandcurativetreatment).

Ciprofloxacinmayalsobeusedtotreatsevereinfectionsinchildrenandadolescentswhenthisisconsideredtobe

necessary.

Treatmentshouldbeinitiatedonlybyphysicianswhoareexperiencedinthetreatmentofcysticfibrosisand/orsevere

infectionsinchildrenandadolescents(seesections4.4and5.1).

4.2Posologyandmethodofadministration

Thedosageisdeterminedbytheindication,theseverityandthesiteoftheinfection,thesusceptibilitytociprofloxacin

ofthecausativeorganism(s),therenalfunctionofthepatientand,inchildrenandadolescentsthebodyweight.

Thedurationoftreatmentdependsontheseverityoftheillnessandontheclinicalandbacteriologicalcourse.

Afterintravenousinitiationoftreatment,thetreatmentcanbeswitchedtooraltreatmentwithtabletorsuspensionif

clinicallyindicatedatthediscretionofthephysician.IVtreatmentshouldbefollowedbyoralrouteassoonaspossible.

Inseverecasesorifthepatientisunabletotaketablets(e.g.patientsonenteralnutrition),itisrecommendedto

commencetherapywithintravenousciprofloxacinuntilaswitchtooraladministrationispossible.

Treatmentofinfectionsduetocertainbacteria(e.g.Pseudomonasaeruginosa,AcinetobacterorStaphylococci)may

requirehigherciprofloxacindosesandco-administrationwithotherappropriateantibacterialagents.

Treatmentofsomeinfections(e.g.pelvicinflammatorydisease,intra-abdominalinfections,infectionsinneutropenic

patientsandinfectionsofbonesandjoints)mayrequireco-administrationwithotherappropriateantibacterialagents

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2012 CRN 2074402 page number: 2

Adults

Indications Dailydoseinmg Totaldurationof

treatment

(includingswitch

tooraltherapyas

soonaspossible)

Infectionsofthelowerrespiratory

tract 400mgtwicedaily

to400mgthree

timesaday 7to14days

Infections of the

upper respiratory

tract Acuteexacerbation

ofchronicsinusitis 400mgtwicedaily

to400mgthree

timesaday 7to14days

Chronic

suppurative otitis

media 400mgtwicedaily

to400mgthree

timesaday 7to14days

Malignantexternal

otitis 400mgthreetimes

aday 28daysupto3

months

Urinary tract

infections Complicated and

uncomplicated

pyelonephritis 400mgtwicedaily

to400mgthree

timesaday 7to21days,itcan

continued for

longerthan21days

some specific

circumstances

(suchasabscesses)

Prostatitis 400mgtwicedaily

to400mgthree

timesaday 2 to 4 weeks

(acute)

Genital tract

infections Epididymo-orchitis

pelvic

inflammatory

diseases 400mgtwicedaily

to400mgthree

timesaday atleast14days

Infections of the

gastro-intestinal

tract and intra-

abdominal

infections Diarrhoea caused

bacterial

pathogens

includingShigella

spp. other than

Shigella

dysenteriaetype1

empirical

treatmentofsevere

travellers’

400mgtwicedaily 1day

Diarrhoea caused

Shigella

dysenteriaetype1 400mgtwicedaily 5days

Diarrhoea caused

byVibriocholerae 400mgtwicedaily 3days

Typhoidfever 400mgtwicedaily 7days

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2012 CRN 2074402 page number: 3

infectionsdueto

Gram-negative

bacteria to400mgthree

timesaday

Infectionsoftheskinandsofttissue 400mgtwicedaily

to400mgthree

timesaday 7to14days

Boneandjointinfections 400mgtwicedaily

to400mgthree

timesaday max.of3months

Treatmentofinfectionsorprophylaxis

ofinfectionsinneutropenicpatients

Ciprofloxacin should be co-

administered with appropriate

antibacterialagent(s)inaccordanceto

officialguidance. 400mgtwicedaily

to400mgthree

timesaday Therapyshouldbe

continuedoverthe

entire period of

neutropenia

Inhalation anthrax post-exposure

prophylaxisandcurativetreatmentfor

personsrequiringparenteraltreatment

Drugadministrationshouldbeginas

soonaspossibleaftersuspectedor

confirmedexposure. 400mgtwicedaily 60daysfromthe

confirmation of

Bacillusanthracis

exposure

Indication Dailydoseinmg Totaldurationof

treatment(including

switchtooraltherapyas

soonaspossible)

Cysticfibrosis 10mg/kgbodyweight

threetimesadaywitha

maximumof400mgper

dose. 10to14days

Complicatedurinarytract

infectionsand

pyelonephritis 6mg/kgbodyweight

threetimesadayto10

mg/kgbodyweightthree

timesadaywitha

maximumof400mgper

dose. 10to21days

Inhalationanthraxpost-

exposurecurative

treatmentforpersons

requiringparenteral

treatment

Drugadministration

shouldbeginassoonas

possibleaftersuspectedor

10mg/kgbodyweight

twicedailyto15mg/kg

bodyweighttwicedaily

withamaximumof400

mgperdose. 60daysfromthe

confirmationofBacillus

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2012 CRN 2074402 page number: 4

Geriatricpatients

Geriatricpatientsshouldreceiveadoseselectedaccordingtotheseverityoftheinfectionandthepatient`screatinine

clearance.

Renalandhepaticimpairment

Recommendedstartingandmaintenancedosesforpatientswithimpairedrenalfunction:

Inpatientswithimpairedliverfunctionnodoseadjustmentisrequired.

Dosinginchildrenwithimpairedrenaland/orhepaticfunctionhasnotbeenstudied.

Methodofadministration

Ciprofloxacinsolutionforinjectionshouldbecheckedvisuallypriortouse.Itmustnotbeusedifcloudy.

Ciprofloxacinshouldbeadministeredbyintravenousinfusion.Forchildren,theinfusiondurationis60minutes.

Inadultpatients,infusiontimeis60minutesfor400mgCiprofloxacinPfizer2mg/mlSolutionforinfusionand30

minutesfor200mgCiprofloxacinPfizer2mg/mlSolutionforinfusion.Slowinfusionintoalargeveinwillminimise

patientdiscomfortandreducetheriskofvenousirritation.

Theinfusionsolutioncanbeinfusedeitherdirectlyoraftermixingwithothercompatibleinfusionsolutions(see

section6.2).

4.3Contraindications

Hypersensitivitytotheactivesubstance,tootherquinolonesortoanyoftheexcipients(seesection6.1).

Concomitantadministrationofciprofloxacinandtizanidine(seesection4.5).

4.4Specialwarningsandprecautionsforuse

SevereinfectionsandmixedinfectionswithGram-positiveandanaerobicpathogens

CiprofloxacinmonotherapyisnotsuitedfortreatmentofsevereinfectionsandinfectionsthatmightbeduetoGram-

positiveoranaerobicpathogens.Insuchinfectionsciprofloxacinmustbeco-administeredwithotherappropriate

antibacterialagents.

StreptococcalInfections(includingStreptococcuspneumoniae)

Othersevereinfections 10mg/kgbodyweight

threetimesadaywitha

maximumof400mgper

dose. Accordingtothetypeof

infections

CreatinineClearance

[mL/min/1.73m²] SerumCreatinine

[µmol/L] IntravenousDose[mg]

>60 <124 SeeUsualDosage.

30-60 124to168 200-400mgevery12h

<30 >169 200-400mgevery24h

Patientsonhaemodialysis >169 200-400mgevery24h

(afterdialysis)

Patientsonperitoneal

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2012 CRN 2074402 page number: 5

Genitaltractinfections

Epididymo-orchitisandpelvicinflammatorydiseasesmaybecausedbyfluoroquinolone-resistantNeisseria

gonorrhoeae.Ciprofloxacinshouldbeco-administeredwithanotherappropriateantibacterialagentunless

ciprofloxacin-resistantNeisseriagonorrhoeaecanbeexcluded.Ifclinicalimprovementisnotachievedafter3daysof

treatment,thetherapyshouldbereconsidered.

Intra-abdominalinfections

Therearelimiteddataontheefficacyofciprofloxacininthetreatmentofpost-surgicalintra-abdominalinfections.

Travellers’diarrhoea

Thechoiceofciprofloxacinshouldtakeintoaccountinformationonresistancetociprofloxacininrelevantpathogensin

thecountriesvisited.

Infectionsofthebonesandjoints

Ciprofloxacinshouldbeusedincombinationwithotherantimicrobialagentsdependingontheresultsofthe

microbiologicaldocumentation.

Inhalationalanthrax

Useinhumansisbasedonin-vitrosusceptibilitydataandonanimalexperimentaldatatogetherwithlimitedhuman

data.Treatingphysiciansshouldrefertonationaland/orinternationalconsensusdocumentsregardingthetreatmentof

anthrax.

Childrenandadolescents

Theuseofciprofloxacininchildrenandadolescentsshouldfollowavailableofficialguidance.Ciprofloxacintreatment

shouldbeinitiatedonlybyphysicianswhoareexperiencedinthetreatmentofcysticfibrosisand/orsevereinfectionsin

childrenandadolescents.

Ciprofloxacinhasbeenshowntocausearthropathyinweight-bearingjointsofimmatureanimals.Safetydatafroma

randomiseddouble-blindstudyonciprofloxacinuseinchildren(ciprofloxacin:n=335,meanage=6.3years;

comparators:n=349,meanage=6.2years;agerange=1to17years)revealedanincidenceofsuspecteddrug-related

arthropathy(discernedfromjoint-relatedclinicalsignsandsymptoms)byDay+42of7.2%and4.6%.Respectively,an

incidenceofdrug-relatedarthropathyby1-yearfollow-upwas9.0%and5.7%.Theincreaseofsuspecteddrug-related

arthropathycasesovertimewasnotstatisticallysignificantbetweengroups.Treatmentshouldbeinitiatedonlyaftera

carefulbenefit/riskevaluation,duetopossibleadverseeventsrelatedtojointsand/orsurroundingtissue.

Broncho-pulmonaryinfectionsincysticfibrosis

Clinicaltrialshaveincludedchildrenandadolescentsaged5-17years.Morelimitedexperienceisavailableintreating

childrenbetween1and5yearsofage.

Complicatedurinarytractinfectionsandpyelonephritis

Ciprofloxacintreatmentofurinarytractinfectionsshouldbeconsideredwhenothertreatmentscannotbeused,and

shouldbebasedontheresultsofthemicrobiologicaldocumentation.

Clinicaltrialshaveincludedchildrenandadolescentsaged1-17years.

Otherspecificsevereinfections

Othersevereinfectionsinaccordancewithofficialguidance,oraftercarefulbenefit-riskevaluationwhenother

treatmentscannotbeused,orafterfailuretoconventionaltherapyandwhenthemicrobiologicaldocumentationcan

justifyaciprofloxacinuse.

Theuseofciprofloxacinforspecificsevereinfectionsotherthanthosementionedabovehasnotbeenevaluatedin

clinicaltrialsandtheclinicalexperienceislimited.Consequently,cautionisadvisedwhentreatingpatientswiththese

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2012 CRN 2074402 page number: 6

Hypersensitivity

Hypersensitivityandallergicreactions,includinganaphylaxisandanaphylactoidreactions,mayoccurfollowinga

singledose(seesection4.8)andmaybelife-threatening.Ifsuchreactionoccurs,ciprofloxacinshouldbediscontinued

andanadequatemedicaltreatmentisrequired.

MusculoskeletalSystem

Ciprofloxacinshouldgenerallynotbeusedinpatientswithahistoryoftendondisease/disorderrelatedtoquinolone

treatment.Nevertheless,inveryrareinstances,aftermicrobiologicaldocumentationofthecausativeorganismand

evaluationoftherisk/benefitbalance,ciprofloxacinmaybeprescribedtothesepatientsforthetreatmentofcertain

severeinfections,particularlyintheeventoffailureofthestandardtherapyorbacterialresistance,wherethe

microbiologicaldatamayjustifytheuseofciprofloxacin.

Tendinitisandtendonrupture(especiallyAchillestendon),sometimesbilateral,mayoccurwithciprofloxacin,assoon

asthefirst48hoursoftreatment.Theriskoftendinopathymaybeincreasedinelderlypatientsorinpatients

concomitantlytreatedwithcorticosteroids(seesection4.8).Atanysignoftendinitis(e.g.painfulswelling,

inflammation),ciprofloxacintreatmentshouldbediscontinued.Careshouldbetakentokeeptheaffectedlimbatrest.

Ciprofloxacinshouldbeusedwithcautioninpatientswithmyastheniagravis(seesection4.8).

Photosensitivity

Ciprofloxacinhasbeenshowntocausephotosensitivityreactions.Patientstakingciprofloxacinshouldbeadvisedto

avoiddirectexposuretoeitherextensivesunlightorUVirradiationduringtreatment(seesection4.8).

CentralNervousSystem

Quinolonesareknowntotriggerseizuresorlowertheseizurethreshold.Ciprofloxacinshouldbeusedwithcautionin

patientswithCNSdisorderswhichmaybepredisposedtoseizure.Ifseizuresoccurciprofloxacinshouldbe

discontinued(seesection4.8).Psychiatricreactionsmayoccurevenafterthefirstadministrationofciprofloxacin.In

rarecases,depressionorpsychosiscanprogresstoself-endangeringbehaviour.Inthesecases,ciprofloxacinshouldbe

discontinued.

Casesofpolyneuropathy(basedonneurologicalsymptomssuchaspain,burning,sensorydisturbancesormuscle

weakness,aloneorincombination)havebeenreportedinpatientsreceivingciprofloxacin.Ciprofloxacinshouldbe

discontinuedinpatientsexperiencingsymptomsofneuropathy,includingpain,burning,tingling,numbness,and/or

weaknessinordertopreventthedevelopmentofanirreversiblecondition(seesection4.8).

Cardiacdisorders

Cautionshouldbetakenwhenusingfluoroquinolones,includingciprofloxacin,inpatientswithknownriskfactorsfor

prolongationoftheQTintervalsuchas,forexample:

congenitallongQTsyndrome

concomitantuseofdrugsthatareknowntoprolongtheQTinterval(e.g.ClassIAandIIIanti-arrhythmics,

tricyclicantidepressants,macrolides,antipsychotics)

uncorrectedelectrolyteimbalance(e.g.hypokalaemia,hypomagnesaemia)

elderly

cardiacdisease(e.g.heartfailure,myocardialinfarction,bradycardia)

(Seesection4.2Elderly,section4.5,section4.8,section4.9).

GastrointestinalSystem

Theoccurrenceofsevereandpersistentdiarrhoeaduringoraftertreatment(includingseveralweeksaftertreatment)

mayindicateanantibiotic-associatedcolitis(life-threateningwithpossiblefataloutcome),requiringimmediate

treatment(seesection4.8).Insuchcases,ciprofloxacinshouldimmediatelybediscontinued,andanappropriate

therapyinitiated.Anti-peristalticdrugsarecontraindicatedinthissituation.

Renalandurinarysystem

Crystalluriarelatedtotheuseofciprofloxacinhasbeenreported(seesection4.8).Patientsreceivingciprofloxacin

shouldbewellhydratedandexcessivealkalinityoftheurineshouldbeavoided.

Hepatobiliarysystem

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2012 CRN 2074402 page number: 7

theeventofanysignsandsymptomsofhepaticdisease(suchasanorexia,jaundice,darkurine,pruritus,ortender

abdomen),treatmentshouldbediscontinued.

Glucose-6-phosphatedehydrogenasedeficiency

Haemolyticreactionshavebeenreportedwithciprofloxacininpatientswithglucose-6-phosphatedehydrogenase

deficiency.Ciprofloxacinshouldbeavoidedinthesepatientsunlessthepotentialbenefitisconsideredtooutweighthe

possiblerisk.Inthiscase,potentialoccurrenceofhaemolysisshouldbemonitored.

Resistance

Duringorfollowingacourseoftreatmentwithciprofloxacinbacteriathatdemonstrateresistancetociprofloxacinmay

beisolated,withorwithoutaclinicallyapparentsuperinfection.Theremaybeaparticularriskofselectingfor

ciprofloxacin-resistantbacteriaduringextendeddurationsoftreatmentandwhentreatingnosocomialinfectionsand/or

infectionscausedbyStaphylococcusandPseudomonasspecies.

CytochromeP450

CiprofloxacininhibitsCYP1A2andthusmaycauseincreasedserumconcentrationofconcomitantlyadministered

substancesmetabolisedbythisenzyme(e.g.theophylline,clozapine,ropinirole,tizanidine).Co-administrationof

ciprofloxacinandtizanidineiscontra-indicated.Therefore,patientstakingthesesubstancesconcomitantlywith

ciprofloxacinshouldbemonitoredcloselyforclinicalsignsofoverdose,anddeterminationofserumconcentrations

(e.g.oftheophylline)maybenecessary(seesection4.5).

Methotrexate

Theconcomitantuseofciprofloxacinwithmethotrexateisnotrecommended(seesection4.5).

Interactionwithtests

Thein-vitroactivityofciprofloxacinagainstMycobacteriumtuberculosismightgivefalsenegativebacteriologicaltest

resultsinspecimensfrompatientscurrentlytakingciprofloxacin.

InjectionSiteReaction

Localintravenoussitereactionshavebeenreportedwiththeintravenousadministrationofciprofloxacin.These

reactionsaremorefrequentiftheinfusiontimeis30minutesorless.Thesemayappearaslocalskinreactionswhich

resolverapidlyuponcompletionoftheinfusion.Subsequentintravenousadministrationisnotcontraindicatedunless

thereactionsrecurorworsen.

NaClLoad

Inpatientsforwhomsodiumintakeisofmedicalconcern(patientswithcongestiveheartfailure,renalfailure,

nephroticsyndrome,etc.),theadditionalsodiumloadshouldbetakenintoaccount(forsodiumchloridecontent,see

section2).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Effectsofothermedicinalproductsonciprofloxacin:

Probenecid

Probenecidinterfereswithrenalsecretionofciprofloxacin.Co-administrationofprobenecidandciprofloxacin

increasesciprofloxacinserumconcentrations.

Effectsofciprofloxacinonothermedicinalproducts:

Tizanidine

Tizanidinemustnotbeadministeredtogetherwithciprofloxacin(seesection4.3).Inaclinicalstudywithhealthy

subjects,therewasanincreaseinserumtizanidineconcentration(C

increase:7-fold,range:4to21-fold;AUC

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2012 CRN 2074402 page number: 8

concentrationisassociatedwithapotentiatedhypotensiveandsedativeeffect.

Methotrexate

Renaltubulartransportofmethotrexatemaybeinhibitedbyconcomitantadministrationofciprofloxacin,potentially

leadingtoincreasedplasmalevelsofmethotrexateandincreasedriskofmethotrexate-associatedtoxicreactions.The

concomitantuseisnotrecommended(seesection4.4).

Theophylline

Concurrentadministrationofciprofloxacinandtheophyllinecancauseanundesirableincreaseinserumtheophylline

concentration.Thiscanleadtotheophylline-inducedsideeffectsthatmayrarelybelifethreateningorfatal.Duringthe

combination,serumtheophyllineconcentrationsshouldbecheckedandthetheophyllinedosereducedasnecessary(see

section4.4).

Otherxanthinederivatives

Onconcurrentadministrationofciprofloxacinandcaffeineorpentoxifylline(oxpentifylline),raisedserum

concentrationsofthesexanthinederivativeswerereported.

Phenytoin

Simultaneousadministrationofciprofloxacinandphenytoinmayresultinincreasedorreducedserumlevelsof

phenytoinsuchthatmonitoringofdruglevelsisrecommended.

Oralanticoagulants

Simultaneousadministrationofciprofloxacinwithwarfarinmayaugmentitsanti-coagulanteffects.Therehavebeen

manyreportsofincreasesinoralanti-coagulantactivityinpatientsreceivingantibacterialagents,including

fluoroquinolones.Theriskmayvarywiththeunderlyinginfection,ageandgeneralstatusofthepatientsothatthe

contributionofthefluoroquinolonetotheincreaseinINR(internationalnormalisedratio)isdifficulttoassess.Itis

recommendedthattheINRshouldbemonitoredfrequentlyduringandshortlyafterco-administrationofciprofloxacin

withanoralanticoagulantagent.

Ropinirole

Itwasshowninaclinicalstudythatconcomitantuseofropinirolewithciprofloxacin,amoderateinhibitorofthe

CYP4501A2isozyme,resultsinanincreaseofC

andAUCofropiniroleby60%and84%,respectively.

Monitoringofropinirole-relatedsideeffectsanddoseadjustmentasappropriateisrecommendedduringandshortly

afterco-administrationwithciprofloxacin(seesection4.4).

Clozapine

Followingconcomitantadministrationof250mgciprofloxacinwithclozapinefor7days,serumconcentrationsof

clozapineandN-desmethylclozapinewereincreasedby29%and31%,respectively.Clinicalsurveillanceand

appropriateadjustmentofclozapinedosageduringandshortlyafterco-administrationwithciprofloxacinareadvised

(seesection4.4).

DrugsknowntoprolongQTinterval

Ciprofloxacin,likeotherfluoroquinolones,shouldbeusedwithcautioninpatientsreceivingdrugsknowntoprolong

theQTinterval(e.g.ClassIAandIIIanti-arrhythmics,tricyclicantidepressants,macrolides,antipsychotics)(see

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2012 CRN 2074402 page number: 9

4.6Fertility,pregnancyandlactation

Pregnancy

Thedatathatareavailableonadministrationofciprofloxacintopregnantwomenindicatesnomalformativeor

feto/neonataltoxicityofciprofloxacin.Animalstudiesdonotindicatedirectorindirectharmfuleffectswithrespectto

reproductivetoxicity.Injuvenileandprenatalanimalsexposedtoquinolones,effectsonimmaturecartilagehavebeen

observed,thus,itcannotbeexcludedthatthedrugcouldcausedamagetoarticularcartilageinthehumanimmature

organism/foetus(seesection5.3).

Asaprecautionarymeasure,itispreferabletoavoidtheuseofciprofloxacinduringpregnancy.

Lactation

Ciprofloxacinisexcretedinbreastmilk.Duetothepotentialriskofarticulardamage,ciprofloxacinshouldnotbeused

duringbreast-feeding.

4.7Effectsonabilitytodriveandusemachines

Duetoitsneurologicaleffects,ciprofloxacinmayaffectreactiontime.Thus,theabilitytodriveortooperatemachinery

maybeimpaired.

4.8Undesirableeffects

Themostcommonlyreportedadversedrugreactions(ADRs)arenausea,diarrhoea,vomitting,transientincreasein

transaminases,rash,andinjectionandinfusionsitereactions.

ADRsderivedfromclinicalstudiesandpost-marketingsurveillancewithCiprofloxacin(oral,intravenousand

sequentialtherapy)sortedbycategoriesoffrequencyarelistedbelow.Thefrequencyanalysistakesintoaccountdata

frombothoralandintravenousadministrationofciprofloxacin.

System

OrganClass Common

1/100to<

1/10 Uncommon

1/1000to<

1/100 Rare

1/10000to

<1/1000 VeryRare<

1/10000 Frequency

notknown

(cannotbe

estimated

from

available

data)

Infections

and

Infestations - Mycotic

superinfections Antibiotic

associated

colitis(very

rarelywith

possiblefatal

outcome)(see

section4.4) - -

Bloodand

Lymphatic

System

Disorders - Eosinophilia Leukopenia

Anaemia

Neutropenia

Leukocytosis

Thrombocytopenia

Thrombocytaemia Haemolytic

anaemia

Agranulocytosis

Pancytopenia

(life-

threatening)

Bonemarrow

depression

(life-

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2012 CRN 2074402 page number: 10

OrganClass 1/100to<

1/10 1/1000to<

1/100 1/10000to

<1/1000 1/10000 notknown

(cannotbe

estimated

from

available

data)

Immune

System

Disorders - - Allergic

reaction

Allergic

oedema/

angiooedema Anaphylactic

reaction

Anaphylactic

shock(life-

threatening)

(seesection

4.4)Serum

sickness-like

Metabolism

andNutrition - Anorexia Hyperglycaemia - -

Psychiatric

Disorders - Psychomotor

hyperactivity/

agitation Confusionand

disorientation

Anxiety

reaction

Abnormal

dreams

Depression

Hallucinations Psychotic

reactions(see

section4.4) -

System

OrganClass Common

1/100to<

1/10 Uncommon

1/1000to<

1/100 Rare

1/10000to

<1/1000 VeryRare<

1/10000 Frequency

notknown

(cannotbe

estimated

from

available

data)

Nervous

System

Disorders - Headache

Dizziness

Sleep

disorders

Taste

disorders Par-and

Dysaesthesia

Hypoaesthesia

Tremor

Seizures (see

section 4.4)

Vertigo Migraine

Disturbed

coordination

Gait

disturbance

Olfactory

nerve

disorders

Intracranial

Peripheral

neuropathy

(seesection

4.4)

Eye

Disorders - - Visual

disturbances Visualcolour

distortions -

Earand

Labyrinth

Disorders - - Tinnitus

Hearingloss/

Hearing

impaired - -

System

OrganClass Common

1/100to<

1/10 Uncommon

1/1000to<

1/100 Rare

1/10000to

<1/1000 VeryRare<

1/10000 Frequency

notknown

(cannotbe

estimated

from

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2012 CRN 2074402 page number: 11

data)

Cardiac

Disorders - - Tachycardia - Ventricular

arrhythmia

andtorsades

depointes*,

ECGQT

prolonged,

(seesection

4.4and4.9).

Vascular

Disorders - - Vasodilation

Hypotension

Syncope Vasculitis -

Respiratory,

Thoracicand

Mediastinal

Disorders - - Dyspnoea

(including

asthmatic

condition) - -

Gastrointestinal

Disorders Nausea

Diarrhoea Vomiting

Gastrointestinal

abdominal

pains

Dyspepsia

Flatulence - Pancreatitis -

System

OrganClass Common

1/100to<

1/10 Uncommon

1/1000to<

1/100 Rare

1/10000to

<1/1000 VeryRare<

1/10000 Frequency

notknown

(cannotbe

estimated

from

available

data)

Hepatobiliary

Disorders - Increasein

transaminases

Increased

bilirubin Hepatic

impairment

Cholestatic

icterus

Hepatitis Livernecrosis

(veryrarely

progressingto

life-

threatening

hepatic

failure)(see

section4.4) -

Skinand

Subcutaneous

Tissue

Disorders - RashPruritus

Urticaria Photosensitivity

reactions(see

section4.4) Petechiae

Erythema

multiforme

Erythema

nodosum

Stevens-

Johnson

syndrome

(potentially

life-

threatening)

Toxic

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2012 CRN 2074402 page number: 12

*ReportedpredominantlyinpatientswithriskfactorsforQTprolongation

Thefollowingundesirableeffectshaveahigherfrequencycategoryinthesubgroupsofpatientsreceivingintravenous

necrolysis

(potentially

life-

threatening)

Musculoskeletal,

Connective

Tissueand

Bone

Disorders - Musculoskeletal

pain (e.g.

extremity

pain, back

pain, chest

pain)

Arthralgia Myalgia

Arthritis

Increased

muscle tone

andcramping Muscular

weakness

Tendinitis

Tendon

rupture

(predominantly

Achilles

tendon)(see

section4.4)

Exacerbation

ofsymptoms

ofmyasthenia

gravis(see

-

System

OrganClass Common

1/100to<

1/10 Uncommon

1/1000to<

1/100 Rare

1/10000to

<1/1000 VeryRare<

1/10000 Frequency

notknown

(cannotbe

estimated

from

available

data)

Renaland

Urinary

Disorders - Renal

impairment Renal failure

Haematuria

Crystalluria

(see section

4.4)

Tubulointerstitial

nephritis - -

General

Disorders

and

Administration

Site

Conditions Injectionand

infusionsite

reactions

(only

intravenous

administration) Asthenia

Fever Oedema

Sweating

(hyperhidrosis) - -

Investigations - Increase in

bloodalkaline

phosphatase Prothrombin

level

abnormal

Increased

amylase -

Common Vomiting,Transientincreaseintransaminases,Rash

Uncommon Thrombocytopenia,Thrombocytaemia,Confusionand

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2012 CRN 2074402 page number: 13

Paediatricpatients

Theincidenceofarthropathy,mentionedabove,isreferringtodatacollectedinstudieswithadults.Inchildren,

arthropathyisreportedtooccurcommonly(seesection4.4).

4.9Overdose

Anoverdoseof12ghasbeenreportedtoleadtomildsymptomsoftoxicity.Anacuteoverdoseof16ghasbeen

reportedtocauseacuterenalfailure.

Symptomsinoverdoseconsistofdizziness,tremor,headache,tiredness,seizures,hallucinations,confusion,abdominal

discomfort,renalandhepaticimpairmentaswellascrystalluriaandhaematuria.Reversiblerenaltoxicityhasbeen

reported.

Intheeventofoverdose,symptomatictreatmentshouldbeimplemented.ECGmonitoringshouldbeundertaken,

becauseofthepossibilityofQTintervalprolongation.

Apartfromroutineemergencymeasures,itisrecommendedtomonitorrenalfunction,includingurinarypHand

acidify,ifrequired,topreventcrystalluria.Patientsshouldbekeptwellhydrated.Onlyasmallquantityof

ciprofloxacin(<10%)iseliminatedbyhaemodialysisorperitonealdialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Fluoroquinolones,ATCcode:J01MA02

Mechanismofaction:

Asafluoroquinoloneantibacterialagent,thebactericidalactionofciprofloxacinresultsfromtheinhibitionofbothtype

IItopoisomerase(DNA-gyrase)andtopoisomeraseIV,requiredforbacterialDNAreplication,transcription,repairand

recombination.

PK/PDrelationship:

Efficacymainlydependsontherelationbetweenthemaximumconcentrationinserum(C

)andtheminimum

inhibitoryconcentration(MIC)ofciprofloxacinforabacterialpathogenandtherelationbetweentheareaunderthe

curve(AUC)andtheMIC.

Mechanismofresistance:

In-vitroresistancetociprofloxacincanbeacquiredthroughastepwiseprocessbytargetsitemutationsinbothDNA

gyraseandtopoisomeraseIV.Thedegreeofcross-resistancebetweenciprofloxacinandotherfluoroquinolonesthat

resultsisvariable.Singlemutationsmaynotresultinclinicalresistance,butmultiplemutationsgenerallyresultin

Vertigo,Visualdisturbances,Hearingloss,Tachycardia,

Vasodilatation,Hypotension,Transienthepaticimpairment,

Cholestaticicterus,Renalfailure,Oedema

Rare Pancytopenia,Bonemarrowdepression,Anaphylacticshock,

Psychoticreactions,Migraine,Olfactorynervedisorders,Hearing

impaired, Vasculitis, Pancreatitis, Liver necrosis, Petechiae,

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2012 CRN 2074402 page number: 14

Impermeabilityand/oractivesubstanceeffluxpumpmechanismsofresistancemayhaveavariableeffecton

susceptibilitytofluoroquinolones,whichdependsonthephysiochemicalpropertiesofthevariousactivesubstances

withintheclassandtheaffinityoftransportsystemsforeachactivesubstance.Allin-vitromechanismsofresistance

arecommonlyobservedinclinicalisolates.Resistancemechanismsthatinactivateotherantibioticssuchaspermeation

barriers(commoninPseudomonasaeruginosa)andeffluxmechanismsmayaffectsusceptibilitytociprofloxacin.

Plasmid-mediatedresistanceencodedbyqnr-geneshasbeenreported.

Spectrumofantibacterialactivity:

Breakpointsseparatesusceptiblestrainsfromstrainswithintermediatesusceptibilityandthelatterfromresistant

strains:

EUCASTRecommendations

Staphylococcusspp.-breakpointsforciprofloxacinrelatetohighdosetherapy.

Non-species-relatedbreakpointshavebeendeterminedmainlyonthebasisofPK/PDdataandareindependent

ofMICdistributionsofspecificspecies.Theyareforuseonlyforspeciesthathavenotbeengivenaspecies-

specificbreakpointandnotforthosespecieswheresusceptibilitytestingisnotrecommended.

Theprevalenceofacquiredresistancemayvarygeographicallyandwithtimeforselectedspeciesandlocalinformation

onresistanceisdesirable,particularlywhentreatingsevereinfections.Asnecessary,expertadviceshouldbesought

whenthelocalprevalenceofresistanceissuchthattheutilityoftheagentinatleastsometypesofinfectionsis

questionable.

Microorganisms Susceptible Resistant

Enterobacteria S 0.5mg/L R>1mg/L

Pseudomonas S 0.5mg/L R>1mg/L

Acinetobacter S 1mg/L R>1mg/L

Staphylococcusspp. 1 S 1mg/L R>1mg/L

Haemophilus

influenzaeand

Moraxellacatarrhalis S 0.5mg/L R>0.5mg/L

Neisseriagonorrhoeae S 0.03mg/L R>0.06mg/L

Neisseriameningitidis S 0.03mg/L R>0.06mg/L

Non-species-related

breakpoints* S 0.5mg/L R>1mg/L

COMMONLYSUSCEPTIBLESPECIES

AerobicGram-positivemicro-organisms

Bacillusanthracis(1)

AerobicGram-negativemicro-organisms

Aeromonasspp.

Brucellaspp.

Citrobacterkoseri

Francisellatularensis

Haemophilusducreyi

Haemophilusinfluenzae*

Legionellaspp.

Moraxellacatarrhalis*

Neisseriameningitidis

Pasteurellaspp.

Salmonellaspp.*

Shigellaspp.*

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2012 CRN 2074402 page number: 15

* Clinicalefficacyhasbeendemonstratedforsusceptibleisolatesinapproved

clinicalindications

Resistancerate 50%inoneormoreEUcountries

($): Naturalintermediatesusceptibilityintheabsenceofacquiredmechanismof

resistance

(1):StudieshavebeenconductedinexperimentalanimalinfectionsduetoinhalationsofBacillusanthracisspores;

thesestudiesrevealthatantibioticsstartingearlyafterexpositionavoidtheoccurrenceofthediseaseifthetreatmentis

Yersiniapestis

Anaerobicmicro-organisms

Mobiluncus

Othermicro-organisms

Chlamydiatrachomatis($)

Chlamydiapneumoniae($)

Mycoplasmahominis($)

Mycoplasmapneumoniae($)

SPECIESFORWHICHACQUIREDRESISTANCEMAYBEA

PROBLEM

AerobicGram-positivemicro-organisms

Enterococcusfaecalis($)

Staphylococcusspp.*(2)

AerobicGram-negativemicro-organisms

Acinetobacterbaumannii+

Burkholderiacepacia+*

Campylobacterspp.+*

Citrobacterfreundii*

Enterobacteraerogenes

Enterobactercloacae*

Escherichiacoli*

Klebsiellaoxytoca

Klebsiellapneumoniae*

Morganellamorganii*

Neisseriagonorrhoeae*

Proteusmirabilis*

Proteusvulgaris*

Providenciaspp.

Pseudomonasaeruginosa*

Pseudomonasfluorescens

Serratiamarcescens*

Anaerobicmicro-organisms

Peptostreptococcusspp.

Propionibacteriumacnes

INHERENTLYRESISTANTORGANISMS

AerobicGram-positivemicro-organisms

Actinomyces

Enteroccusfaecium

Listeriamonocytogenes

AerobicGram-negativemicro-organisms

Stenotrophomonasmaltophilia

Anaerobicmicro-organisms

Exceptedaslistedabove

Othermicro-organisms

Mycoplasmagenitalium

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2012 CRN 2074402 page number: 16

humansubjectsisbasedprimarilyonin-vitrosusceptibilityandonanimalexperimentaldatatogetherwithlimited

humandata.Two-monthtreatmentdurationinadultswithoralciprofloxacingivenatthefollowingdose,500mgbid,

isconsideredaseffectivetopreventanthraxinfectioninhumans.Thetreatingphysicianshouldrefertonational

and/orinternationalconsensusdocumentsregardingtreatmentofanthrax.

(2): Methicillin-resistantS.aureusverycommonlyexpressco-resistancetofluoroquinolones.Therateofresistance

tomethicillinisaround20to50%amongallstaphylococcalspeciesandisusuallyhigherinnosocomialisolates.

5.2Pharmacokineticproperties

Absorption

Followinganintravenousinfusionofciprofloxacinthemeanmaximumserumconcentrationswereachievedattheend

ofinfusion.Pharmacokineticsofciprofloxacinwerelinearoverthedoserangeupto400mgadministered

intravenously.

Comparisonofthepharmacokineticparametersforatwiceadayandthreetimesadayintravenousdoseregimen

indicatednoevidenceofdrugaccumulationforciprofloxacinanditsmetabolites.

A60-minuteintravenousinfusionof200mgciprofloxacinortheoraladministrationof250mgciprofloxacin,both

givenevery12hours,producedanequivalentareaundertheserumconcentrationtimecurve(AUC).

A60-minuteintravenousinfusionof400mgciprofloxacinevery12hourswasbioequivalenttoa500mgoraldose

every12hourswithregardtoAUC.

The400mgintravenousdoseadministeredover60minutesevery12hoursresultedinaC

similartothatobserved

witha750mgoraldose.

A60-minuteinfusionof400mgciprofloxacinevery8hoursisequivalentwithrespecttoAUCto750mgoralregimen

givenevery12hours.

Distribution

Proteinbindingofciprofloxacinislow(20-30%).Ciprofloxacinispresentinplasmalargelyinanon-ionisedformand

hasalargesteadystatedistributionvolumeof2-3L/kgbodyweight.Ciprofloxacinreacheshighconcentrationsina

varietyoftissuessuchaslung(epithelialfluid,alveolarmacrophages,biopsytissue),sinuses,inflamedlesions

(cantharidesblisterfluid),andtheurogenitaltract(urine,prostate,endometrium)wheretotalconcentrationsexceeding

thoseofplasmaconcentrationsarereached.

Metabolism

Lowconcentrationsoffourmetaboliteshavebeenreported,whichwereidentifiedas:desethyleneciprofloxacin(M1),

sulphociprofloxacin(M2),oxociprofloxacin(M3)andformylciprofloxacin(M4).Themetabolitesdisplayin-vitro

antimicrobialactivitybuttoalowerdegreethantheparentcompound.

CiprofloxacinisknowntobeamoderateinhibitoroftheCYP4501A2iso-enzymes.

Elimination

Ciprofloxacinislargelyexcretedunchangedbothrenallyand,toasmallerextent,faecally.

Renalclearanceisbetween180-300mL/kg/handthetotalbodyclearanceisbetween480-600mL/kg/h.Ciprofloxacin

undergoesbothglomerularfiltrationandtubularsecretion.Severelyimpairedrenalfunctionleadstoincreasedhalf

Excretionofciprofloxacin(%ofdose)

IntravenousAdministration

Urine Faeces

Ciprofloxacin 61.5 15.2

Metabolites(M

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2012 CRN 2074402 page number: 17

Non-renalclearanceofciprofloxacinismainlyduetoactivetrans-intestinalsecretionandmetabolism.1%ofthedose

isexcretedviathebiliaryroute.Ciprofloxacinispresentinthebileinhighconcentrations.

Paediatricpatients

Thepharmacokineticdatainpaediatricpatientsarelimited.

InastudyinchildrenC

andAUCwerenotage-dependent(aboveoneyearofage).NonotableincreaseinC

AUCuponmultipledosing(10mg/kgthreetimesdaily)wasobserved.

In10childrenwithseveresepsisC

was6.1mg/L(range4.6-8.3mg/L)aftera1-hourintravenousinfusionof10

mg/kginchildrenagedlessthan1yearcomparedto7.2mg/L(range4.7-11.8mg/L)forchildrenbetween1and5

yearsofage.TheAUCvalueswere17.4mg*h/L(range11.8-32.0mg*h/L)and16.5mg*h/L(range11.0-23.8

mg*h/L)intherespectiveagegroups.

Thesevaluesarewithintherangereportedforadultsattherapeuticdoses.Basedonpopulationpharmacokinetic

analysisofpaediatricpatientswithvariousinfections,thepredictedmeanhalf-lifeinchildrenisapprox.4-5hoursand

thebioavailabilityoftheoralsuspensionrangesfrom50to80%.

5.3Preclinicalsafetydata

Non-clinicaldatarevealnospecialhazardsforhumansbasedonconventionalstudiesofsingledosetoxicity,repeated

dosetoxicity,carcinogenicpotential,ortoxicitytoreproduction.Likeanumberofotherquinolones,ciprofloxacinis

phototoxicinanimalsatclinicallyrelevantexposurelevels.Dataonphotomutagenicity/photocarcinogenicityshowa

weakphotomutagenicorphototumorigeniceffectofciprofloxacinin-vitroandinanimalexperiments.Thiseffectwas

comparabletothatofothergyraseinhibitors.

Articulartolerability:

Asreportedforothergyraseinhibitors,ciprofloxacincausesdamagetothelargeweight-bearingjointsinimmature

animals.Theextentofthecartilagedamagevariesaccordingtoage,speciesanddose;thedamagecanbereducedby

takingtheweightoffthejoints.Studieswithmatureanimals(rat,dog)revealednoevidenceofcartilagelesions.Ina

studyinyoungbeagledogs,ciprofloxacincausedseverearticularchangesattherapeuticdosesaftertwoweeksof

treatment,whichwerestillobservedafter5months.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

LacticAcid

SodiumChloride

HydrochloricAcidforpHadjustment

WaterforInjections

6.2Incompatibilities

Thismedicinalproductmustnotbemixedwithothermedicinalproductsexceptthosementionedinsection6.6.

6.3Shelflife

3years

Afterfirstopening:

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2012 CRN 2074402 page number: 18

Afterdilution:

Chemicalandphysicalin-usestabilityhasbeendemonstratedfor42hoursat25ºC.

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestorage

timesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynottobelongerthan24hoursat

2to8ºC,unlessreconstitution/dilution(etc)hastakenplaceincontrolledandvalidatedasepticconditions.

6.4Specialprecautionsforstorage

Donotstoreabove25ºC.Donotrefrigerateorfreeze.

Keepvial/bottleinoutercartoninordertoprotectfromlight.

Forstorageconditionsofthedilutedmedicinalproduct,seesection6.3.

6.5Natureandcontentsofcontainer

TypeIIclearglass,internallysiliconised,colourlessvial/bottlewithasiliconisedgreybromobutylrubberstopper,

containing50ml,100mlor200mlofCiprofloxacinPfizer2mg/mlSolutionforinfusion.

Packsize:Individualvial/bottleinunitcarton.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Thesolutionshouldbeinspectedvisuallyforparticulatematterordiscolorationpriortoadministration.Thesolution

shouldonlybeusedifclearandfreefromparticles.

CiprofloxacinPfizer2mg/mlSolutionforinfusiondilutedto0.33mg/mlhasbeenshowntobecompatiblewith

Ringer'ssolution,0.9%sodiumchloridesolution,5%and10%glucosesolutions,glucose/salineandfructose10%

solution.

TheproductshouldnotbemixedwithotherdrugproductswhicharechemicallyorphysicallyunstableatitspHof3.9-

4.5.

Theproductshouldbeinfuseddirectlyandadministeredover60minutes.The200mldose(400mg)doseshouldbe

infusedover60minutes.

Forsingleuseonly.Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocal

requirements , immediatelyafteruse.

7MARKETINGAUTHORISATIONHOLDER

PfizerHealthcareIreland,

9Riverwalk,

NationalDigitalPark,

CitywestBusinessCampus,

Dublin24,

Ireland

8MARKETINGAUTHORISATIONNUMBER

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2012 CRN 2074402 page number: 19

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:16thMarch2012

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2012 CRN 2074402 page number: 20