CIPROFLOXACIN REDIBAG

Main information

  • Trade name:
  • CIPROFLOXACIN REDIBAG
  • Dosage:
  • 2
  • Pharmaceutical form:
  • Solution for Injection
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0167/130/001
  • Authorization date:
  • 17-10-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

CiprofloxacinRedibag2mg/ml,SolutionforInfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachmlcontains2mgciprofloxacinin5%w/vglucosemonohydratesolution.

Eachbagwith100mlcontains200mgciprofloxacin.

Eachbagwith200mlcontains400mgciprofloxacin.

Excipient:Glucose(seesection4.4)

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Solutionforinfusion.

Clear,slightlygreenish-yellowsolution.

pHofthesolution:3.5to4.6.

4CLINICALPARTICULARS

4.1TherapeuticIndications

CiprofloxacinRedibag2mg/mLsolutionforinfusionisindicatedforthetreatmentofthefollowinginfections(see

sections4.4and5.1).Specialattentionshouldbepaidtoavailableinformationonresistancetociprofloxacinbefore

commencingtherapy.

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantibacterialagents.

Adults

LowerrespiratorytractinfectionsduetoGram-negativebacteria

exacerbationsofchronicobstructivepulmonarydisease

broncho-pulmonaryinfectionsincysticfibrosisorinbronchiectasis

pneumonia

Chronicsuppurativeotitismedia

AcuteexacerbationofchronicsinusitisespeciallyifthesearecausedbyGram-negativebacteria

Urinarytractinfections

Epididymo-orchitisincludingcasesduetoNeisseriagonorrhoeae

PelvicinflammatorydiseaseincludingcasesduetoNeisseriagonorrhoeae

IntheabovegenitaltractinfectionswhenthoughtorknowntobeduetoNeisseriagonorrhoeaeitisparticularly

importanttoobtainlocalinformationontheprevalenceofresistancetociprofloxacinandtoconfirmsusceptibility

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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

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Adults

Indications Dailydoseinmg Totaldurationof

treatment(including

switchtooral

therapyassoonas

possible)

Infectionsofthelowerrespiratorytract 400mgtwicedailyto

400mgthreetimesa

7to14days

Infectionsofthe

upperrespiratory

tract Acuteexacerbationof

chronicsinusitis 400mgtwicedailyto

400mgthreetimesa

7to14days

Chronicsuppurative

otitismedia 400mgtwicedailyto

400mgthreetimesa

7to14days

Malignantexternalotitis400mgthreetimesa

28daysupto3

months

Urinarytract

infections Complicatedand

uncomplicated

pyelonephritis 400mgtwicedailyto

400mgthreetimesa

7to21days,itcanbe

continuedforlonger

than21daysinsome

specificcircumstances

(suchasabscesses)

Prostatitis 400mgtwicedailyto

400mgthreetimesa

2to4weeks(acute)

Genitaltract

infections Epididymo-orchitisand

pelvicinflammatory

diseases 400mgtwicedailyto

400mgthreetimesa

atleast14days

Indications Dailydoseinmg Totaldurationof

treatment(including

switchtooral

therapyassoonas

possible)

Infectionsofthe

gastro-intestinal

tractandintra-

abdominal

infections Diarrhoeacausedby

bacterialpathogens

includingShigellaspp.

otherthanShigella

dysenteriaetype1and

empiricaltreatmentof

severetravellers’

diarrhoea 400mgtwicedaily 1day

Diarrhoeacausedby

Shigelladysenteriaetype

400mgtwicedaily 5days

Diarrhoeacausedby

Vibriocholerae 400mgtwicedaily 3days

Typhoidfever 400mgtwicedaily 7days

Intra-abdominal

infectionsduetoGram-

negativebacteria 400mgtwicedailyto

400mgthreetimesa

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Childrenandadolescents

Geriatricpatients

Geriatricpatientsshouldreceiveadoseselectedaccordingtotheseverityoftheinfectionandthepatient`screatinine

Infectionsoftheskinandsofttissue 400mgtwicedailyto

400mgthreetimesa

7to14days

Boneandjointinfections 400mgtwicedailyto

400mgthreetimesa

max.of3months

Treatmentofinfectionsorprophylaxisof

infectionsinneutropenicpatients

Ciprofloxacinshouldbeco-administeredwith

appropriateantibacterialagent(s)in

accordancetoofficialguidance. 400mgtwicedailyto

400mgthreetimesa

Therapyshouldbe

continuedoverthe

entireperiodof

neutropenia

Inhalationanthraxpost-exposureprophylaxis

andcurativetreatmentforpersonsrequiring

parenteraltreatmentDrugadministration

shouldbeginassoonaspossibleafter

suspectedorconfirmedexposure. 400mgtwicedaily 60daysfromthe

confirmationof

Bacillusanthracis

exposure

Indication Dailydoseinmg Totaldurationof

treatment(including

switchtooraltherapy

assoonaspossible)

Cysticfibrosis 10mg/kgbodyweightthreetimesa

daywithamaximumof400mgper

dose. 10to14days

Complicatedurinarytract

infectionsand

pyelonephritis 6mg/kgbodyweightthreetimesaday

to10mg/kgbodyweightthreetimesa

daywithamaximumof400mgper

dose. 10to21days

Inhalationanthraxpost-

exposure,prophylacticand

curativetreatmentfor

personsrequiring

parenteraltreatment.Drug

administrationshould

beginassoonaspossible

aftersuspectedor

10mg/kgbodyweighttwicedailyto

15mg/kgbodyweighttwicedaily

withamaximumof400mgperdose. 60daysfromthe

confirmationofBacillus

anthracisexposure

Othersevereinfections 10mg/kgbodyweightthreetimesa

daywithamaximumof400mgper

dose. Accordingtothetypeof

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Renalandhepaticimpairment

Recommendedstartingandmaintenancedosesforpatientswithimpairedrenalfunction:

Inpatientswithimpairedliverfunctionnodoseadjustmentisrequired.

Dosinginchildrenwithimpairedrenaland/orhepaticfunctionhasnotbeenstudied.

Methodofadministration

CiprofloxacinRedibagshouldbecheckedvisuallypriortouse.Itmustnotbeusedifcloudy.

Ciprofloxacinshouldbeadministeredbyintravenousinfusion.Forchildren,theinfusiondurationis60minutes.

Inadultpatients,infusiontimeis60minutesfor400mgCiprofloxacinRedibagand30minutesfor200mg

CiprofloxacinRedibag.Slowinfusionintoalargeveinwillminimisepatientdiscomfortandreducetheriskofvenous

irritation.

Intheabsenceofcompatibilitystudies,CiprofloxacinRedibagmustnotbemixedwithothermedicinalproducts.(see

section6.2).

4.3Contraindications

Hypersensitivitytotheactivesubstance,tootherquinolonesortoanyoftheexcipients(seesection6.1).

Concomitantadministrationofciprofloxacinandtizanidine(seesection4.5).

4.4Specialwarningsandprecautionsforuse

SevereinfectionsandmixedinfectionswithGram-positiveandanaerobicpathogens

CiprofloxacinmonotherapyisnotsuitedfortreatmentofsevereinfectionsandinfectionsthatmightbeduetoGram-

positiveoranaerobicpathogens.Insuchinfectionsciprofloxacinmustbecoadministeredwithotherappropriate

antibacterialagents.

StreptococcalInfections(includingStreptococcuspneumoniae)

Ciprofloxacinisnotrecommendedforthetreatmentofstreptococcalinfectionsduetoinadequateefficacy.

Genitaltractinfections

Epididymo-orchitisandpelvicinflammatorydiseasesmaybecausedbyfluoroquinolone-resistantNeisseria

gonorrhoeae.Ciprofloxacinshouldbeco-administeredwithanotherappropriateantibacterialagentunless

ciprofloxacin-resistantNeisseriagonorrhoeaecanbeexcluded.Ifclinicalimprovementisnotachievedafter3daysof

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(after

dialysis)

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Intra-abdominalinfections

Therearelimiteddataontheefficacyofciprofloxacininthetreatmentofpost-surgicalintra-abdominalinfections.

Travellers’diarrhoea

Thechoiceofciprofloxacinshouldtakeintoaccountinformationonresistancetociprofloxacininrelevantpathogensin

thecountriesvisited.

Infectionsofthebonesandjoints

Ciprofloxacinshouldbeusedincombinationwithotherantimicrobialagentsdependingontheresultsofthe

microbiologicaldocumentation.

Inhalationalanthrax

Useinhumansisbasedonin-vitrosusceptibilitydataandonanimalexperimentaldatatogetherwithlimitedhuman

data.Treatingphysiciansshouldrefertonationaland/orinternationalconsensusdocumentsregardingthetreatmentof

anthrax.

Childrenandadolescents

Theuseofciprofloxacininchildrenandadolescentsshouldfollowavailableofficialguidance.

Ciprofloxacintreatmentshouldbeinitiatedonlybyphysicianswhoareexperiencedinthetreatmentofcysticfibrosis

and/orsevereinfectionsinchildrenandadolescents.

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

infections.

Hypersensitivity

Hypersensitivityandallergicreactions,includinganaphylaxisandanaphylactoidreactions,mayoccurfollowinga

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

andanadequatemedicaltreatmentisrequired.

MusculoskeletalSystem

Ciprofloxacinshouldgenerallynotbeusedinpatientswithahistoryoftendondisease/disorderrelatedtoquinolone

treatment.Nevertheless,inveryrareinstances,aftermicrobiologicaldocumentationofthecausativeorganismand

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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,depressionorpsychosiscanprogresstoselfendangeringbehaviour.Inthesecases,ciprofloxacinshouldbe

discontinued.

Casesofpolyneuropathy(basedonneurologicalsymptomssuchaspain,burning,sensorydisturbancesormuscle

weakness,aloneorincombination)havebeenreportedinpatientsreceivingciprofloxacin.

Ciprofloxacinshouldbediscontinuedinpatientsexperiencingsymptomsofneuropathy,includingpain,burning,

tingling,numbness,and/orweaknessinordertopreventthedevelopmentofanirreversiblecondition(seesection4.8).

Cardiacdisorders

SinceciprofloxacinisassociatedwithcasesofQTprolongation(seesection4.8),cautionshouldbeexercisedwhen

treatingpatientsatriskfortorsadesdepointesarrhythmia.

GastrointestinalSystem

Theoccurrenceofsevereandpersistentdiarrhoeaduringoraftertreatment(includingseveralweeksaftertreatment)

mayindicateanantibiotic-associatedcolitis(life-threateningwithpossiblefataloutcome),requiringimmediate

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

therapyinitiated.Anti-peristalticdrugsarecontraindicatedinthissituation.

Renalandurinarysystem

Crystalluriarelatedtotheuseofciprofloxacinhasbeenreported(seesection4.8).Patientsreceivingciprofloxacin

shouldbewellhydratedandexcessivealkalinityoftheurineshouldbeavoided.

Hepatobiliarysystem

Casesofhepaticnecrosisandlife-threateninghepaticfailurehavebeenreportedwithciprofloxacin(seesection4.8).In

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

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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.

GlucoseLoad

CiprofloxacinRedibagsolutionforinfusioncontains5gglucosein100mLand10gin200mLsolutionforinfusion.

Thisshouldbetakenintoaccountinpatientswithdiabetesmellitus.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Effectsofothermedicinalproductsonciprofloxacin:

Probenecid

Probenecidinterfereswithrenalsecretionofciprofloxacin.Co-administrationofprobenecidandciprofloxacin

increasesciprofloxacinserumconcentrations.

Effectsofciprofloxacinonothermedicinalproducts:

Tizanidine

Tizanidinemustnotbeadministeredtogetherwithciprofloxacin(seesection4.3).Inaclinicalstudywithhealthy

subjects,therewasanincreaseinserumtizanidineconcentration(Cmaxincrease:7-fold,range:4to21-fold;AUC

increase:10-fold,range:6to24-fold)whengivenconcomitantlywithciprofloxacin.Increasedserumtizanidine

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

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Phenytoin

Simultaneousadministrationofciprofloxacinandphenytoinmayresultinincreasedorreducedserumlevelsof

phenytoinsuchthatmonitoringofdruglevelsisrecommended.

Oralanticoagulants

Simultaneousadministrationofciprofloxacinwithwarfarinmayaugmentitsanti-coagulanteffects.Therehavebeen

manyreportsofincreasesinoralanti-coagulantactivityinpatientsreceivingantibacterialagents,including

fluoroquinolones.Theriskmayvarywiththeunderlyinginfection,ageandgeneralstatusofthepatientsothatthe

contributionofthefluoroquinolonetotheincreaseinINR(internationalnormalisedratio)isdifficulttoassess.Itis

recommendedthattheINRshouldbemonitoredfrequentlyduringandshortlyafterco-administrationofciprofloxacin

withanoralanticoagulantagent.

Ropinirole

Itwasshowninaclinicalstudythatconcomitantuseofropinirolewithciprofloxacin,amoderateinhibitorofthe

CYP4501A2isozyme,resultsinanincreaseofCmaxandAUCofropiniroleby60%and84%,respectively.

Monitoringofropinirole-relatedsideeffectsanddoseadjustmentasappropriateisrecommendedduringandshortly

afterco-administrationwithciprofloxacin(seesection4.4).

Clozapine

Followingconcomitantadministrationof250mgciprofloxacinwithclozapinefor7days,serumconcentrationsof

clozapineandN-desmethylclozapinewereincreasedby29%and31%,respectively.Clinicalsurveillanceand

appropriateadjustmentofclozapinedosageduringandshortlyaftercoadministrationwithciprofloxacinareadvised

(seesection4.4)

4.6Pregnancyandlactation

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,theabilitytodriveortooperate

machinerymaybeimpaired.

4.8Undesirableeffects

Themostcommonlyreportedadversedrugreactions(ADRs)arenausea,diarrhoea,vomiting,transientincreaseintransaminases,

rash,andinjectionandinfusionsitereactions.

ADRsderivedfromclinicalstudiesandpost-marketingsurveillancewithCiprofloxacinRedibag(oral,intravenousandsequential

therapy)sortedbycategoriesoffrequencyarelistedbelow.Thefrequencyanalysistakesintoaccountdatafrombothoraland

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SystemOrgan

Class 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)

Infectionsand

Infestations Mycoticsuper-

infections Antibiotic

associatedcolitis

(veryrarelywith

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-

threatening)

ImmuneSystem

Disorders Allergicreaction

Allergicoedema/

angiooedema Anaphylactic

reaction

Anaphylactic

shock(life-

threatening)

(seesection4.4)

Serumsickness-

likereaction

Metabolismand

Nutrition

Disorders Anorexia Hyperglycaemia

Psychiatric

Disorders Psychomotor

hyperactivity/

agitation Confusionand

disorientation

Anxietyreaction

Abnormaldreams

Depression

Hallucinations Psychotic

reactions(see

section4.4)

NervousSystem

Disorders Headache

Dizziness

Sleepdisorders

Tastedisorders Par-and

Dysaesthesia

Hypoaesthesia

TremorSeizures

(seesection4.4)

Vertigo Migraine

Disturbed

coordination

Gaitdisturbance

Olfactorynerve

disorders

Intracranial

hypertension Peripheral

neuropathy

(seesection

4.4)

EyeDisorders Visual

disturbances Visualcolour

distortions

Earand

Labyrinth

Disorders Tinnitus

Hearingloss/

Hearing

impaired

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Disorders arrhythmia,

prolongation,

torsadesde

pointes*

Vascular

Disorders Vasodilatation

Hypotension

Syncope Vasculitis

Respiratory,

Thoracicand

Mediastinal

Disorders Dyspnoea

(including

asthmatic

condition)

Gastrointestinal

Disorders Nausea

Diarrhoea Vomiting

Gastrointestinal

andabdominal

pains

Dyspepsia

Flatulence Pancreatitis

Hepatobiliary

Disorders Increasein

transaminases

Increased

bilirubin Hepatic

impairment

Cholestaticicterus

Hepatitis Livernecrosis

(veryrarely

progressingto

life-threatening

hepaticfailure)

(seesection4.4)

Skinand

Subcutaneous

TissueDisorders RashPruritus

Urticaria Photosensitivity

reactions(see

section4.4) Petechiae

Erythema

multiforme

Erythema

nodosum

Stevens-

Johnson

syndrome

(potentiallylife-

threatening)

Toxicepidermal

necrolysis

(potentiallylife-

threatening)

Musculoskeletal,

Connective

TissueandBone

Disorders Musculo-

skeletalpain

(e.g.extremity

pain,backpain,

chestpain)

Arthralgia Myalgia

Arthritis

Increasedmuscle

toneandcramping Muscular

weakness

Tendinitis

Tendonrupture

(predominantly

Achillestendon)

(seesection

4.4)

Exacerbationof

symptomsof

myasthenia

gravis(see

section4.4)

Renaland

Urinary

Disorders Renal

impairment Renalfailure

Haematuria

Crystalluria(see

section4.4)

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*Theseeventswerereportedduringthepostmarketingperiodandwereobservedpredominantlyamongpatientswithfurtherrisk

factorsforQTprolongation(seesection4.4).

Thefollowingundesirableeffectshaveahigherfrequencycategoryinthesubgroupsofpatientsreceivingintravenousor

sequential(intravenoustooral)treatment:

Paediatricpatients

Theincidenceofarthropathy,mentionedabove,isreferringtodatacollectedinstudieswithadults.Inchildren,arthropathyis

reportedtooccurcommonly(seesection4.4).

4.9Overdose

Anoverdoseof12ghasbeenreportedtoleadtomildsymptomsoftoxicity.Anacuteoverdoseof16ghasbeen

reportedtocauseacuterenalfailure.

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

discomfort,renalandhepaticimpairmentaswellascrystalluriaandhaematuria.

Reversiblerenaltoxicityhasbeenreported.

Apartfromroutineemergencymeasures,itisrecommendedtomonitorrenalfunction,includingurinarypHand

acidify,ifrequired,topreventcrystalluria.Patientsshouldbekeptwellhydrated.Onlyasmallquantityof

ciprofloxacin(<10%)iseliminatedbyhaemodialysisorperitonealdialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Fluoroquinolones,ATCcode:J01MA02

Mechanismofaction:

Asafluoroquinoloneantibacterialagent,thebactericidalactionofciprofloxacinresultsfromtheinhibitionofbothtypeII

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

nephritis

General

Disordersand

Administration

SiteConditions Injectionand

infusionsite

reactions(only

intravenous

administration) AstheniaFever Oedema

Sweating

(hyperhidrosis)

Investigations Increasein

bloodalkaline

phosphatase Prothrombinlevel

abnormal

Increased

amylase

Common Vomiting,Transientincreaseintransaminases,Rash

Uncommon Thrombocytopenia,Thrombocytaemia,Confusionanddisorientation,

Hallucinations,Par-anddysaesthesia,Seizures,Vertigo,Visualdisturbances,

Hearingloss,Tachycardia,Vasodilatation,Hypotension,Transienthepatic

impairment,Cholestaticicterus,Renalfailure,Oedema

Rare Pancytopenia,Bonemarrowdepression,Anaphylacticshock,Psychotic

reactions,Migraine,Olfactorynervedisorders,Hearingimpaired,Vasculitis,

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PK/PDrelationship:

Efficacymainlydependsontherelationbetweenthemaximumconcentrationinserum(C

)andtheminimuminhibitory

concentration(MIC)ofciprofloxacinforabacterialpathogenandtherelationbetweentheareaunderthecurve(AUC)andthe

MIC.

Mechanismofresistance:

In-vitroresistancetociprofloxacincanbeacquiredthroughastepwiseprocessbytargetsitemutationsinbothDNAgyraseand

topoisomeraseIV.Thedegreeofcross-resistancebetweenciprofloxacinandotherfluoroquinolonesthatresultsisvariable.Single

mutationsmaynotresultinclinicalresistance,butmultiplemutationsgenerallyresultinclinicalresistancetomanyorallactive

substanceswithintheclass.

Impermeabilityand/oractivesubstanceeffluxpumpmechanismsofresistancemayhaveavariableeffectonsusceptibilityto

fluoroquinolones,whichdependsonthephysiochemicalpropertiesofthevariousactivesubstanceswithintheclassandthe

affinityoftransportsystemsforeachactivesubstance.Allin-vitromechanismsofresistancearecommonlyobservedinclinical

isolates.Resistancemechanismsthatinactivateotherantibioticssuchaspermeationbarriers(commoninPseudomonas

aeruginosa)andeffluxmechanismsmayaffectsusceptibilitytociprofloxacin.

Plasmid-mediatedresistanceencodedbyqnr-geneshasbeenreported.

Spectrumofantibacterialactivity:

Breakpointsseparatesusceptiblestrainsfromstrainswithintermediatesusceptibilityandthelatterfromresistantstrains:

EUCASTRecommendations

Staphylococcusspp.-breakpointsforciprofloxacinrelatetohighdosetherapy.

Non-species-relatedbreakpointshavebeendeterminedmainlyonthebasisofPK/PDdataandareindependentofMIC

distributionsofspecificspecies.Theyareforuseonlyforspeciesthathavenotbeengivenaspecies-specificbreakpointand

notforthosespecieswheresusceptibilitytestingisnotrecommended.

Theprevalenceofacquiredresistancemayvarygeographicallyandwithtimeforselectedspeciesandlocalinformationon

resistanceisdesirable,particularlywhentreatingsevereinfections.Asnecessary,expertadviceshouldbesoughtwhenthelocal

prevalenceofresistanceissuchthattheutilityoftheagentinatleastsometypesofinfectionsisquestionable.

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

Haemophilusinfluenzaeand

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

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COMMONLYSUSCEPTIBLESPECIES

AerobicGram-positivemicro-organisms

Bacillusanthracis(1)

AerobicGram-negativemicro-organisms

Aeromonasspp.

Brucellaspp.

Citrobacterkoseri

Francisellatularensis

Haemophilusducreyi

Haemophilusinfluenzae*

Legionellaspp.

Moraxellacatarrhalis*

Neisseriameningitidis

Pasteurellaspp.

Salmonellaspp.*

Shigellaspp.*

Vibriospp.

Yersiniapestis

Anaerobicmicro-organisms

Mobiluncus

Othermicro-organisms

Chlamydiatrachomatis($)

Chlamydiapneumoniae($)

Mycoplasmahominis($)

Mycoplasmapneumoniae($)

SPECIESFORWHICHACQUIREDRESISTANCEMAYBEAPROBLEM

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

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5.2Pharmacokineticproperties

Absorption

Followinganintravenousinfusionofciprofloxacinthemeanmaximumserumconcentrationswereachievedattheendof

infusion.Pharmacokineticsofciprofloxacinwerelinearoverthedoserangeupto400mgadministeredintravenously.

Comparisonofthepharmacokineticparametersforatwiceadayandthreetimesadayintravenousdoseregimenindicatedno

evidenceofdrugaccumulationforciprofloxacinanditsmetabolites.

A60-minuteintravenousinfusionof200mgciprofloxacinortheoraladministrationof250mgciprofloxacin,bothgivenevery12

hours,producedanequivalentareaundertheserumconcentrationtimecurve(AUC).

A60-minuteintravenousinfusionof400mgciprofloxacinevery12hourswasbioequivalenttoa500mgoraldoseevery12hours

withregardtoAUC.

The400mgintravenousdoseadministeredover60minutesevery12hoursresultedinaC

similartothatobservedwitha750

mgoraldose.

A60-minuteinfusionof400mgciprofloxacinevery8hoursisequivalentwithrespecttoAUCto750mgoralregimengiven

every12hours.

Distribution

Proteinbindingofciprofloxacinislow(20-30%).Ciprofloxacinispresentinplasmalargelyinanonionisedformandhasalarge

steadystatedistributionvolumeof2-3L/kgbodyweight.Ciprofloxacinreacheshighconcentrationsinavarietyoftissuessuchas

lung(epithelialfluid,alveolarmacrophages,biopsytissue),sinuses,inflamedlesions(cantharidesblisterfluid),andtheurogenital

tract(urine,prostate,endometrium)wheretotalconcentrationsexceedingthoseofplasmaconcentrationsarereached.

Metabolism

Lowconcentrationsoffourmetaboliteshavebeenreported,whichwereidentifiedas:desethyleneciprofloxacin(M1),

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

activitybuttoalowerdegreethantheparentcompound.

CiprofloxacinisknowntobeamoderateinhibitoroftheCYP4501A2iso-enzymes.

Elimination

Othermicro-organisms

Mycoplasmagenitalium

Ureaplasmaurealitycum

*Clinicalefficacyhasbeendemonstratedforsusceptibleisolatesinapprovedclinicalindications

Resistancerate ≥50%inoneormoreEUcountries

($):Naturalintermediatesusceptibilityintheabsenceofacquiredmechanismofresistance

(1):StudieshavebeenconductedinexperimentalanimalinfectionsduetoinhalationsofBacillus

anthracisspores;thesestudiesrevealthatantibioticsstartingearlyafterexpositionavoidthe

occurrenceofthediseaseifthetreatmentismadeuptothedecreaseofthenumberofspores

intheorganismundertheinfectivedose.Therecommendeduseinhumansubjectsisbased

primarilyonin-vitrosusceptibilityandonanimalexperimentaldatatogetherwithlimited

humandata.Two-monthtreatmentdurationinadultswithoralciprofloxacingivenatthe

followingdose,500mgbid,isconsideredaseffectivetopreventanthraxinfectioninhumans.

Thetreatingphysicianshouldrefertonationaland/orinternationalconsensusdocuments

regardingtreatmentofanthrax.

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

rateofresistancetomethicillinisaround20to50%amongallstaphylococcalspeciesandis

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

bothglomerularfiltrationandtubularsecretion.Severelyimpairedrenalfunctionleadstoincreasedhalflivesofciprofloxacinof

upto12h.

Non-renalclearanceofciprofloxacinismainlyduetoactivetrans-intestinalsecretionandmetabolism.1%ofthedoseisexcreted

viathebiliaryroute.Ciprofloxacinispresentinthebileinhighconcentrations.

Paediatricpatients

Thepharmacokineticdatainpaediatricpatientsarelimited.

InastudyinchildrenC

andAUCwerenotage-dependent(aboveoneyearofage).NonotableincreaseinC

andAUCupon

multipledosing(10mg/kgthreetimesdaily)wasobserved.

In10childrenwithseveresepsisC

was6.1mg/L(range4.6-8.3mg/L)aftera1-hourintravenousinfusionof10mg/kgin

childrenagedlessthan1yearcomparedto7.2mg/L(range4.7-11.8mg/L)forchildrenbetween1and5yearsofage.TheAUC

valueswere17.4mg*h/L(range11.8-32.0mg*h/L)and16.5mg*h/L(range11.0-23.8mg*h/L)intherespectiveagegroups.

Thesevaluesarewithintherangereportedforadultsattherapeuticdoses.Basedonpopulationpharmacokineticanalysisof

paediatricpatientswithvariousinfections,thepredictedmeanhalf-lifeinchildrenisapprox.4-5hoursandthebioavailabilityof

theoralsuspensionrangesfrom50to80%.

5.3Preclinicalsafetydata

Non-clinicaldatarevealnospecialhazardsforhumansbasedonconventionalstudiesofsingledosetoxicity,repeateddose

toxicity,carcinogenicpotential,ortoxicitytoreproduction.

Likeanumberofotherquinolones,ciprofloxacinisphototoxicinanimalsatclinicallyrelevantexposurelevels.Dataon

photomutagenicity/photocarcinogenicityshowaweakphotomutagenicorphototumorigeniceffectofciprofloxacinin-vitroandin

animalexperiments.Thiseffectwas

comparabletothatofothergyraseinhibitors.

Articulartolerability:

Asreportedforothergyraseinhibitors,ciprofloxacincausesdamagetothelargeweight-bearingjointsinimmatureanimals.The

extentofthecartilagedamagevariesaccordingtoage,speciesanddose;thedamagecanbereducedbytakingtheweightoffthe

joints.Studieswithmatureanimals(rat,dog)revealednoevidenceofcartilagelesions.Inastudyinyoungbeagledogs,

ciprofloxacincausedseverearticularchangesattherapeuticdosesaftertwoweeksoftreatment,whichwerestillobservedafter5

months.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Glucosemonohydrate

Lacticacid

Hydrochloricacid1N(forpH-adjustment)

Excretionofciprofloxacin(%ofdose)

IntravenousAdministration

Urine Faeces

Ciprofloxacin 61.5 15.2

Metabolites(M

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6.2Incompatibilities

Intheabsenceofcompatibilitystudies,CiprofloxacinRedibagmustnotbemixedwithothermedicinalproducts.

6.3ShelfLife

30months

6.4Specialprecautionsforstorage

Storethebaginitsoriginalpackageinordertoprotectthecontentsfromlightandwatervapourloss.

Donotfreeze.

6.5Natureandcontentsofcontainer

Themedicinalproductissuppliedinaflexibleplasticinfusionbagcomposedofpolyolefinicresins.Twobagsizes

areavailable:100mland200ml.Eachinfusionbagisoverpouchedwithaprotectivealuminiumoverpouch.

Packsizes:

100ml

100ml

100ml

200ml

200ml

200ml

(Notallpacksizesmaybemarketed.)

6.6Specialprecautionsfordisposalandotherhandling

Themedicinalproductisintendedonlyforintravenousinfusionusingsterileequipment.

Eachinfusionbagisintendedforsingleuseonly.

Parenteraldrugsshouldbevisuallyinspectedforparticulatematteranddiscolourationpriortoadministration,

wheneverthesolutionandcontainerpermits.

Becausethemedicinalproductislight-sensitive,donotremovetheinfusionbagfromthefoiloverpouchuntilreadyfor

use,andusepromptlyafteropeningtheoverpouch.Theoverpouchprotectsthecontentsfromlightandisbarrierto

watervapourloss.Theinnerinfusionbagmaintainsthesterilityofthemedicinalproduct.

Donotuseifthesolutioniscloudyorprecipitated,orifthesealisnotintact.

Discardanyunusedportionofthesolutionimmediatelyafteruse.

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

Caution:Donotuseplasticinfusionbagsinseriesconnections.Suchusecouldresultinairembolismduetoresidual

airbeingdrawnfromtheprimarybagbeforetheadministrationofthefluidfromthesecondarybagiscompleted.

TOOPEN

Removetheinfusionbagfromtheoverpouchjustbeforeuse:Teartheoverpouchdownthesideattheslitandremove

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Someopacityoftheplasticbagduetomoistureabsorptionduringthesterilisationprocessmaybeobserved.Thisis

normalanddoesnotaffectthequalityorsafetyofthesolution.Theopacitywilldiminishgradually.

Afterremovingtheinfusionbagfromtheoverpouch,checkthebagforminuteleaksbyfirmlysqueezingtheinfusion

bag.Ifleaksarefound,discardtheproduct,becauseitmaynotbesterile.

PREPARATIONFORADMINISTRATION

Suspendtheinfusionbagfromtheeyeletsupport.

Twistofftheprotectorfromtheaccessportoftheinfusionbag.

Attachanadministrationset.Refertocompletedirectionsaccompanyingthesetforconnection,primingoftheset

andadministrationofthesolution.

Compatibilityofintravenousinfusion

Unlesscompatibilityhasbeenproven,themedicinalproductshouldalwaysbeadministeredseparately.See

Section6.2.

7MARKETINGAUTHORISATIONHOLDER

BaxterHealthcareLimited

CaxtonWay,

Thetford,

Norfolk,

IP243SE

UnitedKingdom.

8MARKETINGAUTHORISATIONNUMBER

PA167/130/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:17thOctober2008

10DATEOFREVISIONOFTHETEXT

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