CIPROFLOXACIN

Main information

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

Documents

Localization

  • Available in:
  • CIPROFLOXACIN Solution for Infusion 2
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0237/063/001
  • Authorization date:
  • 20-08-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995,asamended

MedicinalProducts(ControlofPlacingontheMarket)Regulations,2007,asamended

PA0237/063/001

CaseNo:2085488

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

TransferredfromPA0585/010/004.

TevaUKLimited

BramptonRoad,HampdenPark,Eastbourne,EastSussexBN229AG,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Ciprofloxacin2mg/mlSolutionforInfusion

theparticularsofwhicharesetoutintheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsasmaybespecifiedin

thesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom20/08/2010.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Ciprofloxacin2mg/mlSolutionforInfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

EachpresentationofCiprofloxacin2mg/mlSolutionforInfusioninglassvialscontainsthefollowing:

50mlpacksize:100mgCiprofloxacin(aslactate).

100mlpacksize:200mgCiprofloxacin(aslactate).

200mlpacksize:400mgCiprofloxacin(aslactate).

Excipients

Sodium(354mg/100mlequivalentto154mmolsodiumperlitre).

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

SolutionforInfusion.Clear,yellowishtoslightlyyellowsolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Adults:

Ciprofloxacinisindicatedforthetreatmentofthefollowinginfectionswhencausedbyciprofloxacin-susceptible

bacteria:

Respiratorytractinfections:e.g.lobarandbronchopneumonia,acuteandchronicbronchitis,acuteexacerbationof

cysticfibrosis,bronchiectasis,empyema.Ciprofloxacinisnotrecommendedasfirst-linetherapyforthetreatmentof

pneumococcalpneumonia.CiprofloxacinmaybeusedfortreatingGram-negativepneumonia.

Urinarytractinfections:e.g.uncomplicatedandcomplicatedurethritis,cystitis,pyelonephritis,prostatitis,epididymitis.

Gastro-intestinalinfections:e.g.entericfever,infectivediarrhoea.

Children:

ForthetreatmentofacutepulmonaryexacerbationofcysticfibrosisassociatedwithP.aeruginosainfectionin

paediatricpatientsaged5-17years.

InhalationAnthraxinAdultsandChildren:Toreducetheincidenceorprogressionofdiseasefollowingconfirmedor

suspectedexposuretoaerosolisedBacillusanthracis

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantibacterialagents.

4.2Posologyandmethodofadministration

Adults:

Thedosagerangeforadultsis100-400mgtwicedailyor400mgthreetimesdailyforseverelife-threateninginfections.

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Initialintravenousadministrationmaybefollowedbyoraltreatment.

Thefollowingdosagesforspecifictypesofinfectionarerecommended:

Table1:RecommendedAdultDosage(includingtheElderly)

*Asthepharmacokineticsofciprofloxacinremainunchangedinpatientswithcysticfibrosis,thelowbodyweightof

thesepatientsshouldbetakenintoconsiderationwhendeterminingdosage.

**Canbereducedto400mgb.d.ifcausativeorganismisfoundtobefullysensitive.

Initialintravenousadministrationmaybefollowedbyoraltreatmentatanequivalentdosage.Pharmacokineticstudies

haveshownanintravenousdosageof400mgtwicedailytobeequivalentto500mgtwicedailyorally,andan

intravenousdosageof400mgthreetimesdailyequivalentto750mgtwicedailyorally(intermsofAUC).

ImpairedRenalFunction

Inpatientswithimpairedrenalfunction,dosageadjustmentsarenotusuallyrequiredexceptinthosewithsevererenal

impairment,i.e.serumcreatinine>265 µ mol/1orcreatinineclearance<20ml/minute.Ifadjustmentisnecessary,this

maybeachievedbyreducingthetotaldailydosebyhalf,althoughmonitoringofdrugserumlevelsprovidesthemost

reliablebasisfordoseadjustment.Dialysisreducesserumlevelsofciprofloxacin.

Adolescentsandchildren>5yearsofage

Aswithotherdrugsinitsclass,ciprofloxacinhasbeenshowntocausearthropathyinweight-bearingjointsof

immatureanimals.Althoughanalysisofavailablesafetydatafromciprofloxacinuseinpatientslessthan18yearsof

age,themajorityofwhomhadcysticfibrosis,didnotdiscloseanyevidenceofdrug-relatedcartilageorarticular

Indication Dosage

(mgciprofloxacin)

Treatment

Upperandlowerurinarytractinfections 100mgb.d.

Upperandlowerrespiratorytractinfections

(dependingonseverityandsensitivityof

causativeorganism). 200-400mgb.d.

Forseverelife-threateningrespiratorytract

infectionsandthosewherethecausative

organismislesssensitive.

Pneumococcalpneumonia(second-linewhere

physicianconsidersitappropriate) 400mgt.d.s.

400mgt.d.s.

Cysticfibrosispatientswithpseudomonallower

RTI* 400mgt.d.s.

Gastro-intestinalinfections 200-400mgb.d.

Empirictreatmentofseverelife-threatening

infectionandwherethecausativeorganismis

lesssensitiveordifficult-to-treat,i.e.

Pseudomonasorstaphylococci. 400mgt.d.s.**

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Clinicalandpharmacokineticdatasupporttheuseofciprofloxacininpaediatriccysticfibrosispatients(aged5-17

years)withacutepulmonaryexacerbationassociatedwithP.aeruginosainfection,atadoseof10mg/kgivthree

timesdaily(maximumdailydose1200mg)foraperiodof10-14days.Theinfusionshouldbeadministeredover

60minutes.

Sequentialtherapycanalsobeused.Dosageasfollows:10mg/kgivthreetimesdaily(maximumdailydose

1200mg)followedby20mg/kgorallytwicedaily(maximumdailydose1500mg).

Fortheindicationofinhalationanthrax,therisk-benefitassessmentindicatesthatadministrationofciprofloxacin

topaediatricpatientsatadoseof10mg/kgi.v.twicedaily(maximumdailydoseof800mg)isappropriate.

Forindicationsotherthantreatmentofpulmonaryexacerbationsincysticfibrosisandinhalationanthrax,ciprofloxacin

maybeusedinchildrenandadolescentswherethebenefitisconsideredtooutweighthepotentialrisks.Inthesecasesa

dosageof4–8mg/kgivtwicedailyor5–15mg/kgorallytwicedailyshouldbeadministereddependinguponthe

severityoftheinfection.

Dosinginchildrenwithimpairedrenaland/orhepaticfunctionhasnotbeenstudied.

Durationoftreatment

Thedurationoftreatmentdependsupontheseverityofinfection,clinicalresponseandbacteriologicalfindings.

Foracuteinfections,theusualtreatmentperiodisfivetosevendays.Generally,treatmentshouldbecontinuedforat

least3daysafterthesignsandsymptomsoftheinfectionhavedisappeared.

ForacutepulmonaryexacerbationofcysticfibrosisassociatedwithP.aeruginosainfectioninpaediatricpatients

(aged5-17years),thedurationoftreatmentis10–14days.

Forinhalationanthrax,drugadministrationshouldbeginassoonaspossibleafterconfirmedorsuspected

exposureandthetotaldurationoftreatment(ivand/ororal)shouldbe60days.

4.3Contraindications

Ciprofloxaciniscontra-indicatedin:

patientswithaprevioushistoryofhypersensitivitytociprofloxacinortoother(fluoro)quinolonesortoanyofthe

otheringredients

patientswithahistoryoftendondisordersrelatedtofluoroquinoloneadministration

pregnancyandbreastfeeding

childrenandgrowingadolescentsexceptforthetreatmentofacutepulmonaryexacerbationofcysticfibrosisin

childrenaged5–17yearsandwiththeexceptionofcasesinwhichthebenefitisconsideredtooutweighthe

potentialrisks

childrenunder5years.

Concurrentadministrationofciprofloxacinandtizanidineiscontraindicatedsinceanundesirableincreasein

serumtizanidineconcentrationsassociatedwithclinicallyrelevanttizanidine-inducedside-effects(hypotension,

somnolence)canoccur.

4.4Specialwarningsandprecautionsforuse

Ciprofloxacincancauseserious,potentiallyfatalhypersensitivityreactions,occasionallyfollowingtheinitialdose(see

section4.8).Patientsshoulddiscontinuetreatmentimmediatelyandcontacttheirphysicianoranemergencyphysican,

whowillinitiateappropriateemergencymeasures(e.g.antihistamines,corticosteroids,sympathomimeticsandif

necessaryventilation).

Inpatientswithepilepsyorotherlesionsofthecentralnervoussystem(e.g.reducedconvulsionthreshold,ahistoryof

seizures,diminishedcerebralbloodflow,changesinbrainstructureorstroke)ciprofloxacinisonlytobeusedafter

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patientsatincreasedrisk.

Treatmentshouldbediscontinuediftheside-effects,depressionorpsychosesleadtoself-endangeringbehaviour(see

alsoSection4.8).

Crystalluriarelatedtotheuseofciprofloxacinhasbeenreported.Patientsreceivingciprofloxacinshouldbewell

hydratedandexcessivealkalinityoftheurineshouldbeavoided.

Pseudomembranouscolitisisaparticularformofenterocolitisthatcanoccurwithantibiotics(inmostcasesdueto

Clostridiumdifficile).Ifsevereandpersistentdiarrhoeaoccursduringoraftertreatment,thedoctorshouldbe

consulted.EvenifClostridiumdifficileisonlysuspected,administrationofciprofloxacinshouldbediscontinued

immediatelyandappropriatetreatmentgiven.

Patientswithafamilyhistoryoforactualdefectsinglucose-6-phosphatedehydrogenaseactivityareproneto

haemolyticreactionswithquinolones,andsociprofloxacinshouldbeusedwithcautioninthesepatients.

Patientswithpre-existentsignificantrenalorhepaticdisordersshouldbecarefullymonitoredtodetectany

deteriorationinfunction.Ciprofloxacinshouldbeadministeredwithgreatcautiontopersonswithrenalinsufficiencyor

severedehydration.

Casesofhepaticnecrosisuptolifethreateninghepaticfailurehavebeenreportedwithciprofloxacin(seesection4.8).

Patientsshouldbeadvisedtostoptreatmentandcontacttheirdoctorifsignsandsymptomsofhepaticdiseasedevelop

suchasanorexia,jaundice,darkurine,pruritusortenderabdomen.

Ciprofloxacinhasbeenrarelyassociatedwithphotosensitivity.However,patientsshouldberecommendedtoavoid

prolongedexposuretosunlightorUVradiationduringtreatmentwithciprofloxacin.

Tendonitisand/orruptureoftendons(whichmainlyaffectstheAchillestendon)areobservedduringtreatmentwith

quinoloneantibiotics.Thesereactionsareespeciallyobservedinelderlypatientsandpatientstreatedwith

corticosteroids.Atthefirstsignofpainorinflammation,ciprofloxacinshouldbediscontinuedandtheaffected

extremityshouldbemadenon-weight-bearing.

BecauseciprofloxacinhassomeactivityagainstMycobacteriumtuberculosis,false-negativeculturesmayoccurwhen

specimensareobtainedduringciprofloxacintreatment.

Ciprofloxacinshouldbeusedwithcautioninpatientswithmyastheniagravis.

Studiesinimmatureanimalsshowedciprofloxacinmaycausearthropathyinweight-bearingjoints.However,reviewof

safetydatainpatientsyoungerthan18years(mainlycysticfibrosispatients)revealednosignsofdrugrelateddamage

tocartilageorjoints.

Laboratorytestsmaygiveabnormalfindingsifperformedwhilstpatientsarereceivingciprofloxacin,e.g.increased

alkalinephosphatase;increasesinliverfunctiontests,e.g.transaminasesandcholestaticjaundice,especiallyinpatients

withpreviousliverdamage.

Inpatientsforwhomsodiumintakeisofmedicalconcern(e.g.patientswithcongestiveheartfailure,renalfailure,

nephroticsyndrome),thesodiumcontentofCiproxinInfusionshouldbetakenintoaccount.RefertoSection2,

QualitativeandQuantitativeCompositionforsodiumchloridecontent.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

CiprofloxacininhibitsCYP1A2andthusmaycauseincreasedserumconcentrationofconcomitantlyadministered

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

administrationoftizanidinewithciprofloxaciniscontraindicated(see4.3andbelow).Patientstakingothersubstances

metabolisedbyCYP1A2concomitantlywithciprofloxacinshouldbemonitoredcloselyforclinicalsignsofoverdose,

anddeterminationofserumconcentrations,especiallyoftheophylline,maybenecessary.

Inacrossoverstudy,10healthysubjectsweregivenciprofloxacin500mgorplacebotwicedailyforthreedays,atthe

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(Cmaxincrease:7-fold,range:4to21-fold;AUCincrease:10-fold,range:6to24-fold)whengivenconcomitantly

withciprofloxacincomparedtoplacebo.Associatedwiththeincreasedserumconcentrationswasapotentiated

hypotensiveandsedativeeffect.Tizanidinemustnotbeadministeredtogetherwithciprofloxacin(refertoSection4.3).

InclinicalstudiesitwasdemonstratedthatconcomitantuseofduloxetinewithstronginhibitorsoftheCYP4501A2

isozymesuchasfluvoxamine,mayresultinanincreaseofAUCandCmaxofduloxetine.Althoughnoclinicaldataare

availableonapossibleinteractionwithciprofloxacin,similareffectscanbeexpecteduponconcomitantadministration.

Xanthinederivatives

Concurrentadministrationofciprofloxacinandtheophyllinemaycauseincreasedplasmaconcentrationsof

theophylline(seeabove).Thismayleadtotheophylline-inducedundesirableeffects,whichinveryrarecasesarelife

threatening.Duringconcurrentadministrationoftheophylline,plasmaconcentrationsshouldbemonitored,andthe

theophyllinedoseshouldbeadjustedadequately.Onconcurrentadministrationofciprofloxacinandcaffeineor

pentoxifylline,raisedserumconcentrationsofthesexanthinederivativeswerereported.Wheremonitoringofplasma

levelsisnotpossible,theuseofciprofloxacinshouldbeavoidedinpatientsreceivingtheophylline.Particularcautionis

advisedinthosepatientswithconvulsivedisorders.

NSAIDs

Animaltrialshaveshownthatconcurrentadministrationofhighdosesofaquinoloneandcertainnon-steroidalanti-

inflammatorydrugs(NSAIDs)(butnotacetylsalicylicacid)mayprovokeconvulsions.

Ciclosporin

Atransientincreaseintheconcentrationofplasmacreatinineisseenwhenciprofloxacinandciclosporinare

administeredsimultaneously.Plasmacreatinineconcentrationsshouldbecheckedregularlyinthesepatients.

Anticoagulants

Simultaneousadministrationofciprofloxacinandcoumarinanticoagulants,suchaswarfarin,mayincreasetheeffectof

theanticoagulant.

Glibenclamide

Simultaneousadministrationofciprofloxacinandglibenclamidemayincreasetheeffectofglibenclamide.

Probenecid

Probenecidinhibitstherenalexcretionofciprofloxacinresultinginanincreaseintheplasmaconcentrationof

ciprofloxacin.

Methotrexate

Renaltubulartransportofmethotrexatemaybeinhibitedbyconcomitantadministrationofciprofloxacinpotentially

leadingtoincreasedplasmalevelsofmethotrexate.Thismayincreasetheriskofmethotrexateassociatedtoxic

reactions.Therefore,patientsreceivingmethotrexatetherapyshouldbecarefullymonitoredwhenconcomitant

ciprofloxacintherapyisindicated.

Mexiletine

Simultaneousadministrationofciprofloxacinandmexiletinecanleadtoincreasedplasmaconcentrationsofmexiletine.

Phenytoin

Simultaneousadministrationofciprofloxacinandphenytoinmayresultinincreasedorreducedserumlevelsof

phenytoinsuchthatmonitoringofdruglevelsisrecommended.

Premedicants

Itisrecommendedthatopiatepremedicants(e.g.papaveretum)oropiatepremedicantsusedwithanticholinergic

premedicants(e.g.atropineorhyoscine)arenotusedconcomitantlywithciprofloxacin,astheserumlevelsof

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Co-administrationofciprofloxacinandbenzodiazepinepremedicantshasbeenshownnottoaffectciprofloxacin

plasmalevels.However,sincedecreasedclearanceofdiazepamwithaprolongedhalf-lifehavebeenreportedduring

co-administrationofciprofloxacinanddiazepam,andinanisolatedcasewithmidazolam,carefulmonitoringof

benzodiazepinetherapyisrecommended.

Ropinirole

Apotentialforincreasedplasmalevelsofropinirolewithpossibleincreaseinadverseeffectsexists.Incaseof

combineduse,increasedclinicalmonitoringanddosageadjustmentofropinirolemayberequired.

4.6Pregnancyandlactation

Useduringpregnancyiscontraindicated.Aswithotherquinolones,ciprofloxacinhasbeenshowntocausearthropathy

inimmatureanimalsand,therefore,itsuseinpregnancyiscontraindicated.

Administrationtonursingmothersiscontraindicatedsincequinolonesadministeredattherapeuticdosesareexcretedin

breastmilkinquantitiesthatcanbeexpectedtoaffecttheinfant.

4.7Effectsonabilitytodriveandusemachines

Ciprofloxacincanalterthecapacityforreactionstoanextentthatimpairstheabilitytodriveavehicle,tooperate

machineryortoworksafely,particularlyiftakeninconjunctionwithalcohol.

4.8Undesirableeffects

Themostfrequentlyreportedadversereactionsare:nausea,diarrhoeaandrash.

Adversereactionsarelistedbyfrequency:common>1/100,<1/10);uncommon>1/1,000,<1/100);rare>1/10,000,<

1/1,000);veryrare(<1/10,000).Thefollowingadversereactionshavebeenobserved:

Infectionsandinfestations

Uncommon:moniliasis

Rare:moniliasis(oral),vaginalmoniliasis

Veryrare:moniliasis(gastrointestinal)

Bloodandthelymphaticsystemdisorders

Uncommon:eosinophilia,leukopenia

Rare:anaemia,leukopenia(granulocytopenia),leucocytosis,thrombocytopenia,thrombocythaemia(thrombocytosis)

Veryrare:hemolyticanaemia,agranulocytosis,pancytopenia(lifethreatening),bonemarrowdepression(life

threatening).

Immunesystemdisorders

Rare:allergicreaction,anaphylactoid(anaphylactic)reaction,dyspnoea,larynxoedema.

Veryrare:shock(anaphylactic/anaphylactoidreactionsprogressinginveryrarecasestolifethreateningshock),serum

sicknesslikereaction,angioedema,pruriticrash

Metabolismandnutritiondisorders

Uncommon:anorexia

Rare:hyperglycaemia

Psychiatricandnervoussystemdisorders

Uncommon:headache,dizziness,insomnia,agitation,confusion,tasteperversion(usuallyreversibleupon

discontinuationoftreatment)

Rare:hallucination,paresthesia(peripheralparalgesia),abnormaldreams(nightmares),depression,tremor,convulsion,

hypesthesia,somnolence,exacerbationofsymptomsofmyastheniagravis

Veryrare:grandmalconvulsion,abnormalgait,psychosis(whichmayprogresstoself-endangeringbehaviour),

intracranialhypertension,ataxia,hyperesthesia,hypertonia,parosmia(impairedsmell),anosmia(usuallyreversibleon

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Eyedisorders

Veryrare:abnormalvision(visualdisturbances),diplopia,chromatopsia

Earandlabyrinthdisorders

Veryrare:tinnitus,transitorydeafness(especiallyathighfrequencies)

Cardiacandvasculardisorders

Rare:tachycardia,syncope(fainting),vasodilation(hotflushes),hypotension

Veryrare:vasculitis(petechiae,haemorrhagicbullae,papules,crustformation)

Gastrointestinaldisorders

Common:nausea,diarrhoea

Uncommon:vomiting,dyspepsia,flatulence,abdominalpain

Rare:dysphagia,pseudomembranouscolitis(refertoSection4.4),pancreatitis

Veryrare:lifethreateningpseudomembranouscolitiswithpossiblefataloutcome(refertoSection4.4)

Hepato-biliarydisorders

Uncommon:bilirubinaemia,

Rare:jaundice,cholestaticjaundice,hepatitis

Veryrare:hepaticnecrosisuptolifethreateninghepaticfailure(seesection4.4).

Skinandsubcutaneoustissuedisorders

Common:rash

Uncommon:pruritus,maculopapularrash,urticaria

Rare:photosensitivityreaction,erythemamultiforme(minor),erythemanodosum

Veryrare:Stevens-Johnson-Syndrome,epidermalnecrolysis(Lyell-Syndrome),fixeddrugreaction,petechia

Musculoskeletal,connectivetissueandbonedisorders

Uncommon:arthralgia

Rare:myalgia,jointdisorder(jointswelling),paininextremeties,backpain,myasthenia

Veryrare:twitching,tendinitis(predominantlyachillotendinitisincludingtenosynovitis),partialorcompletetendon

rupture(predominantlyachillestendon)(refertoSection4.4)

Renalandurinarydisorders

Rare:acutekidneyfailure,abnormalkidneyfunction,haematuria,crystalluria,interstitialnephritis

Generaldisordersandadministrationsiteconditions

Uncommon:asthenia(generalfeelingofweakness,tiredness),injectionsitereaction(e.g.oedema/hypersensitivity/

inflammation/pain),(thrombo)-phlebitis(atinfusionsite)

Rare:pain,chestpain,sweating,drugfever,oedema(peripheral,vascular,face)

Investigations

Uncommon:SGOTincreased,SGPTincreased,abnormalliverfunctiontest,alkalinephosphataseincreased,increases

increatinine,increasesinBUN(urea)

Rare:alteredprothrombinvalues

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4.9Overdose

Basedonthelimitedinformationavailableintwocasesofingestionofover18gofciprofloxacin,reversiblerenal

toxicityhasoccurred.Therefore,apartfromroutineemergencymeasures,itisrecommendedtomonitorrenalfunction,

includingurinarypHandacidify,ifrequired,topreventcrystalluria.Patientsmustbekeptwellhydratedand,incase

ofrenaldamageresultinginprolongedoliguria,dialysisshouldbeinitiated.

Serumlevelsofciprofloxacinarereducedbydialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Therapeuticclassification:J01MA02

Mechanismofaction:

Ciprofloxacinisasynthetic4-quinolonederivativeanti-bacterialagentofthefluoroquinoloneclass.Asa

fluoroquinoloneantibacterialagent,ciprofloxacinactsontheDNA-DNA-gyrasecomplexandtopoisomeraseIV.

Resistance

In-vitroinvestigationshaveshownthatresistancetociprofloxaciniscommonlyduetomutationsinbacterial

topoisomerasesandusuallydevelopsslowlyandgradually(“multiple-step”type).

Cross-resistancebetweenfluoroquinolonesmayoccurwhenthemechanismofresistanceisduetomutationsin

bacterialgyrases.Singlemutationsmaynotresultinclinicalresistance,butmultiplemutationsgenerallydoresultin

clinicalresistancetoalldrugswithintheclass.Impermeabilityand/ordrugeffluxpumpmechanismsofresistancemay

haveavariableeffectonsusceptibilitytofluoroquinolones,whichdependsonthephysicochemicalpropertiesofthe

variousdrugswithintheclassandtheaffinityoftransportsystemsforeachdrug.

Breakpoints:

EUCAST: S ≤0.5mg/l;R>1mg/l

Exceptions:

Acinetobacterspp.,Staphylococcusspp.: S ≤1mg/l;R>1mg/l

Streptococcuspneumoniae: S ≤0.03mg/l;R>0.06mg/l

Haemophilusinfluenzae,Moraxellacatarrhalis:S ≤0.5mg/l;R>0.5mg/l

Susceptibility

Theprevalenceofacquiredresistancemayvarygeographicallyandwithtimeforselectedspeciesandlocal

informationonresistanceisdesirable,particularlywhentreatingsevereinfections.Asnecessary,expertadviceshould

besoughtwhenthelocalprevalenceofresistanceissuchthattheutilityoftheagentinatleastsometypesofinfections

isquestionable.

Commonlysusceptiblespecies

Gram-negativebacteria

Aeromonashydrophila

Citrobacterfreundii

Enterobacterspp.

Escherichiacoli

Haemophilusinfluenzae

Moraxellacatarrhalis

Morganellamorganii

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*MRSAareverylikelytoberesistanttociprofloxacinandciprofloxacinshouldnotbeusedtotreatpresumedor

knownMRSAinfectionsunlesstheorganismisknowntobesusceptible.

+mightberegardedasbeingofintermediatesusceptibilitytociprofloxacin.

Proteusmirabilis

Proteusvulgaris

Providenciaspp.

Shigellaspp.

Vibriospp.

Yersiniaenterocolitica

Anaerobes^

Peptococcusspp.

Peptostreptococcusspp.

Veillonellaparvula

Otherpathogens

Legionellapneumophila

Speciesforwhichacquiredresistancemaybeaproblem

Gram-positivebacteria

Staphylococcusaureus(methicillinsensitive)

Staphylococcusaureus(methicillinresistant)*

Streptococcusagalactiae

Streptococcuspneumoniae+

Streptococcuspyogenes+

Gram-negativebacteria

Acinetobacterspp.

Klebsiellaspp.

Pseudomonasaeruginosa

Serratiaspp.

Otherpathogens

Chlamydiaspp.+

Inherentlyresistantorganisms

Gram-positiveaerobes

Enterococcusspp

Gram-negativeaerobes

Stenotrophomonasmaltophila

Flavobacteriummeningosepticum

Nocardiaasteroides

Anaerobes

Bacteroidesfragilis

Bacteroidesthetaiotaomicron

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5.2Pharmacokineticproperties

TheAUCincreasesdoseproportionatelyafteradministrationofbothsingleandrepeatedoral(tablet)andintravenous

doses.Thepharmacokineticprofileofintravenousciprofloxacinwasshowntobelinearoverthedoserange(100mg–

400mg).Followingintravenousadministrationofciprofloxacin,themeanmaximumplasmaconcentrationswere

achievedattheendoftheinfusionperiod.Thatis,fora100mgor200mgdose,30minutes,andfora400mgdose,60

minutes.Reportedplasmalevelsatthistimepointwere1.8mg/l,3.4mg/land3.9mg/l,respectively.Ciprofloxacinis

widelydistributedandhasahighvolumeofdistributioninthetissues,althoughthisisslightlylessintheelderly.

Proteinbindingislow(between19–40%).

Only10–20%ofasingleoralorintravenousdoseiseliminatedasmetabolites(whichexhibitloweractivitythanthe

parentdrug).Fourdifferentantimicrobiallyactivemetaboliteshavebeenreported,desethyleneciprofloxacin(M1),

sulphociprofloxacin(M2),oxaciprofloxacin(M3)andformylciprofloxacin(M4).M2andM3accountforonethird

eachofmetabolisedsubstanceandM1isfoundinsmallamounts(1.3–2.6%ofthedose).

M4hasbeenfoundinverysmallquantities(<0.1%ofthedose).M1-M3haveantimicrobialactivitycomparableto

nalidixicacidandM4foundinthesmallestquantityhasantimicrobialactivitysimilartothatofnorfloxacin.

Eliminationofciprofloxacinanditsmetabolitesoccursrapidly,primarilybythekidney.Aftersingleoraland

intravenousdosesofciprofloxacin,55%and75%respectivelyareeliminatedbythekidneyand39%and14%inthe

faeceswithin5days.Renaleliminationtakesplacemainlyduringthefirst12hoursafterdosingandrenalclearance

levelssuggestthatactivesecretionbytherenaltubulesoccursinadditiontonormalglomerularfiltration.Renal

clearancebetween0.18–0.3l/h.kgandtotalbodyclearancebetween0.48–0.60l/h.kg.Approximately1%ofa

ciprofloxacindoseisexcretedviathebiliaryroute.Theeliminationkineticsarelinearandafterrepeateddosingat12

hourlyintervals,nofurtheraccumulationisdetectedafterthedistributionequilibriumisattained(at4–5halflives).

Theeliminationhalf-lifeofunchangedciprofloxacinoveraperiodof24–48hourspost-doseis3.1–5.1hours.A

totalbodyclearanceofapproximately35l/hwasobservedafterintravenousadministration.

Somestudiescarriedoutwithciprofloxacininpatientswithsevererenalinsufficiency(serumcreatinine>265

micromole/lorcreatinineclearance<20ml/minute)demonstratedeitheradoublingoftheeliminationhalf-life,or

fluctuationsinhalf-lifeincomparisonwithhealthyvolunteers.Itisrecommendedthatthetotaldailydoseshouldbe

reducedbyhalf,inpatientswithsevererenalinsufficiency,althoughmonitoringofdrugserumlevelsprovidesthemost

reliablebasisfordoseadjustmentasnecessary.

Resultsofpharmacokineticstudiesinpaediatriccysticfibrosispatientshaveshownthat20mg/kgorallytwicedailyor

10mg/kgivthreetimesdailyachieveplasmaconcentration/timeprofilescomparabletothoseachievedintheadult

populationatthecurrentlyrecommendeddosageregimen.

5.3Preclinicalsafetydata

Followingextensiveoralandintravenoustoxicologytestingwithciprofloxacin,onlytwofindingsthatmaybe

consideredrelevanttotheuseofciprofloxacininmanwereobserved.Crystalluriawasnotedinthosespeciesof

animalsthathadanormallyalkalineurine.Kidneydamagewithoutthepresenceofcrystalluriawasnotobserved.This

effectisconsideredasecondaryinflammatoryforeign-bodyreaction,duetotheprecipitationofacrystallinecomplex

ofciprofloxacin,magnesiumandproteininthedistaltubulesystemsofthekidneys.Thisisconsiderednottobea

probleminman,becausetheurineisnormallyacidic.However,toavoidtheoccurrenceofcrystalluria,patientsshould

bewellhydratedandexcessivealkalinityoftheurineavoided.

Aswithotherquinolones,damagetotheweight-bearingjointsofonlyjuvenileratsanddogstreatedwithciprofloxacin

wasnotedafterrepeatdosetoxicitytesting.Thiswasmorenoticeableinthedog.Althoughanalysisofavailablesafety

datafromciprofloxacinuseinpaediatricpatientsdidnotdiscloseanyevidenceofdrugrelatedcartilageorarticular

damage,theuseofciprofloxacininchildrenandgrowingadolescentsisgenerallynotrecommended,unlessthebenefits

areconsideredtooutweighthepotentialrisks(withtheexceptionoftreatmentofcysticfibrosis).Additionally,because

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

LacticAcid

SodiumChloride

HydrochloricAcidforpH-adjustment

WaterforInjections

6.2Incompatibilities

Ciprofloxacin2mg/mlSolutionforInfusionisincompatiblewithinjectionsolutions(e.g.penicillins,heparinsolutions)

whicharechemicallyorphysicallyunstableatitspHof3.9–4.5.Unlesscompatibilityisproven,theinfusionshould

alwaysbeadministeredseparately.Thismedicinalproductmustnotbemixedwithothermedicinalproductsexcept

thosementionedinsection6.6.

6.3ShelfLife

3years.

Followingdilution,asoutlinedinsection6.6,chemicalandphysicalin-usestabilityhasbeendemonstratedfor4hours

at25°C.

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestorage

timesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan24hoursat2

to8°C,unlessdilutionhastakenplaceincontrolledandvalidatedasepticconditions.

6.4Specialprecautionsforstorage

Donotrefrigerateorfreeze.

Keepcontainerintheoutercarton.

Forstorageconditionsofthedilutedmedicinalproduct,seesection6.3.

6.5Natureandcontentsofcontainer

Vials(glasstypeI)containing50ml,100mlor200mlofsolutionwitharubberstopperandaluminiumcap,witha

cardboardouter.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Ciprofloxacin2mg/mlSolutionforInfusionhasbeenshowntobecompatiblewithRinger’ssolution,0.9%sodium

chloridesolution,5%and10%glucosesolutions,glucose/salineandfructose10%solution.

Forsingleuseonly.Discardanyunusedportionoftheproductimmediatelyafteruse.

Iftheproductisinadvertentlyrefrigerated,crystalsmayform.Donotuseifcrystalsarepresent.Thesecrystalswill,

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7MARKETINGAUTHORISATIONHOLDER

TevaUKLimited

BramptonRoad

HampdenPark

Eastbourne

EastSussex

BN229AG

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA237/63/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:10 th

August2007

Dateoflastrenewal:28 th

July2008

10DATEOFREVISIONOFTHETEXT

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