CIFOX

Main information

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

Documents

Localization

  • Available in:
  • CIFOX Solution for Infusion 2 Mg/Ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0711/168/001
  • Authorization date:
  • 05-09-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995,asamended

MedicinalProducts(ControlofPlacingontheMarket)Regulations,2007,asamended

PA0711/168/001

CaseNo:2084057

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

RowexLtd

Bantry,Co.Cork,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Cifox2mg/mlSolutionforInfusion

theparticularsofwhicharesetoutintheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsasmaybespecifiedin

thesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom07/07/2010until03/07/2013.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 07/07/2010 CRN 2084057 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cifox2mg/mlSolutionforInfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

100mgCiprofloxacinina50mlsolution(2mg/ml)ashydrochloride

200mgCiprofloxacinina100mlsolution(2mg/ml)ashydrochloride

400mgCiprofloxacinina200mlsolution(2mg/ml)ashydrochloride

Excipient:Sodium15.4mmol(354mg)per100mlofsolution.

Forfulllistofexcipients,,seesection6.1.

3PHARMACEUTICALFORM

SolutionforInfusion.

Aclear,sterile,aqueoussolution.

pHofthesolution3.5-4.5

4CLINICALPARTICULARS

4.1TherapeuticIndications

Adults:

Ciprofloxacinisindicatedforthetreatmentofthefollowinginfectionscausedbysensitivebacteria:

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.

ChildrenandAdolescents:

Ciprofloxacinmaybeusedforthe2 nd

and3 rd

linetreatmentofcomplicatedurinarytractinfectionsandpyelonephritis

inchildrenandadolescents1-17yearsofageandforthetreatmentofacutepulmonaryexacerbationofcysticfibrosis

associatedwithP.aeruginosainchildrenandadolescents5-17yearsofage.TheuseofCifoxinpaediatricpatients

withcomplicatedurinarytractinfectionsandpyelonephritisshouldberestrictedtoinfectionscausedbyorganisms,for

whichCiprofloxacinisthedrugofchoice,basedontheresultsofantimicrobialsusceptibilitytesting.Treatmentshould

beinitiatedbyaphysician,whoisexperiencedinthetreatmentofsevereinfectionsinchildrenandadolescentsand

aftercarefulbenefit/riskevaluation,duetopossibleadverseeventsrelatedtojointsand/orsurroundingtissues(see4.4.

and5.1.).

InhalationAnthraxinAdultsandinChildren:Toreducetheincidenceorprogressionofdiseasefollowingconfirmed

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 07/07/2010 CRN 2084057 page number: 2

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantibacterialagents.

4.2Posologyandmethodofadministration

Generaldosagerecommendations:thedosageofintravenousciprofloxacinisdeterminedbytheseverityandtypeof

infection,thesensitivityofthecausativeorganism(s)andtheage,weightandrenalfunctionofthepatient.

Thedosagerangeforadultsis100-400mgtwicedailyor400mgthreetimesdailyforseverelife-threatening

infections.Theproductshouldbeinfuseddirectlyandadministeredbyshort-terminfusionoveraperiodof30-60

minutes.The400mgdoseshouldbeadministeredoveraperiodof60minutes.Initialintravenousadministrationmay

befollowedbyoraltreatment.

Thefollowingdosagesforspecifictypesofinfectionarerecommended:

Table1:RecommendedAdult(includingtheElderly)Dosage(refertoSection5.1)

*Asthepharmacokineticsofciprofloxacinremainunchangedinpatientswithcysticfibrosis,thelowbodyweightof

thesepatientsshouldbetakenintoconsiderationwhendeterminingdosage.

**Canbereducedto400mgb.d.ifcausativeorganismisfoundtobefullysensitive.

Initialintravenousadministrationmaybefollowedbyoraltreatmentatanequivalentdosage.Pharmacokineticstudies

haveshownanintravenousdosageof400mgtwicedailytobeequivalentto500mgtwicedailyorally,andan

intravenousdosageof400mgthreetimesdailyequivalentto750mgtwicedailyorally(intermsofAUC).

ImpairedRenalFunction

Wherecreatinineclearanceisbetween31and60ml/min/1.73m 2

orwheretheserumcreatinineconcentrationis

Indication Dosage(mgciprofloxacin)

Treatment

Upperandlowerurinarytract

infections 100mgb.d.

Upperandlowerrespiratorytract

infections(dependingonseverity

andsensitivityofcausative

organism). 200-400mgb.d.

Forseverelife-threatening

respiratorytractinfectionsand

thosewherethecausative

organismislesssensitive.

Pneumococcalpneumonia

(second-linewherephysician

considersitappropriate) 400mgt.d.s.

400mgt.d.s.

Cysticfibrosispatientswith

pseudomonallowerRTI* 400mgt.d.s.

Gastro-intestinalinfections 200-400mgb.d.

Empirictreatmentofseverelife-

threateninginfectionandwherethe

causativeorganismislesssensitive

ordifficult-to-treat,i.e.

Pseudomonasorstaphylococci. 400mgt.d.s.**

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 07/07/2010 CRN 2084057 page number: 3

Wherecreatinineclearanceisequalorlessthan30ml/min/1.73m 2

orwheretheserumcreatinineconcentrationisequal

orhigherthan2.0mg/100mlthemaximumdailydoseshouldbe400mgperdayforanintravenousregimen.

Forpatientswithimpairedrenalfunctionundergoinghaemodialysisthemaximumdailydoseshouldbe400mgperday

foranintravenousregimen.Ciprofloxacinshouldbeadministeredondialysisdaysafterdialysis.

Forpatientswithimpairedrenalfunctionandoncontinuousambulatoryperitonealdialysis(CAPD),ciprofloxacin

infusionsolutionshouldbeaddedtothedialysate(intraperitoneal):50mgciprofloxacin/litredialysateadministered4

timesadayevery6hours.

ImpairedHepaticFunction

Noadjustmentofdosageisnecessary.Incasesofimpairedrenalandliverfunctionfollowinstructionsasforimpaired

renalfunction

Elderly

Elderlypatientsshouldreceiveadoseaslowaspossibledependingontheseverityoftheirillnessandthecreatinine

clearance.

Childrenandadolescents

Cysticfibrosis

Clinicalandpharmacokineticdatasupporttheuseofciprofloxacininpaediatriccysticfibrosispatients(aged5-17

years)withacutepulmonaryexacerbationassociatedwithP.aeruginosainfection,atadoseof10mg/kgi.v.three

timesdaily(maximumdailydose1200mg)foraperiodof10-14days.Theinfusionshouldbeadministeredover60

minutes.

Sequentialtherapycanalsobeused.Dosageasfollows:10mg/kgi.v.threetimesdaily(maximumdailydose1200mg)

followedby20mg/kgorallytwicedaily(maximumdailydose1500mg).

Complicatedurinarytractinfectionsandpyelonephritis

Forcomplicatedurinarytractinfectionsorpyelonephritisthedoseis6to10mg/kgIVevery8hourswithamaximum

of400mgperdose.

Inhalationanthrax

Fortheindicationofinhalationanthrax,therisk-benefitassessmentindicatesthatadministrationofciprofloxacinto

paediatricpatientsatadoseof10mg/kgi.v.twicedaily(maximumdailydoseof800mg)isappropriate.

Dosinginchildrenwithimpairedrenaland/orhepaticfunctionhasnotbeenstudied.

DurationofTreatment

Thedurationoftreatmentdependsupontheseverityofinfection,clinicalresponseandbacteriologicalfindings.

Foracuteinfections,theusualtreatmentperiodisfivetosevendays.Generally,treatmentshouldbecontinuedforat

least3daysafterthesignsandsymptomsoftheinfectionhavedisappeared.

ForacutepulmonaryexacerbationofcysticfibrosisassociatedwithP.aeruginosainfectioninpaediatricpatients(aged

5–17years),thedurationoftreatmentis10–14days.

Forcomplicatedurinarytractinfectionsorpyelonephritisinpaediatricpatientsthedurationoftreatmentis10-21days.

Forinhalationanthrax,drugadministrationshouldbeginassoonaspossibleafterconfirmedorsuspectedexposureand

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 07/07/2010 CRN 2084057 page number: 4

Prolongedtreatmentoruseinchronicconditionsshouldonlybeinitiatedunder

Consultantdirectionwithregularsurveillance.

4.3Contraindications

Ciprofloxaciniscontra-indicatedinpatientswhohaveshownhypersensitivitytociprofloxacinoranyoftheexcipients,

orotherquinoloneanti-infectives,orwhohaveahistoryofquinolone-inducedtendondisorder.

Ciprofloxacinisalsocontra-indicatedinchildrenandgrowingadolescentsunlessepiphysealclosuresoflongbones

haveoccurredorexceptwherethebenefitsoftreatmentexceedtherisks.

Concurrentadministrationofciprofloxacinandtizanidineiscontraindicatedsinceanundesirableincreaseinserum

tizanidineconcentrationsassociatedwithclinicallyrelevanttizanidine-inducedside-effects(hypotension,somnolence)

canoccur.

4.4Specialwarningsandprecautionsforuse

Intheeventofhypersensitivity,whichinsomeinstancescanoccurafterthefirstadministration,therapyshouldbe

discontinued.

Ciprofloxacinshouldbeusedwithcautioninepilepticsandpatientswithexistingcentralnervoussystemdisordersora

historyofconvulsivedisordersandonlyifthebenefitsoftreatmentareconsideredtooutweightheriskofpossible

CNSside-effects.CNSside-effectshavebeenreportedafterfirstadministrationofciprofloxacininsomepatients.

Treatmentshouldbediscontinuediftheside-effects,depressionorpsychosesleadtoself-endangeringbehaviour(see

alsoSection4.8).

Crystalluriarelatedtotheuseofciprofloxacinhasbeenreported.Patientsreceivingciprofloxacinshouldbewell

hydratedandexcessivealkalinityoftheurineshouldbeavoided.

Patientswithafamilyhistoryoforactualdefectsinglucose-6-phosphatedehydrogenaseactivityareproneto

haemolyticreactionswithquinolones,andsociprofloxacinshouldbeusedwithcautioninthesepatients.

Tendoninflammationandrupturemayoccurwithquinoloneantibiotics.Suchreactionshavebeenobserved

particularlyinolderpatientsandinthosetreatedconcurrentlywithcorticosteroids.Atthefirstsignofpainor

inflammation,patientsshoulddiscontinueciprofloxacinandresttheaffectedlimbs.

Patientswithpre-existentsignificantrenalorhepaticdisordersshouldbecarefullymonitoredtodetectany

deteriorationinfunction.Itshouldonlybeadministeredwithgreatcautiontopersonswithrenalinsufficiency,or

severedehydration.

EradicationofinfectionduetoPseudomonasinpersonswithcysticfibrosisonlyoccursinaminorityofcases,

particularlyafterrepeatcoursesoftreatmentwithciprofloxacin.Cyclicaloralternatingantibacterialtherapiesmayhelp

reducethenumberofresistantstrains.

Thereisariskofpseudomembranouscolitiswithbroad-spectrumantibioticspossiblyleadingtoafataloutcome.Itis

importanttoconsiderthisinpatientssufferingfromsevere,persistentdiarrhoea.Withciprofloxacinthiseffecthasbeen

reportedrarely.Ifpseudomembranouscolitisissuspectedtreatmentwithciprofloxacinshouldbestoppedand

appropriatetreatmentgiven(e.g.oralvancomycin).Drugsthatinhibitperistalsismustnotbegiven.

Ciprofloxacinhasbeenshowntoproducephotosensitivityreactions.Patientstakingciprofloxacinshouldavoiddirect

exposuretoexcessivesunlightorUV-light.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 07/07/2010 CRN 2084057 page number: 5

Laboratorytestsmaygiveabnormalfindingsifperformedwhilstpatientsarereceivingciprofloxacine.g.increased

alkalinephosphatase;increasesinliverfunctiontestse.g.transaminasesandcholestaticjaundice,especiallyinpatients

withpreviousliverdamage.

Inpatientsforwhomsodiumintakeisofmedicalconcern(e.g.patientswithcongestiveheartfailure,renalfailure,

nephroticsyndrome),thesodiumcontentofCiprofloxacinSolutionforInfusion2mg/mlshouldbetakenintoaccount.

CiprofloxacinSolutionforInfusion2mg/mlcontains900mg/100mlsodiumchlorideequivalentto154mmolsodium

perlitre.Thesodiumchloridecontentofthe50mlcontaineris450mg(7.7mmolsodium).Thesodiumchloride

contentofthe100mlcontaineris900mg(15.4mmolsodium).Thesodiumchloridecontentofthe200mlcontaineris

1800mg(31mmolsodium).

Childrenandadolescents

Ciprofloxacinhasbeenshowntocausearthropathyinweight-bearingjointsofimmatureanimals.Safetydatafroma

randomiseddoubleblindstudyonciprofloxacinuseinchildren(ciprofloxacin:n=335,meanage=6.3years;

comparators:n=349,meanage=6.2years;agerange=1to17years)revealedanincidenceofsuspecteddrugrelated

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

incidenceofdrug-relatedarthropathyby1-yearfollow-upwas9.0%and5.7%.Theincreaseofsuspecteddrugrelated

arthropathyoverthetimewasnotstatisticallysignificantbetweengroups.Treatmentshouldonlybeinitiatedaftera

carefulbenefit/riskevaluation,duetopossibleadverseeventsrelatedtojointsand/orsurroundingtissue.

Theuseofciprofloxacinforindicationsotherthanthetreatmentofacutepulmonaryexacerbationofcysticfibrosis

causedbyP.aeruginosainfection(childrenaged5–17years),complicatedurinarytractinfectionsandpyelonephritis

(childrenaged1–17years)andfortheuseininhalationalanthrax(post-exposure)hasnotbeenevaluatedinclinical

trialsandtheclinicalexperienceislimited.Theuseofciprofloxacinshouldfollowtheofficialguidance.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Probenecidinterfereswithrenalsecretionofciprofloxacin.Co-administrationofprobenecidandciprofloxacin

increasestheciprofloxacinserumconcentrations.

ConcomitantadministrationofciprofloxacinandomeprazoleresultsinslightreductionofC

andAUCof

ciprofloxacin.

Inacrossoverstudy,10healthysubjectsweregivenciprofloxacin500mgorplacebotwicedailyforthreedays,atthe

endofwhichasingledoseoftizanidine4mgwasgiven.Therewasanincreaseintizanidineserumconcentrations

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

withciprofloxacincomparedtoplacebo.Associatedwiththeincreasedserumconcentrationswasapotentiated

hypotensiveandsedativeeffect.Tizanidinemustnotbeadministeredtogetherwithciprofloxacin(refertoSection4.3).

Increasedplasmalevelsoftheophyllinehavebeenobservedfollowingconcurrentadministrationwithciprofloxacin.It

isrecommendedthatthedoseoftheophyllineshouldbereducedandplasmalevelsoftheophyllinemonitored.The

reactionbetweentheophyllineandciprofloxacinispotentiallylifethreatening.Therefore,wheremonitoringofplasma

levelsisnotpossible,theuseofciprofloxacinshouldbeavoidedinpatientsreceivingtheophylline.Particularcautionis

advisedinthosepatientswithconvulsivedisorders.

Renaltubulartransportofmethotrexatemaybeinhibitedbyconcomitantadministrationofciprofloxacinpotentially

leadingtoincreasedplasmalevelsofmethotrexate.Thismayincreasetheriskofmethotrexateassociatedtoxic

reactions.Therefore,patientsreceivingmethotrexatetherapyshouldbecarefullymonitoredwhenconcomitant

ciprofloxacintherapyisindicated.

Animaldatahaveshownthathighdosesofquinolonesincombinationwithsomenon-steroidalanti-inflammatory

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 07/07/2010 CRN 2084057 page number: 6

Transientincreasesinserumcreatininehavebeenseenfollowingconcomitantadministrationofciprofloxacinand

cyclosporin.Therefore,monitoringofserumcreatininelevelsisadvisable(twiceaweek).

Prolongationofbleedingtimehasbeenreportedduringconcomitantadministrationofciprofloxacinandoralanti-

coagulants.

Thesimultaneousadministrationofquinolonesandglibenclamidecanonoccasionpotentiatetheeffectof

glibenclamideresultinginhypoglycaemia.

InclinicalstudiesitwasdemonstratedthatconcomitantuseofduloxetinewithstronginhibitorsoftheCYP4501A2

isozymesuchasfluvoxamine,mayresultinanincreaseofAUCandCmaxofduloxetine.Althoughnoclinicaldataare

availableonapossibleinteractionwithciprofloxacin,similareffectscanbeexpecteduponconcomitantadministration.

CiprofloxacininhibitsCYP1A2andthusmaycauseincreasedserumconcentrationofconcomitantlyadministered

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

Therefore,patientstakingthesesubstancesconcomitantlywithciprofloxacinshouldbemonitoredcloselyforclinical

signsofoverdose,anddeterminationofserumconcentrations,especiallyoftheophylline,maybenecessary.

PhenytoinlevelsmaybealteredwhenCiprofloxacinisusedconcomitantly.

Ciprofloxacinmayinterferewithestimationsofurinary17-ketosteroids,orvanillylmandelicacid.

Concomitantusewithphenylpropionicacid-derivednon-steroidalanti-inflammatorydrugsmayleadtotoxicity,

possiblybecauseofrenaleffects.

4.6Pregnancyandlactation

Ciprofloxacinshouldnotbeusedduringpregnancyorinwomenatriskofpregnancy,norduringlactation.

Reproductionstudiesperformedinmice,ratsandrabbitsusingparenteralandoraladministrationdidnotrevealany

evidenceofteratogenicity,impairmentoffertilityorimpairmentofperi-/post-nataldevelopment.However,aswith

otherquinolones,ciprofloxacinhasbeenshowntocausearthropathyinimmatureanimals,andthereforeitsuseduring

pregnancyorinwomencapableofchild-bearingisnotrecommended.Studieshaveindicatedthatciprofloxacinis

secretedinbreastmilk.Administrationtonursingmothersisthusnotrecommended.

4.7Effectsonabilitytodriveandusemachines

Ciprofloxacincouldresultinimpairmentofthepatient'sabilitytodriveoroperatemachinery,particularlyin

conjunctionwithalcohol.

4.8Undesirableeffects

Themostfrequentlyreportedadversereactionsarenausea,diarrhoeaandrash.

Thefollowingadversereactionshavebeenobserved:

Effectsonthegastrointestinalsystem

Common(>1/100,<1/10):nausea,diarrhoea

Uncommon(>1/1,000,<1/100):SGOTincreased,SGPTincreased,vomiting,dyspepsia,abnormalliverfunctiontest,

alkalinephosphataseincreased,anorexia,flatulence,bilirubinaemia.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 07/07/2010 CRN 2084057 page number: 7

Veryrare(<1/10,000):moniliasis(gastrointestinal),hepatitis,livernecrosis(veryrarelyprogressingtolife-

threateninghepaticfailure),life-threateningpseudomembranouscolitiswithpossiblefataloutcome,pancreatitis

Effectsonthebodyasawhole

Uncommon(>1/1,000,<1/100):abdominalpain,moniliasis,asthenia(generalfeelingofweakness,tiredness),

injectionsitereaction(e.g.oedema/hypersensitivity/inflammation/pain)

Rare(>1/10,000,<1/1,000):pain,paininextremeties,backpain,chestpain

Effectsonthecardiovascularsystem

Uncommon(>1/1,000,<1/100):(thrombo)-phlebitis(atinfusionsite)

Rare(>1/10,000,<1/1,000):tachycardia,migraine,syncope(fainting),vasodilation(hotflushes),hypotension

Veryrare(<1/10,000):vaculitis(petechiae,haemorrhagicbullae,papules,crustformation)

Effectsonthehemicandlymphaticsystem

Uncommon(>1/1,000,<1/100):eosinophilia,leukopenia

Rare(>1/10,000,<1/1,000):anaemia,leukopenia(granulocytopenia),leucocytosis,alteredprothrombinvalues,

thrombocytopenia,thrombocythaemia(thrombocytosis)

Veryrare(<1/10,000):hemolyticanaemia,petechia(punctateskinhaemorrhages),agranulocytosis,pancytopenia

(life-threatening),bonemarrowdepression(life-threatening)

Metabolicandnutritionaldisorders

Uncommon(>1/1,000,<1/100):increasesincreatinine,increasesinBUN(urea)

Rare(>1/10,000,<1/1,000):oedema(peripheral,vascular,face),hyperglycaemia

Veryrare(<1/10,000):amylaseincreased,lipaseincreased

Effectsonthemusculoskeletalsystem

Uncommon(>1/1,000,<1/100):arthralgia(jointpain)

Rare(>1/10,000,<1/1,000):myalgia(muscularpain),jointdisorder(jointswelling)

Veryrare(<1/10,000):myasthenia,tendinitis(predominantlyachillotendinitisincludingtenosynovitis),partialor

completetendonrupture(predominantlyachillestendon),exacerbationofsymptomsofmyastheniagravis.Treatment

shouldbediscontinuedimmediatelyiftendinitisorcompletetendonruptureoccur.

Effectsonthenervoussystem

Uncommon(>1/1,000,<1/100):headache,dizziness,insomnia,agitation,confusion

Rare(>1/10,000,<1/1,000):hallucination,sweating,paresthesia(peripheralparalgesia),anxiety,abnormaldreams

(nightmares),depression,tremor(trembling),convulsion,hypesthesia,somnolence

Veryrare(<1/10,000):grandmalconvulsion,abnormal(unsteady)gait,psychosis(whichmayprogresstoself-

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 07/07/2010 CRN 2084057 page number: 8

Effectsontherespiratorysystem

Rare(>1/10,000,<1/1,000):dyspnoea,larynxoedema

Effectsontheskinandappendages

Common(>1/100,<1/10):rash

Uncommon(>1/1,000,<1/100):pruritis,maculopapularrash,urticaria

Rare(>1/10,000,<1/1,000):photosensitivityreaction

Veryrare(<1/10,000):petechia,erythemamutliforme(minor),erythemanodosum,Stevens-Johnson-Syndrome,

epidermalnecrolysis(Lyell-Syndrome),fixeddrugreaction

Effectsonspecialsenses

Uncommon(>1/1,000,<1/100):tasteperversion(usuallyreversibleupondiscontinuationoftreatment).

Rare(>1/10,000,<1/1,000):tinnitus,transitorydeafness(especiallyathighfrequencies),abnormalvision(visual

disturbances),diplopia,chromatopsia,tasteloss(impairedtaste)

Veryrare(<1/10,000):parosmia(impairedsmell),anosmia(usuallyreversibleondiscontinuation)

Hypersensitivityreactions

Rare(>1/10,000,<1/1,000):allergicreaction,drugfever,anaphylactoid(anaphylactic)reaction.

Veryrare(<1/10,000):shock(anaphylactic/anaphylactoidreactionsprogressinginveryrarecasestolife-threatening

shock),pruriticrash,serumsicknesslikereaction,angioedema

Effectsontheurogenitalsystem

Rare(>1/10,000,<1/1,000):acutekidneyfailure,abnormalkidneyfunction,vaginalmoniliasis,haematuria,

crystalluria,interstitialnephritis

4.9Overdose

Basedonthelimitedinformationavailableintwocasesofingestionofover18gofciprofloxacin,reversiblerenal

toxicityhasoccurred.Therefore,apartfromroutineemergencymeasures,itisrecommendedtomonitorrenalfunction,

includingurinarypHandacidity,ifrequired,topreventcrystalluria.Patientsmustbekeptwellhydrated,andinthe

caseofrenaldamageresultinginprolongedoliguria,dialysisshouldbeinitiated.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 07/07/2010 CRN 2084057 page number: 9

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Fluoroquinoloneantibacterials,ATCcode:J01MA02.

Mechanismofaction

Asafluoroquinoloneantibacterialagent,ciprofloxacinactsonthebacterialenzymesDNA-gyraseandtopoisomerase

IV,whicharerequiredforbacterialDNAreplication,transcription,repairandrecombination.

Mechanismofresistance

Invitroinvestigationshaveshownthatresistancetociprofloxaciniscommonlyduetomutationsinbacterial

topoisomerasesandusuallydevelopsslowlyandgradually('multiple-step'type).Cross-resistancebetween

fluoroquinolonesmayoccurwhenthemechanismofresistanceisduetomutationsinbacterialgyrases.However,

singlemutationsmaynotresultinclinicalresistance,butmultiplemutationsgenerallydoresultinclinicalresistanceto

allactivesubstanceswithintheclass.Impermeabilityand/oractivesubstanceeffluxpumpmechanismsofresistance

mayhaveavariableeffectonsusceptibilitytofluoroquinolones,whichdependsonthephysiochemicalpropertiesof

thevariousactivesubstanceswithintheclassandtheaffinityoftransportsystemsforeachactivesubstance.Plasmid

mediatedresistanceencodedbyqnr-geneshavebeenreported.Resistancemechanismsthatinactivatepenicillins,

cephalosporins,aminoglycosides,macrolides,andtetracyclinesdonotinterferewiththeantibacterialactivityof

ciprofloxacin.

InvitroSusceptibilityData

InaccordancetotheguidancedocumentCPMP/EWP/558/95rev1EUCASTclinicalMICbreakpointsfor

moxifloxacinarelistedtogetherwithClinicalandLaboratoryStandardsInstitute(CLSI,formerlyNCCLS)

interpretativecriteriaforthesusceptibilitytestingofciprofloxacinwherebreakpointsdiffer.CLSIdiscbreakpointsare

alsoincludedsincethemajorityofsusceptibilitytestinginEuropeisperformedbythismethod.

Table2:EUCASTclinicalMICbreakpointsforciprofloxacin(excerptfrom2006-01-31v2.2,

www.escmid.org/sites/index_f.aspx?par=2.4)

Organism

Susceptible

(mg/L) Resistant

(mg/L)

Enterobacteriaceae ≤0.5 >1

Pseudomonas ≤0.5 >1

Staphylococcus 1 ≤1 >1

Streptococcuspneumoniae 2 ≤0.125

>2

HaemophilusinfluenzaeandMoraxella

catarrhalis 3 ≤0.5

>0.5

Neisseriagonorrhoeae ≤0.03 >0.06

Non-speciesrelatedbreakpoints 4 ≤0.5 >1

1.Staphylococcusspp.-breakpointsforciprofloxacinandofloxacinrelateto

highdosetherapy.

2.Streptococcuspneumoniae-wild-typeS.pneumoniaearenotconsidered

susceptibletociprofloxacinorofloxacinandarethereforecategorizedas

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 07/07/2010 CRN 2084057 page number: 10

ClinicalandLaboratoryStandardsInstitute™(CLSI),formerlyNCCLSbreakpointsarepresentedinthetablebelow

forMICtesting(mg/L)ordiscdiffusiontesting(zonediameter[mm])usinga5-µgciprofloxacindisc.

Table3:ClinicalandLaboratoryStandardsInstitute™(CLSI)MIC(mg/L)anddiscdiffusion

3.StrainswithMICvaluesabovetheS/Ibreakpointareveryrareornotyet

reported.Theidentificationandantimicrobialsusceptibilitytestsonanysuch

isolatemustberepeatedandiftheresultisconfirmedtheisolatesenttoa

referencelaboratory.Untilthereisevidenceregardingclinicalresponsefor

confirmedisolateswithMICabovethecurrentresistantbreakpoint(initalics)

theyshouldbereportedresistant.Haemophilus/Moraxella-fluoroquinolone

low-levelresistance(ciprofloxacinMIC:sof0.125-0.5mg/L)mayoccurin

H.influenzae.Thereisnoevidencethatlow-levelresistanceisofclinical

importanceinrespiratorytractinfectionswithH.influenzae.

4.Non-speciesrelatedbreakpointshavebeendeterminedmainlyonthebasisof

PK/PDdataandareindependentofMICdistributionsofspecificspecies.They

areforuseonlyforspeciesthathavenotbeengivenaspecies-specific

breakpointandnotforthosespecieswheresusceptibilitytestingisnot

recommended(markedwith--orIEinthetable).

Organism Susceptible Intermediate Resistant

Enterobacteriaceae ≤1 a

≥21 b 2 a

16-20 b ≥4 a

≤15 b

Pseudomonasaeruginosaand

othernon-Enterobacteriaceae ≤1 a

≥21 b 2 a

16-20 b ≥4 a

≤15 b

Staphylococcusspp. ≤1 a

≥21 b 2 a

16-20 b ≥4 a

≤15b

Enterococcusspp. ≤1 a

≥21 b 2 a

16-20 b ≥4 a

≤15 b

Haemophilusspp. ≤1 c

≥21 d -

Neisseriagonorrhoeae ≤0.06 e

≥41 e 0.12-0.5 e

28-40 e ≥1 e

≤27 e

Thisinterpretivestandardisapplicableonlytobrothdilutiontestsusing

CAMHBincubatedinambientairat33to35°C(donotexceed35°C)for16-20

hours

Thisinterpretivestandardisapplicableonlytodiscdiffusiontestsusing

Mueller-Hintonagarincubatedinambientairat33to35°C(donotexceed35°

C)for16-18hours

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 07/07/2010 CRN 2084057 page number: 11

Theprevalenceofacquiredresistancemayvarygeographicallyandwithtimeforselectedspeciesandlocalinformation

ofresistanceisdesirable,particularlywhentreatingsevereinfections.Asnecessary,expertadviceshouldbesought

wherethelocalprevalenceofresistanceissuchthatutilityoftheagentinatleastsometypesofinfectionsis

questionable.

testswithHaemophilusinfluenzaeandHaemophilusparainfluenzaeusing

Haemophilustestmedium(HTM)brothincubatedinambientairat35°C±2°C

for20–24hours

ThisinterpretivestandardisapplicableonlytodiscdiffusiontestswithH.

influenzaeandH.parainfluenzaeusingHTMincubatedin5%CO

at35°C±2

°Cfor16-18hours

Thisinterpretivestandardisapplicableonlytoagarbasedsusceptibilitytests

usingGCagarand1%definedgrowthsupplementat36±1°C(nottoexceed37°

C)in5%CO

for20-24hours.

Commonlysusceptiblespecies

AerobicGram-positivemicro-organisms

Bacillusanthracis

AerobicGram-negativemicro-organisms

Citrobacterfreundii*

Haemophiliusinfluenzae*

Moraxellacatarrhalis*

Shigellaspp.

Speciesforwhichacquiredresistancemaybeaproblem

AerobicGram-positivemicro-organisms

Staphylococcusaureus(methicillin-susceptible)*

Streptococcuspneumoniae*

AerobicGram-negativemicro-organisms

Burkholderiacepacia +

Campylobacterspp. +

*

Enterobacteraerogenes

Enterobactercloacae*

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 07/07/2010 CRN 2084057 page number: 12

5.2Pharmacokineticproperties

Absorptionoforaldosesofciprofloxacin250mg,500mgand750mgtabletformulationoccursrapidly,mainlyfrom

thesmallintestine,thehalf-lifeofabsorptionbeing2-15minutes.Plasmalevelsaredose-relatedandpeak0.5-2.0hours

afteroraldosing.TheAUCalsoincreasesdoseproportionatelyafteradministrationofbothsingleandrepeatedoral

(tablet)andintravenousdoses.Thepharmacokineticprofileofintravenousciprofloxacinwasshowntobelinearover

thedoserange(100mg-400mg).Followingintravenousadministrationofciprofloxacin,themeanmaximumplasma

concentrationswereachievedattheendoftheinfusionperiod.Thatis,fora100mgor200mgdose,30minutes,and

fora400mgdose,60minutes.

Reportedplasmalevelsatthistimepointwere1.8mg/l,3.4mg/land3.9mg/l,respectively.Theabsolute

bioavailabilityisreportedtobe52-83%andciprofloxacinissubjecttoonlyslightfirst-passmetabolism.

Distributionofciprofloxacinwithintissuesiswideandthevolumeofdistributionhigh,thoughslightlylowerinthe

Klebsiellaoxytoca

Klebsiellapneumoniae*

Morganellamorganii +

*

Neisseriagonorrhoeae*

Proteusmirabilis +

*

Proteusvulgaris*

Providenciaspp.

Pseudomonasaeruginosa +

*

Pseudomonasfluorescens +

Salmonellaspp.*

Serratiamarcescens +

*

InherentlyResistantOrganisms

AerobicGram-positivemicro-organisms

Staphylococcusaureus(methicillin-resistant)

AerobicGram-negativemicro-organisms

Stenotrophomonasmaltophilia

*Clinicalefficacyhasbeendemonstratedforsusceptibleisolatesinapproved

clinicalindications

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 07/07/2010 CRN 2084057 page number: 13

Only10-20%ofasingleoralorintravenousdoseiseliminatedasmetabolites(whichexhibitloweractivitythanthe

parentdrug).Fourdifferentantimicrobiallyactivemetaboliteshavebeenreported,desethyleneciprofloxacin(M1),

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

eachofmetabolisedsubstanceandM1isfoundinsmallamounts(1.3-2.6%ofthedose).M4hasbeenfoundinvery

smallquantities(<0.1%ofthedose).M1-M3haveantimicrobialactivitycomparabletonalidixicacidandM4foundin

thesmallestquantityhasantimicrobialactivitysimilartothatofnorfloxacin.

Eliminationofciprofloxacinanditsmetabolitesoccursrapidly,primarilybythekidney.Aftersingleoraland

intravenousdosesofciprofloxacin,55%and75%respectivelyareeliminatedbythekidneyand39%and14%inthe

faeceswithin5days.Renaleliminationtakesplacemainlyduringthefirst12hoursafterdosingandrenalclearance

levelssuggestthatactivesecretionbytherenaltubulesoccursinadditiontonormalglomerularfiltration.Renal

clearanceisbetween0.18-0.3l/h.kgandtotalbodyclearancebetween0.48-0.60l/h.kg.Approximately1%ofa

ciprofloxacindoseisexcretedviathebiliaryroute.

Theeliminationkineticsarelinearandafterrepeateddosingat12hourlyintervals,nofurtheraccumulationisdetected

afterthedistributionequilibriumisattained(at4-5half-lives).Theeliminationhalf-lifeofunchangedciprofloxacin

overaperiodof24-48hourspost-doseis3.1-5.1hours.Atotalbodyclearanceofapproximately35l/hwasobserved

afterintravenousadministration.

Somestudiescarriedoutwithciprofloxacininseverelyrenallyimpairedpatients(serumcreatinine>265micromole/l

orcreatinineclearance<20ml/minute)demonstratedeitheradoublingoftheeliminationhalf-life,orfluctuationsin

half-lifeincomparisonwithhealthyvolunteers,whereasotherstudiesshowednosignificantcorrelationbetween

eliminationhalf-lifeandcreatinineclearance.However,itisrecommendedthatinseverelyrenallyimpairedpatients,

thetotaldailydoseshouldbereducedbyhalf,althoughmonitoringofdrugserumlevelsprovidesthemostreliable

basisfordoseadjustmentasnecessary.

Childrenandadolescents

Thedataavailabletosubstantiatethepharmacokineticdatainchildrenarelimited.InastudyinchildrenCmaxand

AUCwerenotage-dependent(aboveoneyearofage).NonotableincreaseinCmaxandAUCuponmultipledosing

(10mg/kgthreetimesdaily)wasobserved.In10childrenwithseveresepsis,lessthan1yearofageCmaxwas6.1

mg/L(range4.6–8.3mg/L)aftera1-hourintravenousinfusionatadoselevelof10mg/kg;and7.2mg/L(range4.7–

11.8mg/L)forchildrenbetween1and5yearsofage.TheAUCvalueswere17.4mg*h/L(range11.8–32.0mg*h/L)

and16.5mg*h/L(range11.0–23.8mg*h/L)intherespectiveagegroups.Thesevaluesarewithintherangereported

foradultsattherapeuticdoses.Basedonpopulationpharmacokineticanalysisofpaediatricpatientswithvarious

infections,thepredictedmeanhalf-lifeinchildrenisapprox.4–5hoursandthebioavailabilityoftheoralsuspension

rangesfrom50to80%.

Inhalationanthrax:Ciprofloxacinserumconcentrationsachievedinhumansserveasasurrogateendpointreasonably

likelytopredictclinicalbenefitandprovidethebasisfortherecommendeddoses.

5.3Preclinicalsafetydata

Followingextensiveoralandintravenoustoxicologytestingwithciprofloxacin,onlytwofindingswhichmaybe

consideredrelevanttotheuseofciprofloxacininmanwereobserved.Crystalluriawasnotedinthosespeciesof

animalswhichhadanormallyalkalineurine.Kidneydamagewithoutthepresenceofcrystalluriawasnotobserved.

Thiseffectisconsideredasecondaryinflammatoryforeign-bodyreaction,duetotheprecipitationofacrystalline

complexofciprofloxacin,magnesiumandproteininthedistaltubulesystemofthekidneys.Thisisconsiderednotto

beaprobleminman,becausetheurineisnormallyacidic.However,toavoidtheoccurrenceofcrystalluria,patients

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 07/07/2010 CRN 2084057 page number: 14

Articulartolerabilitystudies

Asreportedforothergyraseinhibitors,ciprofloxacincausesdamagetothelargeweight-bearingjointsinimmature

animals.Theextentofthecartilagedamagevariesaccordingtoage,speciesanddose;thedamagecanbereducedby

takingtheweightoffthejoints.Studieswithmatureanimals(rat,dog)revealednoevidenceofcartilagelesions.Ina

studyinyoungbeagledogsciprofloxacincausedseverearticularchangesattherapeuticdosesaftertwoweeksof

treatment,whichwerestillobservedafter5months.Additionally,becauseofthepotentialofarthropathy,theuseof

ciprofloxacinduringpregnancy,inwomencapableofchildbearingandinnursingmothersisnotrecommended.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

LacticAcid

SodiumChloride

SodiumHydroxide(pHadjuster)

HydrochloricAcid(pHadjuster)

WaterforInjections

6.2Incompatibilities

Ciprofloxacin2mg/mlSolutionforInfusionisnotcompatiblewithinjectionsolutions(e.g.penicillins,heparin

solutions)whicharechemicallyorphysicallyunstableatitspHof3.5-4.5.Unlesscompatibilityisproven,theinfusion

shouldalwaysbeadministeredseparately.Forcompatibleco-infusionsolutionsseeSection6.6.

6.3ShelfLife

Fouryears.

6.4Specialprecautionsforstorage

Keepthebottleintheoutercartoninordertoprotectfromlight.Nospecialprecautionsarerequiredduringthenormal

30-60minuteinfusionperiod.Iftheproductisinadvertentlyremovedfromtheoutercarton,thestabilityoftheproduct

ismaintainedforaperiodofuptofivedaysindaylight.

DonotrefrigerateorfreezeCiprofloxacin2mg/mlSolutionforInfusion.Iftheproductisinadvertentlyrefrigerated,

crystalsmayform.However,thesewillredissolveatroomtemperatureanddonotaffecttheproduct'scharacteristics.

6.5Natureandcontentsofcontainer

ClearGlassTypeIIvialswithOmniflexcoatedbromobutylrubberstopperscontaining50ml,100mlor200mlof

Ciprofloxacin2mg/mlSolutionforInfusionwithaluminiumcrimpingcapwithplasticflip-offtopandwitha

cardboardouter.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Forsingleuseonly.Discardanyunusedcontents.Thesolutionshouldbevisuallyinspectedpriortouseandonlyclear

solutionswithoutparticlesshouldbeused.

Ciprofloxacin2mg/mlSolutionforInfusionshouldbeinfuseddirectlyandbeadministeredbyshort-termintravenous

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 07/07/2010 CRN 2084057 page number: 15

TheproductshouldnotbemixedwithotherdrugproductswhicharechemicallyorphysicallyunstableatitspHof3.5-

4.5(seeSection6.2).However,Ciprofloxacin2mg/mlSolutionforInfusionhasbeenshowntobecompatiblewith

0.9%sodiumchloridesolution,Ringer'ssolution,Ringerlactatesolution,5%and10%glucosesolutions.Unless

compatibilityisproven,theinfusionsolutionshouldalwaysbeadministeredseparately.

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

RowexLtd

Newtown

Bantry

Co.Cork

8MARKETINGAUTHORISATIONNUMBER

PA711/168/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:July4th2008

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 07/07/2010 CRN 2084057 page number: 16