CIPROFLOXACIN NICHE

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1063/037/001
  • Authorization date:
  • 09-01-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

CiprofloxacinNiche2mg/mlSolutionforInfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

1mlofsolutionforinfusioncontainsciprofloxacin(aslactate)equivalentto2mgciprofloxacin.

Eachglassbottlewith 50mlsolutionforinfusioncontains100mgciprofloxacin(aslactate). Thesodiumcontentis177mg

(7.7mmol).

Eachglassbottlewith 100mlsolutionforinfusioncontains200mgciprofloxacin(aslactate). Thesodiumcontentis354mg

(15.4mmol).

Eachglassbottlewith 200mlsolutionforinfusioncontains400mgciprofloxacin(aslactate). Thesodiumcontentis708mg

(30.8mmol).

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Solutionforinfusion.

Clearyellowishtoslightlyyellow,odourlesssolutionfreefromforeignbodies.

ThepH-valueofthesolutionforinfusionrangesfrom3.9to4.5

4CLINICALPARTICULARS

4.1TherapeuticIndications

Ciprofloxacinsolutionforinfusionisindicatedforthetreatmentofthefollowinginfections(seesections4.4and5.1)Special

attentionshouldbepaidtoavailableinformationonresistancetociprofloxacinbeforecommencingtherapy.

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantibacterialagents.

Adults:

LowerrespiratorytractinfectionsduetoGram-negativebacteria

exacerbationsofchronicobstructivepulmonarydisease

broncho-pulmonaryinfectionsincysticfibrosiorinbronchiectasis

pneumonia

Chronicsuppurativeotitismedia

AcuteexacerbationofchronicsinusitisespeciallyifthesearecausedbyGram-negativebacteria

Urinarytractinfections

Epididymo-orchitisincludingcasesduetoNeisseriagonorrhoeae

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IntheabovegenitaltractinfectionswhenthoughtorknowntobeduetoNeisseriagonorrhoeaeitisparticularlyimportantto

obtainlocalinformationontheprevalenceofresistancetociprofloxacinandtoconfirmsusceptibilitybasedonlaboratorytesting.

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

Intra-abdominalinfections

InfectionsoftheskinandsofttissuecausedbyGram-negativebacteria

Malignantexternalotitis

Infectionsofthebonesandjoints

Treatmentofinfectionsinneutropenicpatients

Prophylaxisofinfectionsinneutropenicpatients

Inhalationanthrax(post-exposureprophylaxisandcurativetreatment)

Childrenandadolescents:

Broncho-pulmonaryinfectionsincysticfibrosiscausedbyPseudomonasaeruginosa.

Complicatedurinarytractinfectionsandpyelonephritis

Inhalationanthrax(post-exposureprophylaxisandcurativetreatment

Ciprofloxacinmayalsobeusedtotreatsevereinfectionsinchildrenandadolescentswhenthisisconsideredtobenecessary.

Treatmentshouldbeinitiatedonlybyphysicianswhoareexperiencedinthetreatmentofcysticfibrosisand/orsevereinfectionsin

childrenandadolescents(seesections4.4and5.1).

4.2Posologyandmethodofadministration

Thedosageisdeterminedbytheindication,theseverityandthesiteofinfection,the susceptibilitytociprofloxacin of

thecausativeorganism(s),therenalfunctionofthepatientand inchildrenandadolescents,thebodyweight.

Thedurationoftreatmentdependsontheseverityoftheillnessandontheclinicalandbacteriologicalcourse.

Afterintravenousinitiationoftreatment,thetreatmentcanbeswitchedtooraltreatmentwithtabletorsuspensionifclinically

indicatedatthediscretionofthephysician.IVtreatmentshouldbefollowedbyoralrouteassoonaspossible.

Inseverecasesorifthepatientisunabletotaketablets(e.g.patientsonenteralnutrition),itisrecommendedtocommence

therapywithintravenousciprofloxacinuntilaswitchtooraladministrationispossible.

Treatmentofinfectionsduetocertainbacteria(e.g.Pseudomonasaeruginosa,AcinetobacterorStaphylococci)mayrequirehigher

ciprofloxacindosesandco-administrationwithotherappropriateantibacterialagents.

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

infectionsofbonesandjoints)mayrequireco-administrationwithotherappropriateantibacterialagentsdependingonthe

pathogensinvolved.

Adults

Indications Dailydoseinmg Totaldurationoftreatment

(includingswitchtooral

therapyassoonaspossible)

Infectionsofthelowerrespiratorytract 400mgtwicedailyto400

mgthreetimesaday 7to14days

Infectionsoftheupper

respiratorytract Acute exacerbation of

chronicsinusitis 400mgtwicedailyto400

mgthreetimesaday 7to14days

Chronicsuppurativeotitis

media 400mgtwicedailyto400

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Malignantexternalotitis 400mgthreetimesaday 28daysupto3months

Urinarytractinfections Complicatedand

Uncomplicated

pyelonephritis 400mgtwicedailyto400

mgthreetimesaday 7to21days,itcanbe

continuedforlongerthan21

daysinsomespecific

circumstances(suchas

abscesses)

Prostatitis 400mgtwicedailyto400

mgthreetimesaday 2to4weeks(acute)

Genitaltractinfections Epididymo-orchitisand

pelvicinflammatory

diseases 400mgtwicedailyto400

mgthreetimesaday atleast14days

Infectionsofthe

gastro-intestinaltract

andintraabdominal

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 400mgtwicedailyto400

mgthreetimesaday 5to14days

Infectionsoftheskinandsofttissue 400mgtwicedailyto400

mgthreetimesaday 7to14days

Boneandjointinfections 400mgtwicedailyto400

mgthreetimesaday max.of3months

Treatmentofinfectionsorprophylaxisof

infectionsinneutropenicpatientsCiprofloxacin

shouldbeco-administeredwithappropriate

antibacterialagent(s)inaccordancetoofficial

guidance 400mgtwicedailyto400

mgthreetimesaday Therapyshouldbecontinued

overtheentireperiodof

neutropenia

Inhalationanthraxpost-exposureprophylaxisand

curativetreatmentforpersonsrequiring

parenteraltreatment.

Drugadministrationshouldbeginassoonas

possibleaftersuspectedorconfirmedexposure. 400mgtwicedaily 60daysfromthe

confirmationofBacillus

anthracisexposure

Indications Dailydoseinmg Totaldurationoftreatment

(includingswitchtooral

therapyassoonaspossible)

Cysticfibrosis 10mg/kgbodyweightthree

timesadaywithamaximum

of400mgperdose. 10to14days

Complicatedurinarytractinfectionsand

pyelonephritis 6mg/kgbodyweightthree

timesadayto10mg/kgbody

weightthreetimesadaywith

amaximumof400mgper

dose. 10to21days

Inhalationanthraxpost-exposurecurative

treatmentforpersonsrequiringparenteral

treatment

Drugadministrationshouldbeginassoonas

possibleaftersuspectedorconfirmedexposure.. 10mg/kgbodyweighttwice

dailyto15mg/kgbody

weighttwicedailywitha

maximumof400mgper

dose. 60daysfromthe

confirmationofBacillus

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Geriatricpatients

Geriatricpatientsshouldreceiveadoseselectedaccordingtotheseverityoftheinfectionandthepatient’screatinineclearance.

Renalandhepaticimpairment

Recommendedstartingandmaintenancedosesforpatientswithimpairedrenalfunction:

Inpatientswithimpairedliverfunctionnoadjustmentofdosageisnecessary.

Dosinginchildrenwithimpairedrenaland/orhepaticfunctionhasnotbeenstudied.

Methodofadministration

Ciprofloxacinshouldbecheckedvisuallypriortouse.Itmustnotbeusedifcloudy.

Ciprofloxacinshouldbeadministeredbyintravenousinfusion.Forchildren,theinfusiondurationis60minutes.

Inadultpatients,infusiontimeis60minutesfor400mgCiprofloxacinand30minutesfor200mgCiprofloxacin2mg/mlsolution

forinfusion.Slowinfusionintoalargeveinwillminimisepatientdiscomfortandreducetheriskofvenousirritation.

Theinfusionsolutioncanbeinfusedeitherdirectlyoraftermixingwithothercompatibleinfusionsolutions(seesection6.2).

4.3Contraindications

-Hypersensitivitytotheactivesubstance,tootherquinolonesortoanyoftheexcipients(seesection6.1).

-Concomitantadministrationofciprofloxacinandtizanidine(seesection4.5)

Othersevereinfections 10mg/kgbodyweightthree

timesadaywithamaximum

of400mgperdose. Accordingtothetypeof

infections

Creatinineclearance

[mL/min/1.73m 2

] Serumcreatinine

[µmol/L] IntravenousDose

[mg]

>60 <124 Seeusualdosage

30-60 124to168 200-400mgevery12h

<30 >169 200-400mgevery24h

Patientsonhaemodialysis >169 200-400mgevery24h(after

dialysis)

Patientsonperitonealdialysis >169 200-400mgevery24h

SevereinfectionsandmixedinfectionswithGram-positiveandanaerobicpathogens

CiprofloxacinmonotherapyisnotsuitedfortreatmentofsevereinfectionsandinfectionsthatmightbeduetoGram-positiveor

anaerobicpathogens.Insuchinfectionsciprofloxacinmustbecoadministeredwithotherappropriateantibacterialagents.

StreptococcalInfections(includingStreptococcuspneumoniae)

Ciprofloxacinisnotrecommendedforthetreatmentofstreptococcalinfectionsduetoinadequateefficacy.

Genitaltractinfections

Epididymo-orchitisandpelvicinflammatorydiseasesmaybecausedbyfluoroquinolone-resistantNeisseriagonorrhoeae.

Ciprofloxacinshouldbeco-administeredwithanotherappropriateantibacterialagentunlessciprofloxacin-resistantNeisseria

gonorrhoeaecanbeexcluded.Ifclinicalimprovementisnotachievedafter3daysoftreatment,thetherapyshouldbe

reconsidered.

Intra-abdominalinfections

Therearelimiteddataontheefficacyofciprofloxacininthetreatmentofpost-surgicalintra-abdominalinfections.

Travellers’diarrhoea

Thechoiceofciprofloxacinshouldtakeintoaccountinformationonresistancetociprofloxacininrelevantpathogensinthe

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Infectionsofthebonesandjoints

Ciprofloxacinshouldbeusedincombinationwithotherantimicrobialagentsdependingontheresultsofthemicrobiological

documentation.

Inhalationalanthrax

Useinhumansisbasedonin-vitrosusceptibilitydataandonanimalexperimentaldatatogetherwithlimitedhumandata.

Treatingphysiciansshouldrefertonationaland/orinternationalconsensusdocumentsregardingthetreatmentofanthrax.

Childrenandadolescents

Theuseofciprofloxacininchildrenandadolescentsshouldfollowavailableofficialguidance.

Ciprofloxacintreatmentshouldbeinitiatedonlybyphysicianswhoareexperiencedinthetreatmentofcysticfibrosisand/or

severeinfectionsinchildrenandadolescents.

Ciprofloxacinhasbeenshowntocausearthropathyinweight-bearingjointsofimmatureanimals.Safetydatafromarandomised

double-blindstudyonciprofloxacinuseinchildren(ciprofloxacin:n=335,meanage=6.3years;comparators:n=349,meanage

=6.2years;agerange=1to17years)revealedanincidenceofsuspecteddrug-relatedarthropathy(discernedfromjoint-related

clinicalsignsandsymptoms)byDay+42of7.2%and4.6%.Respectively,anincidenceofdrug-relatedarthropathyby1-year

follow-upwas9.0%and5.7%.Theincreaseofsuspecteddrug-relatedarthropathycasesovertimewasnotstatisticallysignificant

betweengroups.Treatmentshouldbeinitiatedonlyafteracarefulbenefit/riskevaluation,duetopossibleadverseeventsrelated

tojointsand/orsurroundingtissue.

Broncho-pulmonaryinfectionsincysticfibrosis

Clinicaltrialshaveincludedchildrenandadolescentsaged5-17years.Morelimitedexperienceisavailableintreatingchildren

between1and5yearsofage.

Complicatedurinarytractinfectionsandpyelonephritis

Ciprofloxacintreatmentofurinarytractinfectionsshouldbeconsideredwhenothertreatmentscannotbeused,andshouldbe

basedontheresultsofthemicrobiologicaldocumentation.

Clinicaltrialshaveincludedchildrenandadolescentsaged1-17years.

Otherspecificsevereinfections

Othersevereinfectionsinaccordancewithofficialguidance,oraftercarefulbenefit-riskevaluation

whenothertreatmentscannotbeused,orafterfailuretoconventionaltherapyandwhenthe

microbiologicaldocumentationcanjustifyaciprofloxacinuse.

Theuseofciprofloxacinforspecificsevereinfectionsotherthanthosementionedabovehasnotbeen

evaluatedinclinicaltrialsandtheclinicalexperienceislimited.Consequently,cautionisadvised

whentreatingpatientswiththeseinfections.

Hypersensitivity

Hypersensitivityandallergicreactions,includinganaphylaxisandanaphylactoidreactions,mayoccurfollowingasingledose

(seesection4.8)andmaybelife-threatening.Ifsuchreactionoccurs,ciprofloxacinshouldbediscontinuedandanadequate

medicaltreatmentisrequired.

MusculoskeletalSystem

Ciprofloxacinshouldgenerallynotbeusedinpatientswithahistoryoftendondisease/disorderrelatedtoquinolonetreatment.

Nevertheless,inveryrareinstances,aftermicrobiologicaldocumentationofthecausativeorganismandevaluationofthe

risk/benefitbalance,ciprofloxacinmaybeprescribedtothesepatientsforthetreatmentofcertainsevereinfections,particularly

intheeventoffailureofthestandardtherapyorbacterialresistance,wherethemicrobiologicaldatamayjustifytheuseof

ciprofloxacin.

Tendinitisandtendonrupture(especiallyAchillestendon),sometimesbilateral,mayoccurwithciprofloxacin,assoonasthefirst

48hoursoftreatment.Theriskoftendinopathymaybeincreasedinelderlypatientsorinpatientsconcomitantlytreatedwith

corticosteroids(seesection4.8).

Atanysignoftendinitis(e.g.painfulswelling,inflammation),ciprofloxacintreatmentshouldbediscontinued.Careshouldbe

takentokeeptheaffectedlimbatrest.

Ciprofloxacinshouldbeusedwithcautioninpatientswithmyastheniagravis(seesection4.8).

Photosensitivity

Ciprofloxacinhasbeenshowntocausephotosensitivityreactions.Patientstakingciprofloxacinshouldbeadvisedtoavoiddirect

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CentralNervousSystem

Quinolonesareknowntotriggerseizuresorlowertheseizurethreshold.Ciprofloxacinshouldbeusedwithcautioninpatients

withCNSdisorderswhichmaybepredisposedtoseizure.Ifseizuresoccurciprofloxacinshouldbediscontinued(seesection

4.8).Psychiatricreactionsmayoccurevenafterthefirstadministrationofciprofloxacin.Inrarecases,depressionorpsychosis

canprogresstoselfendangeringbehaviour.Inthesecases,ciprofloxacinshouldbediscontinued.

Casesofpolyneuropathy(basedonneurologicalsymptomssuchaspain,burning,sensorydisturbancesormuscleweakness,

aloneorincombination)havebeenreportedinpatientsreceivingciprofloxacin.

Ciprofloxacinshouldbediscontinuedinpatientsexperiencingsymptomsofneuropathy,includingpain,burning,tingling,

numbness,and/orweaknessinordertopreventthedevelopmentofanirreversiblecondition(seesection4.8).

Cardiacdisorders

Cautionshouldbetakenwhenusingfluoroquinolones,includingciprofloxacin,inpatientswithknownriskfactorsfor

prolongationoftheQTintervalsuchas,forexample:

-congenitallongQTsyndrome

-concomitantuseofdrugsthatareknowntoprolongtheQTinterval(e.g.ClassIAandIIIantiarrhythmics,

tricyclicantidepressants,macrolides,antipsychotics)

-uncorrectedelectrolyteimbalance(e.g.hypokalaemia,hypomagnesaemia)

-elderly

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

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

GastrointestinalSystem

Theoccurrenceofsevereandpersistentdiarrhoeaduringoraftertreatment(includingseveralweeksaftertreatment)mayindicate

anantibiotic-associatedcolitis(life-threateningwithpossiblefataloutcome),requiringimmediatetreatment(seesection4.8).In

suchcases,ciprofloxacinshouldimmediatelybediscontinued,andanappropriatetherapyinitiated.Anti-peristalticdrugsare

contraindicatedinthissituation.

Renalandurinarysystem

Crystalluriarelatedtotheuseofciprofloxacinhasbeenreported(seesection4.8).Patientsreceivingciprofloxacinshouldbewell

hydratedandexcessivealkalinityoftheurineshouldbeavoided.

Hepatobiliarysystem

Casesofhepaticnecrosisandlife-threateninghepaticfailurehavebeenreportedwithciprofloxacin(seesection4.8).Intheevent

ofanysignsandsymptomsofhepaticdisease(suchasanorexia,jaundice,darkurine,pruritus,ortenderabdomen),treatment

shouldbediscontinued.

Glucose-6-phosphatedehydrogenasedeficiency

Haemolyticreactionshavebeenreportedwithciprofloxacininpatientswithglucose-6-phosphatedehydrogenasedeficiency.

Ciprofloxacinshouldbeavoidedinthesepatientsunlessthepotentialbenefitisconsideredtooutweighthepossiblerisk.Inthis

case,potentialoccurrenceofhaemolysisshouldbemonitored.

Resistance

Duringorfollowingacourseoftreatmentwithciprofloxacinbacteriathatdemonstrateresistancetociprofloxacinmaybe

isolated,withorwithoutaclinicallyapparentsuperinfection.Theremaybeaparticularriskofselectingforciprofloxacin-

resistantbacteriaduringextendeddurationsoftreatmentandwhentreatingnosocomialinfectionsand/orinfectionscausedby

StaphylococcusandPseudomonasspecies.

CytochromeP450

CiprofloxacininhibitsCYP1A2andthusmaycauseincreasedserumconcentrationofconcomitantlyadministeredsubstances

metabolisedbythisenzyme(e.g.theophylline,clozapine,ropinirole,tizanidine).Co-administrationofciprofloxacinand

tizanidineiscontra-indicated.Therefore,patientstakingthesesubstancesconcomitantlywithciprofloxacinshouldbemonitored

closelyforclinicalsignsofoverdose,anddeterminationofserumconcentrations(e.g.oftheophylline)maybenecessary(see

section4.5).

Methotrexate

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

EffectsofothermedicinalproductsonCiprofloxacin

Probenecid

Probenecidinterfereswiththerenalsecretionofciprofloxacin. Co-administrationofprobenecidandciprofloxacin

increasesciprofloxacinserumconcentrations.

EffectsofCiprofloxacinonothermedicinalproducts:

Tizanidine

Tizanidinemustnotbeadministeredtogetherwithciprofloxacin(seesection4.3). Inaclinicalstudywithhealthy

subjects,therewasanincreaseinserumtizanidineconcentration(C

increase:7-fold,range:4to21-fold;AUCincrease:10-

fold,range:6to24-fold)whengivenconcomitantlywithciprofloxacin.Increasedserumtizanidineconcentrationisassociated

withpotentiatedhypotensiveandsedativeeffect.

Methotrexate

Renaltubulartransportofmethotrexatemaybeinhibitedbyconcomitantadministrationofciprofloxacinpotentiallyleadingto

increasedplasmalevelsofmethotrexateandincreasedriskofmethotrexate-associatedtoxicreactions.Theconcomitantuseisnot

recommended(seesection4.4).

Theophylline

Concurrentadministrationofciprofloxacinandtheophyllinecancauseanundesirableincreaseinserumtheophylline

concentration.Thiscanleadtotheophylline-inducedundesirablesideeffectsthatmayrarelybelifethreateningorfatal.During

thecombinationserumtheophyllineconcentrationsshouldbecheckedandthetheophyllinedosereducedasnecessary(seesection

4.4).

Otherxanthinederivatives

Onconcurrentadministrationofciprofloxacinandcaffeineorpentoxyfylline(oxpentifylline),raisedserumconcentrationsofthese

xanthinederivativeswerereported.

Phenytoin

Simultaneousadministrationofciprofloxacinandphenytoinmayresultinincreasedorreducedserumlevelsofphenytoinsuch

thatmonitoringofdruglevelsisrecommended.

Oralanticoagulants

Simultaneousadministrationofciprofloxacinwithwarfarinmayaugmentitsanti-coagulanteffects.Therehavebeenmanyreports

ofincreasesinoralanti-coagulantactivityinpatientsreceivingantibacterialagents,includingfluoroquinolones.Theriskmayvary

withtheunderlyinginfection,ageandgeneralstatusofthepatientsothatthecontributionofthefluoroquinolonetotheincreasein

INR(internationalnormalisedratio)isdifficulttoassess.ItisrecommendedthattheINRshouldbemonitoredfrequentlyduring

Interactionwithtests

Thein-vitroactivityofciprofloxacinagainstMycobacteriumtuberculosismightgivefalsenegativebacteriologicaltestresultsin

specimensfrompatientscurrentlytakingciprofloxacin.

InjectionSiteReaction

Localintravenoussitereactionshavebeenreportedwiththeintravenousadministrationofciprofloxacin.Thesereactionsare

morefrequentiftheinfusiontimeis30minutesorless.Thesemayappearaslocalskinreactionswhichresolverapidlyupon

completionoftheinfusion.Subsequentintravenousadministrationisnotcontraindicatedunlessthereactionsrecurorworsen.

NaClLoad

Inpatientsforwhomsodiumintakeisofmedicalconcern(patientswithcongestiveheartfailure,renalfailure,nephrotic

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Ropinirole

Itwasshowninaclinicalstudythatconcomitantuseofropinirolewithciprofloxacin,amoderateinhibitoroftheCYP4501A2

isozyme,resultsinanincreaseofC

andAUCofropiniroleby60%and84%,respectively.Monitoringofropinirole-related

sideeffectsanddoseadjustmentasappropriateisrecommendedduringandshortlyafterco-administrationwithciprofloxacin(see

section4.4).

Clozapine

Followingconcomitantadministrationof250mgciprofloxacinwithclozapinefor7days,serumconcentrationsofclozapineand

N-desmethylclozapinewereincreasedby29%and31%,respectively.

Clinicalsurveillanceandappropriateadjustmentofclozapinedosageduringandshortlyaftercoadministrationwithciprofloxacin

areadvised(seesection4.4).

DrugsknowntoprolongQTinterval

Ciprofloxacin,likeotherfluoroquinolones,shouldbeusedwithcautioninpatientsreceivingdrugsknowntoprolongtheQT

interval(e.g.ClassIAandIIIanti-arrhythmics,tricyclicantidepressants,macrolides,antipsychotics)(seesection4.4).

4.6Fertility,pregnancyandlactation

Pregnancy

Thedata thatareavailableonadministrationofciprofloxacintopregnantwomenindicatesnomalformativeorfeto/neonatal

toxicityofciprofloxacin.Animalstudiesdonotindicatedirectorindirectharmfuleffectswithrespecttoreproductivetoxicity.In

juvenileandprenatalanimalexposedtoquinolones,effectsonimmaturecartilagehavebeenobserved,thus,itcannotbeexcluded

thatthedrugcouldcausedamagetoarticularcartilageinthehumanimmatureorganism/foetus(seesection5.3).

Asaprecautionarymeasure,itispreferabletoavoidtheuseofciprofloxacinduringpregnancy.

Lactation

Ciprofloxacinisexcretedinbreastmilk.Duetothepotentialriskofarticulardamage,ciprofloxacinshouldnotbeusedduring

breast-feeding.

4.7Effectsonabilitytodriveandusemachines

4.8Undesirableeffects

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

rash,andinjectionandinfusionsitereactions.

ADRsderivedfromclinicalstudiesandpost-marketingsurveillancewithCiprofloxacin(oral,intravenousandsequentialtherapy)

sortedbycategoriesoffrequencyarelistedbelow.Thefrequencyanalysistakesintoaccountdatafrombothoralandintravenous

Duetoitsneurologicaleffects,ciprofloxacinmayaffectreactiontime.Thus,theabilitytodriveortooperatemachinerymaybe

impaired.

SystemOrgan

Class Common

1/100to

<1/10 Uncommon

1/1,000to

<1/100 Rare

1/10,000to<

1/1,000 VeryRare

<1/10,000 Frequency

notknown

(cannotbe

estimated

fromavailable

data)

Infectionsand

Infestations Mycotic

superinfections Antibiotic

associatedcolitis

(veryrarelywith

possiblefatal

outcome)(see

section4.4)

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Lymphatic

System

Disorders Anaemia

Neutropenia

Leukocytosis

Thrombocytopenia

Thrombocytaemia anaemia

Agranulocytosis

Pancytopenia

(lifethreatening)

Bonemarrow

depression

(lifethreatening)

ImmuneSystem

Disorders Allergicreaction

Allergicoedema/

angiooedema Anaphylactic

reaction

Anaphylactic

shock

(lifethreatening)

(seesection4.4)

Serum

sicknesslike

reaction

Metabolismand

Nutrition

Disorders Anorexia Hyperglycaemia

Psychiatric

Disorders Psychomotor

hyperactivity/

agitation Confusionand

disorientation

Anxietyreaction

Abnormaldreams

Depression

Hallucinations Psychotic

reactions(see

section4.4)

NervousSystem

Disorders Headache

DizzinessSleep

disordersTaste

disorders Par-and

Dysaesthesia

Hypoaesthesia

TremorSeizures

(seesection4.4)

Vertigo Migraine

Disturbed

coordination

Gait

disturbance

Olfactorynerve

disorders

Intracranial

hypertension Peripheral

neuropathy

(seesection

4.4)

EyeDisorders Visual

disturbances Visualcolour

distortions

Earand

Labyrinth

Disorders TinnitusHearing

loss/Hearing

impaired

Cardiac

Disorders Tachycardia Ventricular

arrhythmia

andtorsades

depointes

(reported

predominantly

inpatients

withrisk

factors

forQT

prolongation),

ECGQT

prolonged

(seesection

4.4and4.9).

Vascular

Disorders Vasodilatation

Hypotension

Syncope Vasculitis

Respiratory,

Thoracicand

Mediastinal

Disorders Dyspnoea

(including

asthmatic

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Thefollowingundesirableeffectshaveahigherfrequencycategoryinthesubgroupsofpatientsreceivingintravenousor

Gastrointestinal

Disorders Nausea

Diarrhoea Vomiting

Gastrointestinal

andabdominal

painsDyspepsia

Flatulence Pancreatitis

Hepatobiliary

Disorders Increasein

transaminases

Increased

bilirubin Hepatic

impairment

Cholestaticicterus

Hepatitis Livernecrosis

(veryrarely

progressingto

life-threatening

hepaticfailure)

(seesection4.4)

Skinand

Subcutaneous

TissueDisorders Rash

Pruritus

Urticaria Photosensitivity

reactions(see

section4.4) Petechiae

Erythema

multiforme

Erythema

nodosum

Stevens-

Johnson

syndrome

(potentially

lifethreatening)

Toxic

epidermal

necrolysis

(potentially

lifethreatening)

Musculoskeletal,

Connective

TissueandBone

Disorders Musculoskeletal

pain(e.g.

extremitypain,

backpain,chest

pain)

Arthralgia Myalgia

Arthritis

Increasedmuscle

toneandcramping Muscular

weakness

Tendinitis

Tendonrupture

(predominantly

Achilles

tendon)(see

section4.4)

Exacerbationof

symptomsof

myasthenia

gravis(see

section4.4)

Renaland

Urinary

Disorders Renal

impairment Renalfailure

Haematuria

Crystalluria(see

section4.4)

Tubulointerstitial

nephritis

General

Disordersand

Administration

SiteConditions Injectionand

infusionsite

reactions(only

intravenous

administration) AstheniaFever OedemaSweating

(hyperhidrosis)

Investigations Increasein

bloodalkaline

phosphatase Prothrombinlevel

abnormal

Increasedamylase

Common Vomiting,Transientincreaseintransaminases,Rash

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Paediatricpatients

Theincidenceofarthropathy,mentionedabove,isreferringtodatacollectedinstudieswithadults.Inchildren,arthropathyis

reportedtooccurcommonly(seesection4.4).

4.9Overdose

Anoverdoseof12ghasbeenreportedtoleadtomildsymptomsoftoxicity.Anacuteoverdoseof16ghasbeen

reportedtocauseacuterenalfailure.

Symptomsofoverdosemayincludedizziness,tremor,headache,tiredness,seizures,hallucinations,confusion,

abdominaldiscomfort,renalandhepaticimpairmentaswellas crystalluria,andhaematuria.

Reversiblerenaltoxicityhasbeenreported.

Apartfromroutineemergencymeasures,itisalsorecommendedtomonitorrenalfunction,includingurinarypHandacidify,if

required,topreventcrystalluria.Patientsshouldbekeptwellhydrated.Onlyasmallquantityofciprofloxacin(<10%)is

eliminatedbyhaemodialysisorperitonealdialysis.

Intheeventofoverdose,symptomatictreatmentshouldbeimplemented.ECGmonitoringshouldbeundertaken,becauseofthe

possibilityofQTintervalprolongation.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:fluoroquinolones

ATCCode:J01MA02

Mechanismofaction:

Asafluoroquinoloneantibacterialagent,thebactericidalactionofciprofloxacinresultsfromtheinhibitionofbothtypeII

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

recombination.

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-genes

anddysaesthesia,Seizures,Vertigo,Visualdisturbances,Hearingloss,Tachycardia,

Vasodilatation,Hypotension,Transienthepaticimpairment,Cholestaticicterus,Renal

failure,Oedema

Rare Pancytopenia,Bonemarrowdepression,Anaphylacticshock,Psychoticreactions,Migraine,

Olfactorynervedisorders,Hearingimpaired,Vasculitis,Pancreatitis,Livernecrosis,

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Spectrumofantibacterialactivity:

Breakpointsseparatesusceptiblestrainsfromstrainswithintermediatesusceptibilityandthelatterfromresistantstrains:

EUCASTRecommendations

Staphylococcusspp.-breakpointsforciprofloxacinrelatetohighdosetherapy.

Non-species-relatedbreakpointshavebeendeterminedmainlyonthebasisofPK/PDdataandareindependentofMIC

distributionsofspecificspecies.Theyareforuseonlyforspeciesthathavenotbeengivenaspecies-specificbreakpoint

andnotforthosespecieswheresusceptibilitytestingisnotrecommended.

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-relatedbreakpoints* S 0.5mg/L R >

1mg/L

COMMONLYSUSCEPTIBLESPECIES

AerobicGram-positivemicro-organisms

Bacillusanthracis(1)

AerobicGram-negativemicro-organisms

Aeromonasspp.

Brucellaspp.

Citrobacterkoseri

Francisellatularensis

Haemophilusducreyi

Haemophilusinfluenzae*

Legionellaspp.

Moraxellacatarrhalis*

Neisseriameningitidis

Pasteurellaspp.

Salmonellaspp.*

Shigellaspp.*

Vibriospp.

Yersiniapestis

Anaerobicmicro-organisms

Mobiluncus

Othermicro-organisms

Chlamydiatrachomatis($)

Chlamydiapneumoniae($)

Mycoplasmahominis($)

Mycoplasmapneumoniae($)

SPECIESFORWHICHACQUIREDRESISTANCEMAYBEAPROBLEM

AerobicGram-positivemicro-organisms

Enterococcusfaecalis($)

Staphylococcusspp.*(2)

AerobicGram-negativemicro-organisms

Acinetobacterbaumannii

+

Burkholderiacepacia

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5.2Pharmacokineticproperties

Absorption

Followinganintravenousinfusionofciprofloxacinthemeanmaximumserumconcentrationswereachievedattheendof

infusion.Pharmacokineticsofciprofloxacinwerelinearoverthedoserangeupto400mgadministeredintravenously.

Comparisonofthepharmacokineticparametersforatwiceadayandthreetimesadayintravenousdoseregimenindicatedno

Campylobacterspp.

Citrobacterfreundii*

Enterobacteraerogenes

Enterobactercloacae*

Escherichiacoli*

Klebsiellaoxytoca

Klebsiellapneumoniae*

Morganellamorganii*

Neisseriagonorrhoeae*

Proteusmirabilis*

Proteusvulgaris*

Providenciaspp.

Pseudomonasaeruginosa*

Pseudomonasfluorescens

Serratiamarcescens*

Anaerobicmicro-organisms

Peptostreptococcusspp.

Propionibacteriumacnes

INHERENTLYRESISTANTORGANISMS

AerobicGram-positivemicro-organisms

Actinomyces

Enteroccusfaecium

Listeriamonocytogenes

AerobicGram-negativemicro-organisms

Stenotrophomonasmaltophilia

Anaerobicmicro-organisms

Exceptedaslistedabove

Othermicro-organisms

Mycoplasmagenitalium

Ureaplasmaurealitycum

*Clinicalefficacyhasbeendemonstratedforsusceptibleisolatesinapprovedclinical

indications.

Resistancerate 50%inoneormoreEUcountries

($):Naturalintermediatesusceptibilityintheabsenceofacquiredmechanismofresistance

(1):StudieshavebeenconductedinexperimentalanimalinfectionsduetoinhalationsofBacillusanthracis

spores;thesestudiesrevealthatantibioticsstartingearlyafterexpositionavoidtheoccurrenceofthedisease

ifthetreatmentismadeuptothedecreaseofthenumberofsporesintheorganismundertheinfectivedose.

Therecommendeduseinhumansubjectsisbasedprimarilyonin-vitrosusceptibilityandonanimal

experimentaldatatogetherwithlimitedhumandata.Two-monthtreatmentdurationinadultswithoral

ciprofloxacingivenatthefollowingdose,500mgbid,isconsideredaseffectivetopreventanthraxinection

inhumans.Thetreatingphysicianshouldrefertonationaland/orinternationalconsensusdocuments

regardingtreatmentofanthrax.

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

resistancetomethicillinisaround20to50%amongallstaphylococcalspeciesandisusuallyhigherin

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A60-minuteintravenousinfusionof200mgciprofloxacinortheoraladministrationof250mgciprofloxacin,bothgivenevery12

hours,producedanequivalentareaundertheserumconcentrationtimecurve(AUC).

A60-minuteintravenousinfusionof400mgciprofloxacinevery12hourswasbioequivalenttoa500mgoraldoseevery12hours

withregardtoAUC.

The400mgintravenousdoseadministeredover60minutesevery12hoursresultedinaC

similartothatobservedwitha750

mgoraldose.

A60-minuteinfusionof400mgciprofloxacinevery8hoursisequivalentwithrespecttoAUCto750mgoralregimengiven

every12hours.

Distribution

Proteinbindingofciprofloxacinislow(20-30%). Ciprofloxacinispresentinplasmalargelyinanon-ionisedformandhasa

largesteadystatedistributionvolumeof2-3L/kgbodyweight.Ciprofloxacinreacheshighconcentrationsinavarietyoftissues

suchaslung(epithelialfluid,alveolarmacrophages,biopsytissue),sinuses,inflamedlesions(cantharidesblisterfluid),andthe

urogenitaltract(urine,prostate,endometrium)wheretotalconcentrationsexceedingthoseofplasmaconcentrationsarereached.

Metabolism

Lowconcentrationsoffourmetaboliteshavebeenreported,whichwereidentifiedas:desethyleneciprofloxacin(M1),

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

activitybuttoalowerdegreethantheparentcompound.

CiprofloxacinisknowntobeamoderateinhibitoroftheCYP4501A2iso-enzymes.

Elimination

Ciprofloxacinislargelyexcretedunchangedbothrenallyand,toasmallerextent,faecally.

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

Excretionofciprofloxacin(%ofdose)

Intravenousadministration

Urine Faeces

Ciprofloxacin 61.5 15.2

Metabolites(M

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5.3Preclinicalsafetydata

Non-clinicaldatarevealnospecialhazardsforhumansbasedonconventionalstudiesofsingledosetoxicity,repeateddose

toxicity,carcinogenicpotential,ortoxicitytoreproduction.

Likeanumberofotherquinolones,ciprofloxacinisphototoxicinanimalsatclinicallyrelevantexposurelevels.Dataon

photomutagenicity/photocarcinogenicityshowaweakphotomutagenicorphototumorigeniceffectofciprofloxacinin-vitroandin

animalexperiments.Thiseffectwascomparabletothatofothergyraseinhibitors.

Articulartolerability:

Asreportedforothergyraseinhibitors,ciprofloxacincausesdamagetothelargeweight-bearingjointsinimmatureanimals.The

extentofthecartilagedamagevariesaccordingtoage,speciesanddose;thedamagecanbereducedbytakingtheweightoffthe

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

ciprofloxacincausedseverearticularchangesattherapeuticdosesaftertwoweeksoftreatment,whichwerestillobservedafter5

months.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

LacticAcid(90%)

SodiumChloride

Hydrochloricacid1N(forpH-adjustmentonly)

Waterforinjection

6.2Incompatibilities

Thismedicinalproductmustnotbemixedwithothermedicinalproductsexceptthosementionedinsection6.6.

Thefollowingactivesubstancesorsolutionfordilutionshouldnotbeadministeredsimultaneously,e.g.:

Penicillins,Heparinsolutions,whicharechemicallyandphysicallyunstableatthepHofCiprofloxacin2mg/ml(pH

3.9-4.5).

6.3Shelflife

3years.

Onceopeneduseimmediately.

Oncediluted:Chemicalandphysicalin-usestabilityhasbeendemonstratedfor4hoursat25 o

Fromthemicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,thein-use

storagetimesandconditionspriortousearetheresponsibilityoftheuser.

6.4Specialprecautionsforstorage

Donotrefrigerateorfreeze.

Keepthecontainerintheoutercartoninordertoprotectfromlight.

Forstorageconditionsofdilutedproduct,seesection6.3.

6.5Natureandcontentsofcontainer

TransparentTypeIglassvialwithrubberstopperandaluminiumcap

Packsizes:

1vialwith50ml/100ml/200mlcontains100mg/200mg/400mgofCiprofloxacin(aslactate).

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6.6Specialprecautionsfordisposalandotherhandling

Ciprofloxacin2mg/mlsolutionforinfusioniscompatiblewithRingerlactatesolution, ,0.9%sodiumchloridesolution,

5%and10%glucosesolutions,and5%and10%fructosesolutions.Whenciprofloxacininfusionsolutionsaremixedwith

compatibleinfusionsolutions,formicrobialreasonsandlightsensitivitythesesolutionsmustbeadministeredshortlyafter

mixture.

Astheinfusionsolutionissensitivetolight,onlyremovethebottlesfromthefoldingboxforuse.Indaylightthefullefficacyof

thesolutionisguaranteedoveraperiodof3days.

Forsingleuseonly.

Ifproductisinadvertentlyrefrigerated,crystalsmayform.Donotuseifcrystalsarepresent.Thesecrystalswill,

however,redissolveatroomtemperatureanddonotadverselyaffectthequalityofthisproduct.

The(diluted)solutionshouldbeinspectedvisuallyforparticulatematteranddiscolorationpriortoadministration.Only

clearandcolourlessorslightlycolouredsolutionshouldbeused.

7MARKETINGAUTHORISATIONHOLDER

NicheGenericsLimited

1TheCamCentre

WilburyWay

Hitchin

Herts

SG40TW

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA1063/37/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:14 th

March2008

Dateoflastrenewal:22 nd

March2010

10DATEOFREVISIONOFTHETEXT

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