CIPROFLOXACIN PFIZER

Main information

  • Trade name:
  • CIPROFLOXACIN PFIZER
  • Dosage:
  • 250 Base Milligrams
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0822/028/001
  • Authorization date:
  • 08-07-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

CiprofloxacinPfizer250mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains250mgciprofloxacin(asciprofloxacinhydrochloride).

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

Whitetooffwhite,round,film-coatedtablets,withascorelineononesideanddebossedwith‘F’,‘23’oneitherside

ofascorelineontheotherside.

Thescorelineisonlytofacilitatebreakingforeaseofswallowingandnottodivideintoequaldoses.

4CLINICALPARTICULARS

4.1TherapeuticIndications

CiprofloxacinPfizerfilm-coatedtabletsareindicatedforthetreatmentofthefollowinginfections(seesections4.4and

5.1).Specialattentionshouldbepaidtoavailableinformationonresistancetociprofloxacinbeforecommencing

therapy.

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantibacterialagents.

Adults

LowerrespiratorytractinfectionsduetoGram-negativebacteria

exacerbationsofchronicobstructivepulmonarydisease

broncho-pulmonaryinfectionsincysticfibrosisorinbronchiectasis

pneumonia

Chronicsuppurativeotitismedia

AcuteexacerbationofchronicsinusitisespeciallyifthesearecausedbyGram-negativebacteria

Urinarytractinfections

Gonococcaluretritisandcervicitis

Epididymo-orchitisincludingcasesduetoNeisseriagonorrhoeae.

PelvicinflammatorydiseaseincludingcasesduetoNeisseriagonorrhoeae

IntheabovegenitaltractinfectionswhenthoughtorknowntobeduetoNeisseriagonorrhoeaeitisparticularly

importanttoobtainlocalinformationontheprevalenceofresistancetociprofloxacinandtoconfirmsusceptibility

basedonlaboratorytesting.

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

Intra-abdominalinfections

InfectionsoftheskinandsofttissuecausedbyGram-negativebacteria

Malignantexternalotitis

Infectionsofthebonesandjoints

Treatmentofinfectionsinneutropenicpatients

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ProphylaxisofinvasiveinfectionsduetoNeisseriameningitidis

Inhalationanthrax(post-exposureprophylaxisandcurativetreatment)

Childrenandadolescents

Broncho-pulmonaryinfectionsincysticfibrosiscausedbyPseudomonasaeruginosa

Complicatedurinarytractinfectionsandpyelonephritis

Inhalationanthrax(post-exposureprophylaxisandcurativetreatment)

Ciprofloxacinmayalsobeusedtotreatsevereinfectionsinchildrenandadolescentswhenthisisconsideredtobe

necessary.

Treatmentshouldbeinitiatedonlybyphysicianswhoareexperiencedinthetreatmentofcysticfibrosisand/orsevere

infectionsinchildrenandadolescents(seesections4.4and5.1).

4.2Posologyandmethodofadministration

Thedosageisdeterminedbytheindication,theseverityandthesiteoftheinfection,thesusceptibilitytociprofloxacin

ofthecausativeorganism(s),therenalfunctionofthepatientand,inchildrenandadolescentsthebodyweight.

Thedurationoftreatmentdependsontheseverityoftheillnessandontheclinicalandbacteriologicalcourse.

Treatmentofinfectionsduetocertainbacteria(e.g.Pseudomonasaeruginosa,AcinetobacterorStaphylococci)may

requirehigherciprofloxacindosesandco-administrationwithotherappropriateantibacterialagents.

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

patientsandinfectionsofbonesandjoints)mayrequireco-administrationwithotherappropriateantibacterialagents

dependingonthepathogensinvolved.

Adults

Indications Dailydoseinmg Totaldurationof

treatment(potentially

includinginitial

parenteraltreatment

withciprofloxacin)

Infectionsofthelowerrespiratorytract 500mgtwicedaily

750mgtwicedaily 7to14days

Infectionsofthe

upperrespiratory

tract Acuteexacerbationof

chronicsinusitis 500mgtwicedaily

750mgtwicedaily 7to14days

Chronicsuppurative

otitismedia 500mgtwicedaily

750mgtwicedaily 7to14days

Malignantexternalotitis 750mgtwicedaily 28daysupto3months

Urinarytract

infections Uncomplicatedcystitis 250mgtwicedaily

500mgtwicedaily 3days

Inpre-menopausalwomen,500mgsingledose

maybeused

Complicatedcystitis,

Uncomplicated

pyelonephritis 500mgtwicedaily 7days

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pyelonephritis to

750mgtwicedaily continuedforlongerthan

21daysinsomespecific

circumstances(suchas

abscesses)

Prostatitis 500mgtwicedaily

750mgtwicedaily 2to4weeks(acute)

4to6weeks(chronic)

Genitaltract

infections Gonococcaluretritisand

cervicitis 500mgasasingle

dose 1day(singledose)

Epididymo-orchitisand

pelvicinflammatory

diseases 500mgtwicedaily

750mgtwicedaily atleast14days

Infectionsofthe

gastro-intestinal

tractand

intraabdominal

infections Diarrhoeacausedby

bacterialpathogens

including

Shigellaspp.otherthan

Shigelladysenteriaetype

1andempirical

treatmentofsevere

travellers’diarrhoea 500mgtwicedaily 1day

Diarrhoeacausedby

Shigelladysenteriaetype

500mgtwicedaily 5days

Diarrhoeacausedby

Vibriocholerae 500mgtwicedaily 3days

Typhoidfever 500mgtwicedaily 7days

Intra-abdominal

infectionsdueto

Gram-negativebacteria 500mgtwicedaily

750mgtwicedaily 5to14days

Infectionsoftheskinandsofttissue 500mgtwicedaily

750mgtwicedaily 7to14days

Boneandjointinfections 500mgtwicedaily

750mgtwicedaily max.of3months

Treatmentofinfectionsorprophylaxisof

infectionsinneutropenicpatients

Ciprofloxacinshouldbeco-administered

withappropriateantibacterialagent(s)in

accordancetoofficialguidance. 500mgtwicedaily

750mgtwicedaily Therapyshouldbe

continuedovertheentire

periodofneutropenia

Prophylaxisofinvasiveinfectionsdueto

Neisseriameningitidis 500mgasasingle

dose 1day(singledose)

Inhalationanthraxpost-exposureprophylaxis

andcurativetreatmentforpersonsableto

receivetreatmentbyoralroutewhen

clinicallyappropriate.Drugadministration

shouldbeginassoonaspossibleafter

suspectedorconfirmedexposure. 500mgtwicedaily 60daysfromthe

confirmationof

Bacillusanthracis

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Childrenandadolescents

Geriatricpatients

Geriatricpatientsshouldreceiveadoseselectedaccordingtotheseverityoftheinfectionandthepatient’screatinine

clearance.

Renalandhepaticimpairment

Recommendedstartingandmaintenancedosesforpatientswithimpairedrenalfunction:

Inpatientswithimpairedliverfunctionnodoseadjustmentisrequired.

Dosinginchildrenwithimpairedrenaland/orhepaticfunctionhasnotbeenstudied.

Methodofadministration

Tabletsaretobeswallowedunchewedwithfluid.Theycanbetakenindependentofmealtimes.Iftakenonanempty

stomach,theactivesubstanceisabsorbedmorerapidly.Ciprofloxacintabletsshouldnotbetakenwithdairyproducts

Indications Dailydoseinmg Totaldurationoftreatment

(potentiallyincludinginitial

parenteraltreatmentwith

ciprofloxacin)

Cysticfibrosis 20mg/kgbodyweighttwice

dailywithamaximumof750mg

perdose. 10to14days

Complicatedurinarytract

infectionsand

pyelonephritis 10mg/kgbodyweighttwice

dailyto20mg/kgbodyweight

twicedailywithamaximumof

750mgperdose. 10to21days

Inhalationanthraxpost-

exposureprophylaxisand

curativetreatmentfor

personsabletoreceive

treatmentbyoralroute

whenclinically

appropriate.Drug

administrationshould

beginassoonaspossible

aftersuspectedor

10mg/kgbodyweighttwice

dailyto15mg/kgbodyweight

twicedailywithamaximumof

500mgperdose. 60daysfromthe

confirmationofBacillus

anthracisexposure

Othersevereinfections 20mg/kgbodyweighttwice

dailywithamaximumof750mg

perdose. Accordingtothetypeof

infections

CreatinineClearance

[mL/min/1.73m²] SerumCreatinine

[µmol/L] OralDose

[mg]

>60 <124 SeeUsualDosage.

30-60 124to168 250-500mgevery12h

<30 >169 250-500mgevery24h

Patientsonhaemodialysis >169 250-500mgevery24h(afterdialysis)

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Inseverecasesorifthepatientisunabletotaketablets(e.g.patientsonenteralnutrition),itisrecommendedto

commencetherapywithintravenousciprofloxacinuntilaswitchtooraladministrationispossible.

4.3Contraindications

Hypersensitivitytotheactivesubstance,tootherquinolonesortoanyoftheexcipients(seesection6.1).

Concomitantadministrationofciprofloxacinandtizanidine(seesection4.5).

4.4Specialwarningsandprecautionsforuse

SevereinfectionsandmixedinfectionswithGram-positiveandanaerobicpathogens

CiprofloxacinmonotherapyisnotsuitedfortreatmentofsevereinfectionsandinfectionsthatmightbeduetoGram-

positiveoranaerobicpathogens.Insuchinfectionsciprofloxacinmustbeco-administeredwithotherappropriate

antibacterialagents.

StreptococcalInfections(includingStreptococcuspneumoniae)

Ciprofloxacinisnotrecommendedforthetreatmentofstreptococcalinfectionsduetoinadequateefficacy.

Genitaltractinfections

Epididymo-orchitisandpelvicinflammatorydiseasesmaybecausedbyfluoroquinolone-resistantNeisseria

gonorrhoeae.Ciprofloxacinshouldbeco-administeredwithanotherappropriateantibacterialagentunless

ciprofloxacin-resistantNeisseriagonorrhoeaecanbeexcluded.Ifclinicalimprovementisnotachievedafter3daysof

treatment,thetherapyshouldbereconsidered.

Intra-abdominalinfections

Therearelimiteddataontheefficacyofciprofloxacininthetreatmentofpost-surgicalintra-abdominalinfections.

Travellers’diarrhoea

Thechoiceofciprofloxacinshouldtakeintoaccountinformationonresistancetociprofloxacininrelevantpathogensin

thecountriesvisited.

Infectionsofthebonesandjoints

Ciprofloxacinshouldbeusedincombinationwithotherantimicrobialagentsdependingontheresultsofthe

microbiologicaldocumentation.

Inhalationalanthrax

Useinhumansisbasedonin-vitrosusceptibilitydataandonanimalexperimentaldatatogetherwithlimitedhuman

data.Treatingphysiciansshouldrefertonationaland/orinternationalconsensusdocumentsregardingthetreatmentof

anthrax.

Childrenandadolescents

Theuseofciprofloxacininchildrenandadolescentsshouldfollowavailableofficialguidance.Ciprofloxacintreatment

shouldbeinitiatedonlybyphysicianswhoareexperiencedinthetreatmentofcysticfibrosisand/orsevereinfectionsin

childrenandadolescents.

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Safetydatafromarandomiseddouble-blindstudyonciprofloxacinuseinchildren(ciprofloxacin:n=335,meanage=

6.3years;comparators:n=349,meanage=6.2years;agerange=1to17years)revealedanincidenceofsuspected

drug-relatedarthropathy(discernedfromjoint-relatedclinicalsignsandsymptoms)byDay+42of7.2%and4.6%.

Respectively,anincidenceofdrug-relatedarthropathyby1-yearfollow-upwas9.0%and5.7%.Theincreaseof

suspecteddrug-relatedarthropathycasesovertimewasnotstatisticallysignificantbetweengroups.Treatmentshould

beinitiatedonlyafteracarefulbenefit/riskevaluation,duetopossibleadverseeventsrelatedtojointsand/or

surroundingtissue.

Broncho-pulmonaryinfectionsincysticfibrosis

Clinicaltrialshaveincludedchildrenandadolescentsaged5-17years.Morelimitedexperienceisavailableintreating

childrenbetween1and5yearsofage.

Complicatedurinarytractinfectionsandpyelonephritis

Ciprofloxacintreatmentofurinarytractinfectionsshouldbeconsideredwhenothertreatmentscannotbeused,and

shouldbebasedontheresultsofthemicrobiologicaldocumentation.

Clinicaltrialshaveincludedchildrenandadolescentsaged1-17years.

Otherspecificsevereinfections

Othersevereinfectionsinaccordancewithofficialguidance,oraftercarefulbenefit-riskevaluationwhenother

treatmentscannotbeused,orafterfailuretoconventionaltherapyandwhenthemicrobiologicaldocumentationcan

justifyaciprofloxacinuse.

Theuseofciprofloxacinforspecificsevereinfectionsotherthanthosementionedabovehasnotbeenevaluatedin

clinicaltrialsandtheclinicalexperienceislimited.Consequently,cautionisadvisedwhentreatingpatientswiththese

infections.

Hypersensitivity

Hypersensitivityandallergicreactions,includinganaphylaxisandanaphylactoidreactions,mayoccurfollowinga

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

andanadequatemedicaltreatmentisrequired.

MusculoskeletalSystem

Ciprofloxacinshouldgenerallynotbeusedinpatientswithahistoryoftendondisease/disorderrelatedtoquinolone

treatment.Nevertheless,inveryrareinstances,aftermicrobiologicaldocumentationofthecausativeorganismand

evaluationoftherisk/benefitbalance,ciprofloxacinmaybeprescribedtothesepatientsforthetreatmentofcertain

severeinfections,particularlyintheeventoffailureofthestandardtherapyorbacterialresistance,wherethe

microbiologicaldatamayjustifytheuseofciprofloxacin.

Tendinitisandtendonrupture(especiallyAchillestendon),sometimesbilateral,mayoccurwithciprofloxacin,assoon

asthefirst48hoursoftreatment.Theriskoftendinopathymaybeincreasedinelderlypatientsorinpatients

concomitantlytreatedwithcorticosteroids(seesection4.8).

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

shouldbetakentokeeptheaffectedlimbatrest.

Ciprofloxacinshouldbeusedwithcautioninpatientswithmyastheniagravis(seesection4.8).

Photosensitivity

Ciprofloxacinhasbeenshowntocausephotosensitivityreactions.Patientstakingciprofloxacinshouldbeadvisedto

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CentralNervousSystem

Quinolonesareknowntotriggerseizuresorlowertheseizurethreshold.Ciprofloxacinshouldbeusedwithcautionin

patientswithCNSdisorders,whichmaybepredisposedtoseizure.Ifseizuresoccurciprofloxacinshouldbe

discontinued(seesection4.8).Psychiatricreactionsmayoccurevenafterthefirstadministrationofciprofloxacin.In

rarecases,depressionorpsychosiscanprogresstoselfendangeringbehaviour.Inthesecases,ciprofloxacinshouldbe

discontinued.

Casesofpolyneuropathy(basedonneurologicalsymptomssuchaspain,burning,sensorydisturbancesormuscle

weakness,aloneorincombination)havebeenreportedinpatientsreceivingciprofloxacin.

Ciprofloxacinshouldbediscontinuedinpatientsexperiencingsymptomsofneuropathy,includingpain,burning,

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

Cardiacdisorders

Cautionshouldbetakenwhenusingfluoroquinolones,includingciprofloxacin,inpatientswithknownriskfactorsfor

prolongationoftheQTintervalsuchas,forexample:

congenitallongQTsyndrome

concomitantuseofdrugsthatareknowntoprolongtheQTinterval(e.g.ClassIAandIIIanti-arrhythmics,

tricyclicantidepressants,macrolides,antipsychotics)

uncorrectedelectrolyteimbalance(e.g.hypokalaemia,hypomagnesaemia)

elderly

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

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

GastrointestinalSystem

Theoccurrenceofsevereandpersistentdiarrhoeaduringoraftertreatment(includingseveralweeksaftertreatment)

mayindicateanantibiotic-associatedcolitis(life-threateningwithpossiblefataloutcome),requiringimmediate

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

therapyinitiated.Anti-peristalticdrugsarecontraindicatedinthissituation.

Renalandurinarysystem

Crystalluriarelatedtotheuseofciprofloxacinhasbeenreported(seesection4.8).Patientsreceivingciprofloxacin

shouldbewellhydratedandexcessivealkalinityoftheurineshouldbeavoided.

Hepatobiliarysystem

Casesofhepaticnecrosisandlife-threateninghepaticfailurehavebeenreportedwithciprofloxacin(seesection4.8).In

theeventofanysignsandsymptomsofhepaticdisease(suchasanorexia,jaundice,darkurine,pruritus,ortender

abdomen),treatmentshouldbediscontinued.

Glucose-6-phosphatedehydrogenasedeficiency

Haemolyticreactionshavebeenreportedwithciprofloxacininpatientswithglucose-6-phosphatedehydrogenase

deficiency.Ciprofloxacinshouldbeavoidedinthesepatientsunlessthepotentialbenefitisconsideredtooutweighthe

possiblerisk.Inthiscase,potentialoccurrenceofhaemolysisshouldbemonitored.

Resistance

Duringorfollowingacourseoftreatmentwithciprofloxacinbacteriathatdemonstrateresistancetociprofloxacinmay

beisolated,withorwithoutaclinicallyapparentsuperinfection.Theremaybeaparticularriskofselectingfor

ciprofloxacin-resistantbacteriaduringextendeddurationsoftreatmentandwhentreatingnosocomialinfectionsand/or

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CytochromeP450

CiprofloxacininhibitsCYP1A2andthusmaycauseincreasedserumconcentrationofconcomitantlyadministered

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

ciprofloxacinandtizanidineiscontra-indicated.

Therefore,patientstakingthesesubstancesconcomitantlywithciprofloxacinshouldbemonitoredcloselyforclinical

signsofoverdose,anddeterminationofserumconcentrations(e.g.oftheophylline)maybenecessary(seesection4.5).

Methotrexate

Theconcomitantuseofciprofloxacinwithmethotrexateisnotrecommended(seesection4.5).

Interactionwithtests

Thein-vitroactivityofciprofloxacinagainstMycobacteriumtuberculosismightgivefalsenegativebacteriologicaltest

resultsinspecimensfrompatientscurrentlytakingciprofloxacin.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Effectsofotherproductsonciprofloxacin:

ChelationComplexFormation

Thesimultaneousadministrationofciprofloxacin(oral)andmultivalentcation-containingdrugsandmineral

supplements(e.g.calcium,magnesium,aluminium,iron),polymericphosphatebinders(e.g.sevelamer),sucralfateor

antacids,andhighlybuffereddrugs(e.g.didanosinetablets)containingmagnesium,aluminium,orcalciumreducesthe

absorptionofciprofloxacin.Consequently,ciprofloxacinshouldbeadministeredeither1-2hoursbeforeoratleast4

hoursafterthesepreparations.TherestrictiondoesnotapplytoantacidsbelongingtotheclassofH2receptorblockers.

FoodandDairyProducts

Dietarycalciumaspartofamealdoesnotsignificantlyaffectabsorption.However,theconcurrentadministrationof

dairyproductsormineral-fortifieddrinksalone(e.g.milk,yoghurt,calcium-fortifiedorangejuice)withciprofloxacin

shouldbeavoidedbecauseabsorptionofciprofloxacinmaybereduced.

Probenecid

Probenecidinterfereswithrenalsecretionofciprofloxacin.Co-administrationofprobenecidandciprofloxacin

increasesciprofloxacinserumconcentrations.

Effectsofciprofloxacinonothermedicinalproducts:

Tizanidine

Tizanidinemustnotbeadministeredtogetherwithciprofloxacin(seesection4.3).Inaclinicalstudywithhealthy

subjects,therewasanincreaseinserumtizanidineconcentration(C

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

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

concentrationisassociatedwithapotentiatedhypotensiveandsedativeeffect.

Methotrexate

Renaltubulartransportofmethotrexatemaybeinhibitedbyconcomitantadministrationofciprofloxacin,potentially

leadingtoincreasedplasmalevelsofmethotrexateandincreasedriskofmethotrexate-associatedtoxicreactions.The

concomitantuseisnotrecommended(seesection4.4).

Theophylline

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concentration.Thiscanleadtotheophylline-inducedsideeffectsthatmayrarelybelifethreateningorfatal.Duringthe

combination,serumtheophyllineconcentrationsshouldbecheckedandthetheophyllinedosereducedasnecessary(see

section4.4).

Otherxanthinederivatives

Onconcurrentadministrationofciprofloxacinandcaffeineorpentoxifylline(oxpentifylline),raisedserum

concentrationsofthesexanthinederivativeswerereported.

Phenytoin

Simultaneousadministrationofciprofloxacinandphenytoinmayresultinincreasedorreducedserumlevelsof

phenytoinsuchthatmonitoringofdruglevelsisrecommended.

Oralanticoagulants

Simultaneousadministrationofciprofloxacinwithwarfarinmayaugmentitsanti-coagulanteffects.Therehavebeen

manyreportsofincreasesinoralanticoagulantactivityinpatientsreceivingantibacterialagents,including

fluoroquinolones.Theriskmayvarywiththeunderlyinginfection,ageandgeneralstatusofthepatientsothatthe

contributionofthefluoroquinolonetotheincreaseinINR(internationalnormalisedratio)isdifficulttoassess.Itis

recommendedthattheINRshouldbemonitoredfrequentlyduringandshortlyafterco-administrationofciprofloxacin

withanoralanticoagulantagent.

Ropinirole

Itwasshowninaclinicalstudythatconcomitantuseofropinirolewithciprofloxacin,amoderateinhibitorofthe

CYP4501A2isozyme,resultsinanincreaseofC

andAUCofropiniroleby60%and84%,respectively.

Monitoringofropinirole-relatedsideeffectsanddoseadjustmentasappropriateisrecommendedduringandshortly

afterco-administrationwithciprofloxacin(seesection4.4).

Clozapine

Followingconcomitantadministrationof250mgciprofloxacinwithclozapinefor7days,serumconcentrationsof

clozapineandN-desmethylclozapinewereincreasedby29%and31%,respectively.Clinicalsurveillanceand

appropriateadjustmentofclozapinedosageduringandshortlyaftercoadministrationwithciprofloxacinareadvised

(seesection4.4).

DrugsknowntoprolongQTinterval

Ciprofloxacin,likeotherfluoroquinolones,shouldbeusedwithcautioninpatientsreceivingdrugsknowntoprolong

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

section4.4).

4.6Fertility,pregnancyandlactation

Pregnancy

Thedatathatareavailableonadministrationofciprofloxacintopregnantwomenindicatesnomalformativeor

feto/neonataltoxicityofciprofloxacin.Animalstudiesdonotindicatedirectorindirectharmfuleffectswithrespectto

reproductivetoxicity.Injuvenileandprenatalanimalsexposedtoquinolones,effectsonimmaturecartilagehavebeen

observed,thus,itcannotbeexcludedthatthedrugcouldcausedamagetoarticularcartilageinthehumanimmature

organism/foetus(seesection5.3).

Asaprecautionarymeasure,itispreferabletoavoidtheuseofciprofloxacinduringpregnancy.

Lactation

Ciprofloxacinisexcretedinbreastmilk.Duetothepotentialriskofarticulardamage,ciprofloxacinshouldnotbeused

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4.7Effectsonabilitytodriveandusemachines

Duetoitsneurologicaleffects,ciprofloxacinmayaffectreactiontime.Thus,theabilitytodriveortooperatemachinery

maybeimpaired.

4.8Undesirableeffects

Themostcommonlyreportedadversedrugreactions(ADRs)arenauseaanddiarrhoea.

ADRsderivedfromclinicalstudiesandpost-marketingsurveillancewithciprofloxacin(oral,intravenous,and

sequentialtherapy)sortedbycategoriesoffrequencyarelistedbelow.Thefrequencyanalysistakesintoaccountdata

frombothoralandintravenousadministrationofciprofloxacin.

SystemOrgan

Class Common

1/100

<1/10 Uncommon

1/1000

<1/100 Rare

1/10000

<1/1000 VeryRare

<1/10000 Frequency

notknown

(cannotbe

estimated

from

available

data)

Infectionsand

Infestations Mycotic

superinfections Antibiotic

associatedcolitis

(veryrarelywith

possiblefatal

outcome)(see

section4.4)

Bloodand

Lymphatic

System

Disorders Eosinophilia Leukopenia

Anaemia

Neutropenia

Leukocytosis

Thrombocytopenia

Thrombocytaemia Haemolytic

anaemia

Agranulocytosis

Pancytopenia

(lifethreatening)

Bonemarrow

depression

(lifethreatening)

Immune

System

Disorders Allergicreaction

Allergic

oedema/

angiooedema Anaphylactic

reaction

Anaphylactic

shock

(lifethreatening)

(seesection4.4)

Serumsickness

likereaction

Metabolism

and

Nutrition

Disorders Anorexia Hyperglycaemia

Psychiatric

Disorders Psychomotor

hyperactivity/

agitation Confusionand

disorientation

Anxietyreaction

Abnormal

dreams

Depression

Hallucinations Psychotic

reactions(see

section4.4)

Nervous

System Headache

Dizziness Par-and

Dysaesthesia Migraine

Disturbed Peripheral

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Disorders Sleepdisorders

Tastedisorders Hypoaesthesia

TremorSeizures

(seesection4.4)

Vertigo coordination

Gait

Disturbance

Olfactorynerve

disorders

Intracranial

hypertension (seesection

4.4)

EyeDisorders Visual

disturbances Visualcolour

Distortions

Earand

Labyrinth

Disorders Tinnitus

Hearingloss/

Hearing

impaired

Cardiac

Disorders Tachycardia Ventricular

arrhythmia

torsadesde

pointes*,

ECGQT

prolonged

(seesection

4.4and

4.9).

Vascular

Disorders Vasodilatation

Hypotension

Syncope Vasculitis

Respiratory,

Thoracicand

Mediastinal

Disorders Dyspnoea

(including

asthmatic

condition)

Gastrointestinal

Disorders Nausea

Diarrhoea Vomiting

Gastrointestinal

andabdominal

painsDyspepsia

Flatulence Pancreatitis

Hepatobiliary

Disorders Increasein

transaminases

Increased

bilirubin Hepatic

impairment

Cholestatic

icterus

Hepatitis Livernecrosis

(veryrarely

progressingto

life-threatening

hepaticfailure)

(seesection4.4)

Skinand

Subcutaneous

Tissue

Disorders Rash

Pruritus

Urticaria Photosensitivity

reactions(see

section4.4) Petechiae

Erythema

multiforme

Erythema

nodosum

Stevens-

Johnson

syndrome

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*reportedpredominantlyinpatientswithriskfactorsforQTprolongation.

Paediatricpatients

Theincidenceofarthropathy,mentionedabove,isreferringtodatacollectedinstudieswithadults.Inchildren,

arthropathyisreportedtooccurcommonly(seesection4.4).

4.9Overdose

Anoverdoseof12ghasbeenreportedtoleadtomildsymptomsoftoxicity.Anacuteoverdoseof16ghasbeen

reportedtocauseacuterenalfailure.

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

discomfort,renalandhepaticimpairmentaswellascrystalluriaandhaematuria.Reversiblerenaltoxicityhasbeen

reported.

Intheeventofoverdose,symptomatictreatmentshouldbeimplemented.ECGmonitoringshouldbeundertaken,

becauseofthepossibilityofQTintervalprolongation.

Apartfromroutineemergencymeasures,itisrecommendedtomonitorrenalfunction,includingurinarypHand

lifethreatening)

Toxic

epidermal

necrolysis

(potentially

lifethreatening)

Musculoskeletal,

Connective

Tissueand

Bone

Disorders Musculoskeletal

pain(e.g.

extremitypain,

backpain,chest

pain)Arthralgia Myalgia

Arthritis

Increasedmuscle

toneand

cramping 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

Site

Conditions Asthenia

Fever Oedema

Sweating

(hyperhidrosis)

Investigations Increasein

bloodalkaline

phosphatase Prothrombin

levelabnormal

Increased

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Onlyasmallquantityofciprofloxacin(<10%)iseliminatedbyhaemodialysisorperitonealdialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Fluoroquinolones,ATCcode:J01MA02

Mechanismofaction:

Asafluoroquinoloneantibacterialagent,thebactericidalactionofciprofloxacinresultsfromtheinhibitionofbothtype

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

recombination.

PK/PDrelationship:

Efficacymainlydependsontherelationbetweenthemaximumconcentrationinserum(C

)andtheminimum

inhibitoryconcentration(MIC)ofciprofloxacinforabacterialpathogenandtherelationbetweentheareaunderthe

curve(AUC)andtheMIC.

Mechanismofresistance:

In-vitroresistancetociprofloxacincanbeacquiredthroughastepwiseprocessbytargetsitemutationsinbothDNA

gyraseandtopoisomeraseIV.Thedegreeofcross-resistancebetweenciprofloxacinandotherfluoroquinolonesthat

resultsisvariable.Singlemutationsmaynotresultinclinicalresistance,butmultiplemutationsgenerallyresultin

clinicalresistancetomanyorallactivesubstanceswithintheclass.

Impermeabilityand/oractivesubstanceeffluxpumpmechanismsofresistancemayhaveavariableeffecton

susceptibilitytofluoroquinolones,whichdependsonthephysiochemicalpropertiesofthevariousactivesubstances

withintheclassandtheaffinityoftransportsystemsforeachactivesubstance.Allin-vitromechanismsofresistance

arecommonlyobservedinclinicalisolates.Resistancemechanismsthatinactivateotherantibioticssuchaspermeation

barriers(commoninPseudomonasaeruginosa)andeffluxmechanismsmayaffectsusceptibilitytociprofloxacin.

Plasmid-mediatedresistanceencodedbyqnr-geneshasbeenreported.

Spectrumofantibacterialactivity:

Breakpointsseparatesusceptiblestrainsfromstrainswithintermediatesusceptibilityandthelatterfromresistant

strains:

EUCASTRecommendations

Microorganisms Susceptible Resistant

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

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

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

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

Haemophilusinfluenzaeand

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

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

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

Non-species-related

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*Non-species-relatedbreakpointshavebeendeterminedmainlyonthebasisofPK/PDdataandareindependentof

MICdistributionsofspecificspecies.Theyareforuseonlyforspeciesthathavenotbeengivenaspecies-specific

breakpointandnotforthosespecieswheresusceptibilitytestingisnotrecommended.

Theprevalenceofacquiredresistancemayvarygeographicallyandwithtimeforselectedspeciesandlocalinformation

onresistanceisdesirable,particularlywhentreatingsevereinfections.Asnecessary,expertadviceshouldbesought

whenthelocalprevalenceofresistanceissuchthattheutilityoftheagentinatleastsometypesofinfectionsis

questionable.

Groupingsofrelevantspeciesaccordingtociprofloxacinsusceptibility(forStreptococcusspeciesseesection4.4)

COMMONLYSUSCEPTIBLESPECIES

AerobicGram-positivemicro-organisms

Bacillusanthracis(1)

AerobicGram-negativemicro-organisms

Aeromonasspp.

Brucellaspp.

Citrobacterkoseri

Francisellatularensis

Haemophilusducreyi

Haemophilusinfluenzae*

Legionellaspp.

Moraxellacatarrhalis*

Neisseriameningitidis

Pasteurellaspp.

Salmonellaspp.*

Shigellaspp.*

Vibriospp.

Yersiniapestis

Anaerobicmicro-organisms

Mobiluncus

Othermicro-organisms

Chlamydiatrachomatis($)

Chlamydiapneumoniae($)

Mycoplasmahominis($)

Mycoplasmapneumoniae($)

SPECIESFORWHICHACQUIREDRESISTANCEMAYBEAPROBLEM

AerobicGram-positivemicro-organisms

Enterococcusfaecalis($)

Staphylococcusspp.*(2)

AerobicGram-negativemicro-organisms

Acinetobacterbaumannii +

Burkholderiacepacia +

*

Campylobacterspp. +

*

Citrobacterfreundii*

Enterobacteraerogenes

Enterobactercloacae*

Escherichiacoli*

Klebsiellaoxytoca

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5.2Pharmacokineticproperties

Absorption

Followingoraladministrationofsingledosesof250mg,500mg,and750mgofciprofloxacintablets,ciprofloxacinis

absorbedrapidlyandextensively,mainlyfromthesmallintestine,reachingmaximumserumconcentrations1-2hours

later.

Singledosesof100-750mgproduceddose-dependentmaximumserumconcentrations(C

)between0.56and3.7

mg/L.Serumconcentrationsincreaseproportionatelywithdosesupto1000mg.

Morganellamorganii*

Neisseriagonorrhoeae*

Proteusmirabilis*

Proteusvulgaris*

Providenciaspp.

Pseudomonasaeruginosa*

Pseudomonasfluorescens

Serratiamarcescens*

Anaerobicmicro-organisms

Peptostreptococcusspp.

Propionibacteriumacnes

INHERENTLYRESISTANTORGANISMS

AerobicGram-positivemicro-organisms

Actinomyces

Enterococcusfaecium

Listeriamonocytogenes

AerobicGram-negativemicro-organisms

Stenotrophomonasmaltophilia

Anaerobicmicro-organisms

Exceptedaslistedabove

Othermicro-organisms

Mycoplasmagenitalium

Ureaplasmaurealitycum

*Clinicalefficacyhasbeendemonstratedforsusceptibleisolatesinapprovedclinical

indications

Resistancerate 50%inoneormoreEUcountries

($):Naturalintermediatesusceptibilityintheabsenceofacquiredmechanismofresistance

(1):Studieshavebeenconductedinexperimentalanimalinfectionsduetoinhalationsof

Bacillusanthracisspores;thesestudiesrevealthatantibioticsstartingearlyafterexposition

avoidtheoccurrenceofthediseaseifthetreatmentismadeuptothedecreaseofthenumber

ofsporesintheorganismundertheinfectivedose.Therecommendeduseinhumansubjects

isbasedprimarilyonin-vitrosusceptibilityandonanimalexperimentaldatatogetherwith

limitedhumandata.Two-monthtreatmentdurationinadultswithoralciprofloxacingivenat

thefollowingdose,500mgbid,isconsideredaseffectivetopreventanthraxinfectionin

humans.Thetreatingphysicianshouldrefertonationaland/orinternationalconsensus

documentsregardingtreatmentofanthrax.

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

Therateofresistancetomethicillinisaround20to50%amongallstaphylococcalspecies

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A500mgoraldosegivenevery12hourshasbeenshowntoproduceanareaundertheserumconcentration-timecurve

(AUC)equivalenttothatproducedbyanintravenousinfusionof400mgciprofloxacingivenover60minutesevery12

hours.

Distribution

Proteinbindingofciprofloxacinislow(20-30%).Ciprofloxacinispresentinplasmalargelyinanonionisedformand

hasalargesteadystatedistributionvolumeof2-3L/kgbodyweight.

Ciprofloxacinreacheshighconcentrationsinavarietyoftissuessuchaslung(epithelialfluid,alveolarmacrophages,

biopsytissue),sinuses,inflamedlesions(cantharidesblisterfluid),andtheurogenitaltract(urine,prostate,

endometrium)wheretotalconcentrationsexceedingthoseofplasmaconcentrationsarereached.

Metabolism

Lowconcentrationsoffourmetaboliteshavebeenreported,whichwereidentifiedas:

desethyleneciprofloxacin(M1),sulphociprofloxacin(M2),oxociprofloxacin(M3)andformylciprofloxacin(M4).

Themetabolitesdisplayin-vitroantimicrobialactivitybuttoalowerdegreethantheparentcompound.

CiprofloxacinisknowntobeamoderateinhibitoroftheCYP4501A2iso-enzymes.

Elimination

Ciprofloxacinislargelyexcretedunchangedbothrenallyand,toasmallerextent,faecally.Theserumeliminationhalf-

lifeinsubjectswithnormalrenalfunctionisapproximately4-7hours.

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

undergoesbothglomerularfiltrationandtubularsecretion.Severelyimpairedrenalfunctionleadstoincreasedhalf

livesofciprofloxacinofupto12h.

Non-renalclearanceofciprofloxacinismainlyduetoactivetrans-intestinalsecretionandmetabolism.

1%ofthedoseisexcretedviathebiliaryroute.Ciprofloxacinispresentinthebileinhighconcentrations.

Paediatricpatients

Thepharmacokineticdatainpaediatricpatientsarelimited.

InastudyinchildrenC

andAUCwerenotage-dependent(aboveoneyearofage).NonotableincreaseinC

AUCuponmultipledosing(10mg/kgthreetimesdaily)wasobserved.

In10childrenwithseveresepsisC

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

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

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

mg*h/L)intherespectiveagegroups.

Thesevaluesarewithintherangereportedforadultsattherapeuticdoses.Basedonpopulationpharmacokinetic

analysisofpaediatricpatientswithvariousinfections,thepredictedmeanhalf-lifeinchildrenisapprox.4-5hoursand

Excretionofciprofloxacin(%ofdose)

OralAdministration

Urine Faeces

Ciprofloxacin 44.7 25.0

Metabolites(M

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5.3Preclinicalsafetydata

Non-clinicaldatarevealnospecialhazardsforhumansbasedonconventionalstudiesofsingledosetoxicity,repeated

dosetoxicity,carcinogenicpotential,ortoxicitytoreproduction.

Likeanumberofotherquinolones,ciprofloxacinisphototoxicinanimalsatclinicallyrelevantexposurelevels.Data

onphotomutagenicity/photocarcinogenicityshowaweakphotomutagenicorphototumorigeniceffectofciprofloxacin

in-vitroandinanimalexperiments.Thiseffectwascomparabletothatofothergyraseinhibitors.

Articulartolerability:

Asreportedforothergyraseinhibitors,ciprofloxacincausesdamagetothelargeweight-bearingjointsinimmature

animals.Theextentofthecartilagedamagevariesaccordingtoage,speciesanddose;thedamagecanbereducedby

takingtheweightoffthejoints.Studieswithmatureanimals(rat,dog)revealednoevidenceofcartilagelesions.Ina

studyinyoungbeagledogs,ciprofloxacincausedseverearticularchangesattherapeuticdosesaftertwoweeksof

treatment,whichwerestillobservedafter5months.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Cellulose,microcrystalline

Sodiumstarchglycolate(TypeA)

Povidone(K30)

Silicacolloidalanhydrous

Magnesiumstearate

Filmcoating:

Hypromellose

Macrogol(400)

Titaniumdioxide

6.2Incompatibilities

Notapplicable.

6.3Shelflife

4years

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions

6.5Natureandcontentsofcontainer

PVC/PVdC-Aluminiumfoilblisterspackedincarton.

Packsizes:6,10,12,14,16,20,28,50,100and120film-coatedtablets

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

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7MARKETINGAUTHORISATIONHOLDER

PfizerHealthcareIreland

9Riverwalk

NationalDigitalPark

CitywestBusinessCampus

Dublin24

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA822/28/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:8thJuly2011

10DATEOFREVISIONOFTHETEXT

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