CIPLOX

Main information

  • Trade name:
  • CIPLOX Film Coated Tablet 100 Base Milligrams
  • Dosage:
  • 100 Base Milligrams
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CIPLOX Film Coated Tablet 100 Base Milligrams
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1380/049/001
  • Authorization date:
  • 16-05-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995,asamended

MedicinalProducts(ControlofPlacingontheMarket)Regulations,2007,asamended

PA1380/049/001

CaseNo:2067491

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

ActavisGroupPTCehf

Reykjavikurvegi76-78,220Hafnarfjordur,Iceland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Ciplox100mgFilm-coatedTablets

theparticularsofwhicharesetoutintheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsasmaybespecifiedin

thesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom02/07/2009.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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Date Printed 15/06/2010 CRN 2067491 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Ciplox100mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontainsciprofloxacin100mgasthehydrochloride.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Whiteoryellowish,8mmround,biconvex,filmcoatedtabletsmarked‘C100’.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Ciprofloxacintabletsareindicatedforthetreatmentofthefollowinginfections(seesection4.4and5.1).Special

attentionshouldbepaidtoavailableinformationonresistancetociprofloxacinbeforecommencingtherapy.

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantibacterialagents.

Adults

LowerrespiratorytractinfectionsduetoGram-negativebacteria

-exacerbationsofchronicobstructivepulmonarydisease

-broncho-pulmonaryinfectionsincysticfibrosisorinbronchiectasis

-pneumonia

Chronicsuppurativeotitismedia

AcuteexacerbationofchronicsinusitisespeciallyifthesearecausedbyGram-negativebacteria

Urinarytractinfections

Gonococcaluretritisandcervicitis

Epididymo-orchitisincludingcasesduetoNeisseriagonorrhoeae

PelvicinflammatorydiseaseincludingcasesduetoNeisseriagonorrhoeae

IntheabovegenitaltractinfectionswhenthoughtorknowntobeduetoNeisseriagonorrhoeaeitis

particularlyimportanttoobtainlocalinformationontheprevalenceofresistancetociprofloxacinand

toconfirmsusceptibilitybasedonlaboratorytesting.

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

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InfectionsoftheskinandsofttissuecausedbyGram-negativebacteria

Malignantexternalotitis

Infectionsofthebonesandjoints

Treatmentofinfectionsinneutropenicpatients

Prophylaxisofinfectionsinneutropenicpatients

ProphylaxisofinvasiveinfectionsduetoNeisseriameningitides

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 Totaldurationoftreatment

(potentiallyincludinginitial

parenteraltreatmentwith

ciprofloxacin)

Infectionsofthelowerrespiratorytract 500mgtwicedailyto

750mgtwicedaily 7to14days

Infectionsofthe

upperrespiratory

tract Acuteexacerbationof

chronicsinusitis 500mgtwicedailyto

750mgtwicedaily 7to14days

Chronicsuppurative

otitismedia 500mgtwicedailyto

750mgtwicedaily 7to14days

Malignantexternal

otitis 750mgtwicedaily 28daysupto3months

Urinarytract

infections Uncomplicatedcystitis 250mgtwicedailyto

500mgtwicedaily 3days

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Complicatedcystitis,

Uncomplicated

pyelonephritis 500mgtwicedaily 7days

Complicated

pyelonephritis 500mgtwicedailyto

750mgtwicedaily Atleast10days,itcanbecontinued

forlongerthan21daysinsome

specificcircumstances(suchas

abscesses)

Prostatitis 500mgtwicedailyto

750mgtwicedaily 2to4weeks(acute)to4to6weeks

(chronic)

Genitaltract

infections Gonococcaluretritis

andcervicitis 500mgasasingle

dose 1day(singledose)

Epididymo-orchitisand

pelvicinflammatory

diseases 500mgtwicedailyto

750mgtwicedaily Atleast14days

Infectionsofthe

gastro-intestinal

tractandintra-

abdominal

infections Diarrhoeacausedby

bacterialpathogens

includingShigellaspp.

otherthanShigella

dysenteriaetype1and

empiricaltreatmentof

severetravellers’

diarrhoea 500mgtwicedaily 1day

Diarrhoeacausedby

Shigelladysenteriae

type1 500mgtwicedaily 5days

Diarrhoeacausedby

Vibriocholerae 500mgtwicedaily 3days

Typhoidfever 500mgtwicedaily 7days

Intra-abdominal

infectionsduetoGram-

negativebacteria 500mgtwicedailyto

750mgtwicedaily 5to14days

Infectionsoftheskinandsofttissue 500mgtwicedailyto

750mgtwicedaily 7to14days

Boneandjointinfections 500mgtwicedailyto

750mgtwicedaily Max.of3months

Treatmentofinfectionsorprophylaxisof

infectionsinneutropenicpatients.

Ciprofloxacinshouldbeco-administered

withappropriateantibacterialagent(s)in

accordancetoofficialguidance. 500mgtwicedailyto

750mgtwicedaily Therapyshouldbecontinuedover

theentireperiodofneutropenia

Prophylaxisofinvasiveinfectionsdueto

Neisseriameningitidis 500mgasasingle

dose 1day(singledose)

Inhalationanthraxpost-exposure

prophylaxisandcurativetreatmentfor

personsabletoreceivetreatmentbyoral

routewhenclinicallyappropriate.

Drugadministrationshouldbeginassoon

aspossibleaftersuspectedorconfirmed

exposure. 500mgtwicedaily 60daysfromtheconfirmationof

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Childrenandadolescents

Geriatricpatients

Geriatricpatientsshouldreceiveadoseselectedaccordingtotheseverityoftheinfectionandthepatient’screatinine

clearance.

Renalandhepaticimpairment

Recommendedstartingandmaintenancedosesforpatientswithimpairedrenalfunction:

CreatinineClearance SerumCreatinine OralDose

[mL/min/1.73m 2 ] [µmol/L] [mg]

>60 <124 SeeUsualDosage

30-60 124to168 250-500mgevery12h

<30 >169 250-500mgevery24h

Patientsofhaemodialysis >169 250-500mgevery24h

(afterdialysis)

Patientsonperitonealdialysis >169 250-500mgevery24h

Inpatientswithimpairedliverfunctionnodoseadjustmentisrequired.

Dosinginchildrenwithimpairedrenaland/orhepaticfunctionhasnotbeenstudied.

Methodofadministration

Tabletsaretobeswallowedunchewedwithfluid.Theycanbetakenindependentofmealtimes.Iftakenonanempty

stomach,theactivesubstanceisabsorbedmorerapidly.Ciprofloxacintabletsshouldnotbetakenwithdairyproducts

Indications Dailydoseinmg Totaldurationoftreatment

(potentiallyincludinginitial

parenteraltreatmentwith

ciprofloxacin)

Cysticfibrosis 20mg/kgbodyweighttwice

dailywithamaximumof750

mgperdose 10to14days

Complicatedurinarytract

infectionsandpyelonephritis 10mg/kgbodyweighttwice

dailyto20mg/kgbodyweight

twicedailywithamaximumof

750mgperdose. 10to21days

Inhalationanthraxpost-exposure

prophylaxisandcurative

treatmentforpersonsableto

receivetreatmentbyoralroute

whenclinicallyappropriate.

Drugadministrationshould

beginassoonaspossibleafter

suspectedorconfirmed

10mg/kgbodyweighttwice

dailyto15mg/kgbodyweight

twicedailywithamaximumof

500mgperdose. 60daysfromtheconfirmationof

Bacillusanthracisexposure

Othersevereinfections 20mg/kgbodyweighttwice

dailywithamaximumof750

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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.Insuchinfectionsciprofloxacinmustbecoadministeredwithotherappropriate

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.

Ciprofloxacintreatmentshouldbeinitiatedonlybyphysicianswhoareexperiencedinthetreatmentofcysticfibrosis

and/orsevereinfectionsinchildrenandadolescents.

Ciprofloxacinhasbeenshowntocausearthropathyinweight-bearingjointsofimmatureanimals.Safetydatafroma

randomiseddouble-blindstudyonciprofloxacinuseinchildren(ciprofloxacin:n=335,meanage=6.3years;

comparators:n=349,meanage=6.2years;agerange=1to17years)revealedanincidenceofsuspecteddrug-related

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

incidenceofdrug-relatedarthropathyby1-yearfollow-upwas9.0%and5.7%.Theincreaseofsuspecteddrug-related

arthropathycasesovertimewasnotstatisticallysignificantbetweengroups.Treatmentshouldbeinitiatedonlyaftera

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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

avoiddirectexposuretoeitherextensivesunlightorUVirradiationduringtreatment(seesection4.8).

CentralNervousSystem

Quinolonesareknowntotriggerseizuresorlowertheseizurethreshold.Ciprofloxacinshouldbeusedwithcautionin

patientswithCNSdisorderswhichmaybepredisposedtoseizure.Ifseizuresoccurciprofloxacinshouldbe

discontinued(seesection4.8).Psychiatricreactionsmayoccurevenafterthefirstadministrationofciprofloxacin.In

rarecases,depressionorpsychosiscanprogresstoselfendangeringbehaviour.Inthesecases,ciprofloxacinshouldbe

discontinued.

Casesofpolyneuropathy(basedonneurologicalsymptomssuchaspain,burning,sensorydisturbancesormuscle

weakness,aloneorincombination)havebeenreportedinpatientsreceivingciprofloxacin.Ciprofloxacinshouldbe

discontinuedinpatientsexperiencingsymptomsofneuropathy,includingpain,burning,tingling,numbness,and/or

weaknessinordertopreventthedevelopmentofanirreversiblecondition(seesection4.8).

Cardiacdisorders

SinceciprofloxacinisassociatedwithcasesofQTprolongation(seesection4.8),cautionshouldbeexercisedwhen

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GastrointestinalSystem

Theoccurrenceofsevereandpersistentdiarrhoeaduringoraftertreatment(includingseveralweeksaftertreatment)

mayindicateanantibiotic-associatedcolitis(life-threateningwithpossiblefataloutcome),requiringimmediate

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

therapyinitiated.Anti-peristalticdrugsarecontraindicatedinthissituation.

Renalandurinarysystem

Crystalluriarelatedtotheuseofciprofloxacinhasbeenreported(seesection4.8).Patientsreceivingciprofloxacin

shouldbewellhydratedandexcessivealkalinityoftheurineshouldbeavoided.

Hepatobiliarysystem

Casesofhepaticnecrosisandlife-threateninghepaticfailurehavebeenreportedwithciprofloxacin(seesection4.8).In

theeventofanysignsandsymptomsofhepaticdisease(suchasanorexia,jaundice,darkurine,pruritus,ortender

abdomen),treatmentshouldbediscontinued.

Glucose-6-phosphatedehydrogenasedeficiency

Haemolyticreactionshavebeenreportedwithciprofloxacininpatientswithglucose-6-phosphatedehydrogenase

deficiency.Ciprofloxacinshouldbeavoidedinthesepatientsunlessthepotentialbenefitisconsideredtooutweighthe

possiblerisk.Inthiscase,potentialoccurrenceofhaemolysisshouldbemonitored.

Resistance

Duringorfollowingacourseoftreatmentwithciprofloxacinbacteriathatdemonstrateresistancetociprofloxacinmay

beisolated,withorwithoutaclinicallyapparentsuperinfection.Theremaybeaparticularriskofselectingfor

ciprofloxacin-resistantbacteriaduringextendeddurationsoftreatmentandwhentreatingnosocomialinfectionsand/or

infectionscausedbyStaphylococcusandPseudomonasspecies.

CytochromeP450

CiprofloxacininhibitsCYP1A2andthusmaycauseincreasedserumconcentrationofconcomitantlyadministered

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

ciprofloxacinandtizanidineiscontra-indicated.Therefore,patientstakingthesesubstancesconcomitantlywith

ciprofloxacinshouldbemonitoredcloselyforclinicalsignsofoverdose,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

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

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

concentrationisassociatedwithapotentiatedhypotensiveandsedativeeffect.

Methotrexate

Renaltubulartransportofmethotrexatemaybeinhibitedbyconcomitantadministrationofciprofloxacin,potentially

leadingtoincreasedplasmalevelsofmethotrexateandincreasedriskofmethotrexate-associatedtoxicreactions.The

concomitantuseisnotrecommended(seesection4.4).

Theophylline

Concurrentadministrationofciprofloxacinandtheophyllinecancauseanundesirableincreaseinserumtheophylline

concentration.Thiscanleadtotheophylline-inducedsideeffectsthatmayrarelybelifethreateningorfatal.Duringthe

combination,serumtheophyllineconcentrationsshouldbecheckedandthetheophyllinedosereducedasnecessary(see

section4.4).

Otherxanthinederivatives

Onconcurrentadministrationofciprofloxacinandcaffeineorpentoxifylline(oxpentifylline),raisedserum

concentrationsofthesexanthinederivativeswerereported.

Phenytoin

Simultaneousadministrationofciprofloxacinandphenytoinmayresultinincreasedorreducedserumlevelsof

phenytoinsuchthatmonitoringofdruglevelsisrecommended.

Oralanticoagulants

Simultaneousadministrationofciprofloxacinwithwarfarinmayaugmentitsanti-coagulanteffects.Therehavebeen

manyreportsofincreasesinoralanticoagulantactivityinpatientsreceivingantibacterialagents,including

fluoroquinolones.Theriskmayvarywiththeunderlyinginfection,ageandgeneralstatusofthepatientsothatthe

contributionofthefluoroquinolonetotheincreaseinINR(internationalnormalisedratio)isdifficulttoassess.Itis

recommendedthattheINRshouldbemonitoredfrequentlyduringandshortlyafterco-administrationofciprofloxacin

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Ropinirole

Itwasshowninaclinicalstudythatconcomitantuseofropinirolewithciprofloxacin,amoderateinhibitorofthe

CYP4501A2isozyme,resultsinanincreaseofCmaxandAUCofropiniroleby60%and84%,respectively.

Monitoringofropinirole-relatedsideeffectsanddoseadjustmentasappropriateisrecommendedduringandshortly

afterco-administrationwithciprofloxacin(seesection4.4).

Clozapine

Followingconcomitantadministrationof250mgciprofloxacinwithclozapinefor7days,serumconcentrationsof

clozapineandN-desmethylclozapinewereincreasedby29%and31%,respectively.Clinicalsurveillanceand

appropriateadjustmentofclozapinedosageduringandshortlyaftercoadministrationwithciprofloxacinareadvised

(seesection4.4).

4.6Pregnancyandlactation

Pregnancy

Thedatathatareavailableonadministrationofciprofloxacintopregnantwomenindicatesnomalformativeor

feto/neonataltoxicityofciprofloxacin.Animalstudiesdonotindicatedirectorindirectharmfuleffectswithrespectto

reproductivetoxicity.Injuvenileandprenatalanimalsexposedtoquinolones,effectsonimmaturecartilagehavebeen

observed,thus,itcannotbeexcludedthatthedrugcouldcausedamagetoarticularcartilageinthehumanimmature

organism/foetus(seesection5.3).

Asaprecautionarymeasure,itispreferabletoavoidtheuseofciprofloxacinduringpregnancy.

Lactation

Ciprofloxacinisexcretedinbreastmilk.Duetothepotentialriskofarticulardamage,ciprofloxacinshouldnotbeused

duringbreast-feeding.

4.7Effectsonabilitytodriveandusemachines

Duetoitsneurologicaleffects,ciprofloxacinmayaffectreactiontime.Thus,theabilitytodriveortooperate

machinerymaybeimpaired.

4.8Undesirableeffects

Themostcommonlyreportedadversedrugreactions(ADRs)arenauseaanddiarrhoea.

ADRsderivedfromclinicalstudiesandpost-marketingsurveillancewithciprofloxacin(oral,intravenous,and

sequentialtherapy)sortedbycategoriesoffrequencyarelistedbelow.Thefrequencyanalysistakesintoaccountdata

frombothoralandintravenousadministrationofciprofloxacin.

SystemOrgan

Class Common

≥1/100

to<1/10 Uncommon

≥1/1000to

<1/100 Rare

≥1/10000to

<1/1000 VeryRare

<1/10000 Frequencynot

known

(cannotbe

estimatedfrom

availabledata)

Infectionsand

Infestations Mycotic

superinfections Antibioticassociated

colitis(veryrarely

withpossiblefatal

outcome)(seesection

4.4)

Bloodand

Lymphatic

SystemDisorders Eosinophilia Leukopenia

Anaemia

Neutropenia Haemolytic

anaemia

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Leukocytosis

Thrombocytopenia

Thrombocytaemia Pancytopenia

(life-

threatening)

Bonemarrow

depression(life-

threatening)

ImmuneSystem

Disorders Allergicreaction

Allergicoedema/

angiooedema Anaphylactic

reaction

Anaphylactic

shock(life-

threatening)(see

section4.4)

Serumsickness-

likereaction

Metabolismand

Nutrition

Disorders Anorexia Hyperglycaemia

Psychiatric

Disorders Psychomotor

hyperactivity/

agitation Confusionand

disorientation

Anxietyreaction

Abnormaldreams

Depression

Hallucinations Psychotic

reactions(see

section4.4)

NervousSystem

Disorders Headache

Diziness

SleepDisorders

TasteDisorders Par-andDysaesthesia

Hypoaesthesia

Tremor

Seizures(seesection

4.4)

Vertigo Migraine

Disturbed

coordination

Gaitdisturbance

Olfactorynerve

disorders

Intracranial

hypertension Peripheral

neuropathy(see

section4.4)

EyeDisorders Visualdisturbances Visualcolour

distortions

Earand

Labyrinth

Disorders Tinnitus

Hearingloss/Hearing

impaired

Cardiac

Disorders Tachycardia Ventricular

arrhythmia,QT

prolongation,

tosadesde

pointes*

Vascular

Disorders Vasodilatation

Hypotension

Syncope Vasculitis

Respiratory,

Thoracicand

Medistinal

Disorders Dyspnoea(including

asthmaticcondition)

Gastrointestinal

Disorders Nausea

Diarrhoea Vomiting

Gastrointestinal

andabdominal

pains

Dyspepsia

Flatulence Pancreatitis

Hepatobillary

Disorders Increasein

transaminases Hepaticimpairment

Cholestaticicterus Livernecrosis

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*Theseeventswerereportedduringthepostmarketingperiodandwereobservedpredominantlyamongpatientswith

furtherriskfactorsforQTprolongation(seesection4.4).

Paediatricpatients

Theincidenceofarthropathy,mentionedabove,isreferringtodatacollectedinstudieswithadults.Inchildren,

arthropathyisreportedtooccurcommonly(seesection4.4).

4.9Overdose

Anoverdoseof12ghasbeenreportedtoleadtomildsymptomsoftoxicity.Anacuteoverdoseof16ghasbeen

Increased

bilirubin Hepatitis progressingto

life-threatening

hepaticfailure)

(seesection4.4)

Skinand

Subcutaneous

TissueDisorders Rash

Pruritus

Urticaria Photosensitivity

reactions(seesection

4.4) Petechiae

Erythema

multiforme

Erythema

nodosum

Stevens-Johnson

syndrome

(potentiallylife-

threatening)

Toxicepidermal

necrolysis

(potentiallylife-

threatening)

Musculoskeletal,

ConnectiveTissue

andBone

Disorders Musculoskeletal

pain(e.g.

extremitypain,

backpain,chest

pain)

Arthralgia Myalgia

Arthritis

Increasedmuscletone

andcramping Muscular

weakness

Tendinitis

Tendonrupture

(predominantly

Achillestendon)

(seesection4.4)

Exacerbationof

symptomsof

myasthenia

gravis(see

section4.4)

Renaland

Urinary

Disorders Renal

impairment Renalfailure

Haematuria

Crystalluria(see

section4.4)

Tubulointerstitial

nephritis

General

Disordersand

Administration

SiteConditions Asthenia

Fever Oedema

Sweating

(hyperhidrosis)

Investigations Increasein

bloodalkaline

phosphatase Prothrombinlevel

abnormal

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

discomfort,renalandhepaticimpairmentaswellascrystalluriaandhaematuria.Reversiblerenaltoxicityhasbeen

reported.

Apartfromroutineemergencymeasures,itisrecommendedtomonitorrenalfunction,includingurinarypHand

acidify,ifrequired,topreventcrystalluria.Patientsshouldbekeptwellhydrated.Onlyasmallquantityof

ciprofloxacin(<10%)iseliminatedbyhaemodialysisorperitonealdialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Fluoroquinolones,ATCcode:J01MA02

Mechanismofaction:

Asafluoroquinoloneantibacterialagent,thebactericidalactionofciprofloxacinresultsfromtheinhibitionofbothtype

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

recombination.

PK/PDrelationship:

Efficacymainlydependsontherelationbetweenthemaximumconcentrationinserum(Cmax)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

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1Staphylococcusspp.–breakpointsforciprofloxacinrelatetohighdosetherapy.

*Non-species-relatedbreakpointshavebeendeterminedmainlyonthebasisofPK/PDdataandareindependentof

MICdistributionsofspecificspecies.Theyareforuseonlyforspeciesthathavenotbeengivenaspecies-specific

breakpointandnotforthosespecieswheresusceptibilitytestingisnotrecommended.

Theprevalenceofacquiredresistancemayvarygeographicallyandwithtimeforselectedspeciesandlocalinformation

onresistanceisdesirable,particularlywhentreatingsevereinfections.Asnecessary,expertadviceshouldbesought

whenthelocalprevalenceofresistanceissuchthattheutilityoftheagentinatleastsometypesofinfectionsis

questionable.

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

Non-species-related

breakpoints* 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+*

Campylobacterspp.+*

Citrobacterfreundii*

Enterobacteraerogenes

Enterobactercloacae*

Escherichiacoli*

Klebsiellaoxytoca

Klebsiellapneumoniae*

Morganellamorganii*

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5.2Pharmacokineticproperties

Absorption

Followingoraladministrationofsingledosesof250mg,500mg,and750mgofciprofloxacintablets,ciprofloxacinis

absorbedrapidlyandextensively,mainlyfromthesmallintestine,reachingmaximumserumconcentrations1-2hours

later.

Singledosesof100-750mgproduceddose-dependentmaximumserumconcentrations(C max )between0.56and3.7

mg/L.Serumconcentrationsincreaseproportionatelywithdosesupto1000mg.

Theabsolutebioavailabilityisapproximately70-80%.

A500mgoraldosegivenevery12hourshasbeenshowntoproduceanareaundertheserumconcentration-timecurve

(AUC)equivalenttothatproducedbyanintravenousinfusionof400mgciprofloxacingivenover60minutesevery12

hours.

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

Clinicalefficacyhasbeendemonstratedforsusceptibleisolatesinapproved

clinicalindications

Resistancerate ≥50%inoneormoreEUcountries

($): NaturalIntermediatesusceptibilityintheabsenceofacquiredmechanismof

resistance

(1): Studieshavebeenconductedinexperimentalanimalinfectionsduetoinhalations

ofBacillusanthracisspores;thesestudiesrevealthatantibioticsstartingearlyafter

expositionavoidtheoccurrenceofthediseaseifthetreatmentismadeuptothedecrease

ofthenumberofsporesintheorganismundertheinfectivedose.Therecommendeduse

inhumansubjectsisbasedprimarilyonin-vitrosusceptibilityandonanimal

experimentaldatatogetherwithlimitedhumandata.Two-monthtreatmentdurationin

adultswithoralciprofloxacingivenatthefollowingdose,500mgbid,isconsideredas

effectivetopreventanthraxinfectioninhumans.Thetreatingphysicianshouldreferto

nationaland/orinternationalconsensusdocumentsregardingtreatmentofanthrax.

(2): Methicillin-resistantS.aureusverycommonlyexpressco-resistanceto

fluoroquinolones.Therateofresistancetomethicillinisaround20to50%amongall

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Proteinbindingofciprofloxacinislow(20-30%).Ciprofloxacinispresentinplasmalargelyinanonionisedformand

hasalargesteadystatedistributionvolumeof2-3L/kgbodyweight.Ciprofloxacinreacheshighconcentrationsina

varietyoftissuessuchaslung(epithelialfluid,alveolarmacrophages,biopsytissue),sinuses,inflamedlesions

(cantharidesblisterfluid),andtheurogenitaltract(urine,prostate,endometrium)wheretotalconcentrationsexceeding

thoseofplasmaconcentrationsarereached.

Metabolism

Lowconcentrationsoffourmetaboliteshavebeenreported,whichwereidentifiedas:desethyleneciprofloxacin(M1),

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

antimicrobialactivitybuttoalowerdegreethantheparentcompound.

CiprofloxacinisknowntobeamoderateinhibitoroftheCYP4501A2iso-enzymes.

Elimination

Ciprofloxacinislargelyexcretedunchangedbothrenallyand,toasmallerextent,faecally.Theserumeliminationhalf-

lifeinsubjectswithnormalrenalfunctionisapproximately4-7hours.

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

undergoesbothglomerularfiltrationandtubularsecretion.Severelyimpairedrenalfunctionleadstoincreasedhalf

livesofciprofloxacinofupto12h.

Non-renalclearanceofciprofloxacinismainlyduetoactivetrans-intestinalsecretionandmetabolism.1%ofthedose

isexcretedviathebiliaryroute.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

thebioavailabilityoftheoralsuspensionrangesfrom50to80%.

5.3Preclinicalsafetydata

Non-clinicaldatarevealnospecialhazardsforhumansbasedonconventionalstudiesofsingledosetoxicity,repeated

dosetoxicity,carcinogenicpotential,ortoxicitytoreproduction.

Likeanumberofotherquinolones,ciprofloxacinisphototoxicinanimalsatclinicallyrelevantexposurelevels.

Excretionofciprofloxacin(%ofdose)

OralAdministration

Urine Faeces

Ciprofloxacin 44.7 25.0

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ciprofloxacinin-vitroandinanimalexperiments.Thiseffectwascomparabletothatofothergyraseinhibitors.

Articulartolerability:

Asreportedforothergyraseinhibitors,ciprofloxacincausesdamagetothelargeweight-bearingjointsinimmature

animals.Theextentofthecartilagedamagevariesaccordingtoage,speciesanddose;thedamagecanbereducedby

takingtheweightoffthejoints.Studieswithmatureanimals(rat,dog)revealednoevidenceofcartilagelesions.Ina

studyinyoungbeagledogs,ciprofloxacincausedseverearticularchangesattherapeuticdosesaftertwoweeksof

treatment,whichwerestillobservedafter5months.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Core:

Microcrystallinecellulose

Crospovidone

Silicacolloidalanhydrous

Magnesiumstearate

Film-coat:

Hypromellose

Macrogol400

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

5years.

6.4Specialprecautionsforstorage

Nospecialprecautions.

6.5Natureandcontentsofcontainer

Blisterstripsof20µmAluminiumand250µmPVCinacardboardoutercontainer.Packsize:6,7,10,14,28,30,56,

60,84,90,100,120,150tablets.

Notallpacksizesmaybemarketed

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

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7MARKETINGAUTHORISATIONHOLDER

ActavisGroupPTCehf

Reykjavikurvegi76-78

220Hafnarfjordur

Iceland

8MARKETINGAUTHORISATIONNUMBER

PA1380/49/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:2 nd

July2004

Dateoflastrenewal:2 nd

July2009

10DATEOFREVISIONOFTHETEXT

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