CIPROXIN

Main information

  • Trade name:
  • CIPROXIN Film Coated Tablet 250 Milligram
  • Dosage:
  • 250 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CIPROXIN Film Coated Tablet 250 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1328/074/001
  • Authorization date:
  • 13-04-2007
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995

MEDICINALPRODUCTS(LICENSINGANDSALE)REGULATIONS,1998

(S.I.No.142of1998)

PPA1328/074/001

CaseNo:2029783

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

B&SHealthcare

Unit4,BradfieldRoad,Ruislip,Middlesex,HA40NU,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Ciproxin250mgFilm-CoatedTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom13/04/2007until12/04/2012.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Ciproxin250mgFilm-CoatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilmcoatedtabletcontains291.0mgciprofloxacinhydrochlorideequivalentto250mgCiprofloxacin.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

ProductimportedfromItaly:

Film-coatedtablet,round,whitetoslightlyyellow,markedwithBayercrossononesideand‘CIP’,abreaklineand

‘250’impressedontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Ciprofloxacinisindicatedforthetreatmentofthefollowinginfectionscausedbysensitivebacteria:

Adults:

Respiratorytractinfections:e.g.lobarandbronchopneumonia,acuteandchronicbronchitis,acuteexacerbationof

cysticfibrosis,bronchiectasis,empyema.Ciprofloxacinisnotrecommendedasfirst-linetherapyforthetreatmentof

pneumococcalpneumonia(seeSection4.4).Incircumstanceswhereaphysicianconsidersitappropriatetouse

ciprofloxacininpatientswithpneumococcalpneumonia,adoseof750mgtwicedailyshouldprovideadequatecoverin

themajorityofcases(seeSection4.2).CiprofloxacinmaybeusedfortreatingGram-negativepneumonia.

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

epididymitis.

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

Gonorrhoea:includingurethral,rectalandpharyngealgonorrhoeacausedbybeta-lactamaseproducingorganismsor

organismsmoderatelysensitivetopenicillin.

Children:

ForthetreatmentofacutepulmonaryexacerbationofcysticfibrosisassociatedwithP.aeruginosainfectionin

paediatricpatientsaged5-17years.

InhalationAnthraxinAdultsandChildren:Toreducetheincidenceorprogressionofdiseasefollowingconfirmed

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4.2Posologyandmethodofadministration

Generaldosagerecommendations:thedosageofciprofloxacintabletsisdeterminedbytheseverityandtypeof

infection,thesensitivityofthecausativeorganism(s)andtheage,weightandrenalfunctionofthepatient.Ciproxin

Tabletsshouldbeswallowedwholewithanadequateamountofliquid.

IfCiproxinTabletsaretakenonanemptystomach,theactivesubstanceisabsorbedmorerapidly.Inthiscase,the

tabletsshouldnotbetakenconcurrentlywithdairyproductsorwithmineralfortifieddrinksalone(e.g.milk,yoghurt,

calciumfortifiedorangejuice).However,anormaldietthatwillcontainsmallamountsofcalcium,doesnot

significantlyaffectciprofloxacinabsorption.

Adults

Thedosagerangeforadultsis100-750mgtwicedaily.Thefollowingdosagesforspecifictypesofinfectionare

recommended:

Table1:RecommendedAdultDosage

*Asthepharmacokineticsofciprofloxacinremainunchangedinpatientswithcysticfibrosis,thelowbodyweightof

thesepatientsshouldbetakenintoconsiderationwhendeterminingdosage.

**Bothdosesareequallyeffectiveintreatingacute,uncomplicatedcystitis.

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ImpairedRenalFunction

Dosageadjustmentsarenotusuallyrequired,exceptinpatientswithsevererenalimpairment(serumcreatinine>265

micromole/lorcreatinineclearance<20ml/minute).Ifadjustmentisnecessary,thismaybeachievedbyreducingthe

totaldailydosebyhalf,althoughmonitoringofdrugserumlevelsprovidesthemostreliablebasisfordoseadjustment.

Dialysisreducesserumlevelsofciprofloxacin.

Elderly

Indication Dosage(mgciprofloxacin)

Treatment

Gonorrhoea 250mgsingledose

Acute,uncomplicatedcystitis 100mgb.d.or250mgb.d.**

Upperandlowerurinarytractinfections

(dependingonseverity) 250-500mgb.d.

Upperandlowerrespiratorytractinfections

(dependingonseverity)

Pneumococcalpneumonia(second-linewhere

physicianconsidersitappropriate) 250-750mgb.d.

750mgb.d.

Cysticfibrosispatientswithpseudomonallower

RTI* 750mgb.d.

Otherinfections 500-750mgb.d.

Severeinfections,particularlydueto

Pseudomonas,staphylococciandstreptococci 750mgb.d.

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Adolescentsandchildren

Aswithotherdrugsinitsclass,ciprofloxacinhasbeenshowntocausearthropathyinweight-bearingjointsof

immatureanimals.Althoughanalysisofavailablesafetydatafromciprofloxacinuseinpatientslessthan18yearsof

age,themajorityofwhomhadcysticfibrosis,didnotdiscloseanyevidenceofdrug-relatedcartilageorarticular

damage,itsuseinthepaediatricpopulationisgenerallynotrecommended.

Clinicalandpharmacokineticdatasupporttheuseofciprofloxacininpaediatriccysticfibrosispatients(aged5-17

years)withacutepulmonaryexacerbationassociatedwithP.aeruginosainfection,atadoseof20mg/kgorallytwice

daily(maximumdailydose1500mg).

Fortheindicationofinhalationanthrax,therisk-benefitassessmentindicatesthatadministrationofciprofloxacinto

paediatricpatientsatadoseof15mg/kgorallytwicedaily(maximumdailydoseof1000mg)isappropriate.

Forindicationsotherthantreatmentofpulmonaryexacerbationsincysticfibrosisandinhalationanthrax,ciprofloxacin

maybeusedinchildrenandadolescentswherethebenefitisconsideredtooutweighthepotentialrisks.

Dosinginchildrenwithimpairedrenaland/orhepaticfunctionhasnotbeenstudied.

DurationofTreatment

Thedurationoftreatmentdependsupontheseverityofinfection,clinicalresponseandbacteriologicalfindings.

Inacute,uncomplicatedcystitisthetreatmentperiodisthreedayswithCiproxin100mgTabletsorCiproxin250mg

Tablets.

Inotheracuteinfectionstheusualtreatmentperiodis5to10dayswithCiproxinTablets.Generally,treatmentshould

becontinuedforatleastthreedaysafterthesignsandsymptomsoftheinfectionhavedisappeared.

Prolongedtreatmentoruseinchronicconditionsshouldonlybeinitiatedunderconsultantdirectionwithregular

surveillance.

ForacutepulmonaryexacerbationofcysticfibrosisassociatedwithP.aeruginosainfectioninpaediatricpatients(aged

5–17years),thedurationoftreatmentis10-14days.

Forinhalationanthrax,drugadministrationshouldbeginassoonaspossibleafterconfirmedorsuspectedexposureand

shouldbecontinuedfor60days.

4.3Contraindications

Ciprofloxaciniscontra-indicatedinpatientswhohaveshownhypersensitivitytociprofloxacinoranyoftheexcipients,

orotherquinoloneanti-infectives,orwhohaveahistoryofquinolone-inducedtendondisorder.

Ciprofloxacinisalsocontra-indicatedinchildrenandgrowingadolescentsunlessepiphysealclosuresoflongbones

haveoccurredorexceptwherethebenefitsoftreatmentexceedtherisks.

Concurrentadministrationofciprofloxacinandtizanidineiscontraindicatedsinceanundesirableincreaseinserum

tizanidineconcentrationsassociatedwithclinicallyrelevanttizanidine-inducedside-effects(hypotension,somnolence)

canoccur.

4.4Specialwarningsandprecautionsforuse

Intheeventofhypersensitivity,whichinsomeinstancescanoccurafterthefirstadministration,therapyshouldbe

discontinued.

Ciprofloxacinshouldbeusedwithcautioninepilepticsandpatientswithexistingcentralnervoussystemdisordersora

historyofconvulsivedisordersandonlyifthebenefitsoftreatmentareconsideredtooutweightheriskofpossible

CNSside-effects.CNSside-effectshavebeenreportedafterfirstadministrationofciprofloxacininsomepatients.

Treatmentshouldbediscontinuediftheside-effects,depressionorpsychosesleadtoself-endangeringbehaviour(see

alsoSection4.8).

Crystalluriarelatedtotheuseofciprofloxacinhasbeenreported.Patientsreceivingciprofloxacinshouldbewell

hydratedandexcessivealkalinityoftheurineshouldbeavoided.

Patientswithafamilyhistoryoforactualdefectsinglucose-6-phosphatedehydrogenaseactivityareproneto

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Ciprofloxacinisnotrecommendedasfirst-linetherapyforthetreatmentofpneumococcalpneumonia.Streptococcus

pneumoniaeisthemostfrequentpathogenresponsibleforcommunityacquiredpneumonia.

Tendoninflammationandrupturemayoccurwithquinoloneantibiotics.Suchreactionshavebeenobserved

particularlyinolderpatientsandinthosetreatedconcurrentlywithcorticosteroids.Atthefirstsignofpainor

inflammation,patientsshoulddiscontinueciprofloxacinandresttheaffectedlimbs.

Toxicologicalstudieshaveshownthatadministrationofoxyquinoloneantibacterialagentsatdoseshigherthanthe

therapeuticrangecanproduceerosionofthecartilageinweight-bearingjointsinimmatureanimalsofsomespecies.

Nosuchlesionshavebeenshowntooccurinmantodate.Thisproductshouldnotbeprescribedforchildrenorthosein

whombonegrowthiscontinuing,withtheexceptionofpaediatriccysticfibrosispatientsorforthetreatmentof

inhalationanthrax,unlessthebenefitofshort-termuseisregardedasexceedingtherisk.

Patientswithpre-existentsignificantrenalorhepaticdisordersshouldbecarefullymonitoredtodetectany

deteriorationinfunction.Itshouldonlybeadministeredwithgreatcautiontopersonswithrenalinsufficiency,or

severedehydration.

Thereisariskofpseudomembranouscolitiswithbroad-spectrumantibioticspossiblyleadingtoafataloutcome.Itis

importanttoconsiderthisinpatientssufferingfromsevere,persistentdiarrhoea.Withciprofloxacinthiseffecthasbeen

reportedrarely.Ifpseudomembranouscolitisissuspectedtreatmentwithciprofloxacinshouldbestoppedand

appropriatetreatmentgiven(e.g.oralvancomycin).Drugsthatinhibitperistalsismustnotbegiven.

Ciprofloxacinhasbeenshowntoproducephotosensitivityreactions.Patientstakingciprofloxacinshouldavoiddirect

exposuretoexcessivesunlightorUV-light.Therapyshouldbediscontinuedifphotosensitisation(i.e.,sunburn-like

skinreactions)occur.

Laboratorytestsmaygiveabnormalfindingsifperformedwhilstpatientsarereceivingciprofloxacine.g.increased

alkalinephosphatase;increasesinliverfunctiontestse.g.transaminasesandcholestaticjaundice,especiallyinpatients

withpreviousliverdamage.

EradicationofinfectionduetoPseudomonasinpersonswithcysticfibrosisonlyoccursinaminorityofcases,

particularlyafterrepeatcoursesoftreatmentwithciprofloxacin.Cyclicaloralternatingantibacterialtherapiesmayhelp

reducethenumberofresistantstrains.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Increasedplasmalevelsoftheophyllinehavebeenobservedfollowingconcurrentadministrationwithciprofloxacin.It

isrecommendedthatthedoseoftheophyllineshouldbereducedandplasmalevelsoftheophyllinemonitored.The

reactionbetweentheophyllineandciprofloxacinispotentiallylifethreatening.Therefore,wheremonitoringofplasma

levelsisnotpossible,theuseofciprofloxacinshouldbeavoidedinpatientsreceivingtheophylline.Particularcautionis

advisedinthosepatientswithconvulsivedisorders.

CiprofloxacininhibitsCYP1A2andthusmaycauseincreasedserumconcentrationofconcomitantlyadministered

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

Therefore,patientstakingthesesubstancesconcomitantlywithciprofloxacinshouldbemonitoredcloselyforclinical

signsofoverdose,anddeterminationofserumconcentrations,especiallyoftheophylline,maybenecessary.

Inacrossoverstudy,10healthysubjectsweregivenciprofloxacin500mgorplacebotwicedailyforthreedays,atthe

endofwhichasingledoseoftizanidine4mgwasgiven.Therewasanincreaseintizanidineserumconcentrations

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

withciprofloxacincomparedtoplacebo.Associatedwiththeincreasedserumconcentrationswasapotentiated

hypotensiveandsedativeeffect.Tizanidinemustnotbeadministeredtogetherwithciprofloxacin(refertoSection4.3).

InclinicalstudiesitwasdemonstratedthatconcomitantuseofduloxetinewithstronginhibitorsoftheCYP4501A2

isozymesuchasfluvoxamine,mayresultinanincreaseofAUCandCmaxofduloxetine.Althoughnoclinicaldataare

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PhenytoinlevelsmaybealteredwhenCiproxinisusedconcomitantly.

CiproxinTabletsshouldnotbeadministeredwithinfourhoursmultivalentcationicdrugsandmineralsupplements(e.g.

calcium,magnesium,aluminiumoriron),polymericphosphatebinders(e.g.sevelamer),sucralfateorantacidsand

highlybuffereddrugs(e.g.antiretrovirals)asinterferencewithabsorptionmayoccur.Whenappropriate,patients

shouldbeadvisednottoself-medicatewithpreparationscontainingthesecompoundsduringtherapywith

ciprofloxacin.ThisrestrictiondoesnotapplytotheclassofH2receptorblockerdrugs.

Theconcurrentadministrationofdairyproductsorfortifieddrinksalone(e.g.milk,yoghurt,calciumfortifiedorange

juice)andciprofloxacinshouldbeavoidedbecauseabsorptionofciprofloxacinmaybereduced.Howeveranormal

diet,thatwillcontainsmallamountsofcalcium,doesnotsignificantlyaffectciprofloxacinabsorption.

Prolongationofclottingtimehasbeenreportedduringconcomitantadministrationofciprofloxacinandoralanti-

coagulants.

Ciprofloxacinmayinterferewithestimationsofurinary17-ketosteroids,orvanillylmandelicacid.

Animaldatahaveshownthathighdosesofquinolonesincombinationwithsomenon-steroidalanti-inflammatory

drugs,(e.g.fenbufen,butnotacetylsalicylicacid)canleadtoconvulsions.

Transientincreasesinserumcreatininehavebeenseenfollowingconcomitantadministrationofciprofloxacinand

cyclosporin.Therefore,monitoringofserumcreatininelevelsisadvisable.

Concomitantusewithsomephenylpropionicacid-derivednon-steroidalanti-inflammatorydrugsmayleadtotoxicity

possiblybecauseofrenaleffects.

Thesimultaneousadministrationofquinolonesandglibenclamidecanonoccasionpotentiatetheeffectof

glibenclamideresultinginhypoglycaemia.

Renaltubulartransportofmethotrexatemaybeinhibitedbyconcomitantadministrationofciprofloxacinpotentially

leadingtoincreasedplasmalevelsofmethotrexate.Thismayincreasetheriskofmethotrexateassociatedtoxic

reactions.Therefore,patientsreceivingmethotrexatetherapyshouldbecarefullymonitoredwhenconcomitant

ciprofloxacintherapyisindicated.

Concomitantusewithprobenecidreducestherenalclearanceofciprofloxacin,resultinginincreasedquinoloneplasma

levels.

Theuseofmetoclopramidewithciprofloxacinmayacceleratetheabsorptionofciprofloxacin.

4.6Pregnancyandlactation

Ciprofloxacinshouldnotbeusedduringpregnancy,orinwomenatriskofpregnancynorduringlactation.

Reproductionstudiesperformedinmice,ratsandrabbitsusingparenteralandoraladministrationdidnotrevealany

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

otherquinolones,ciprofloxacinhasbeenshowntocausearthropathyinimmatureanimals,andthereforeitsuseduring

pregnancyorinwomencapableofchild-bearingisnotrecommended.Studieshaveindicatedthatciprofloxacinis

secretedinbreastmilk.Administrationtonursingmothersisthusnotrecommended.

4.7Effectsonabilitytodriveandusemachines

Ciprofloxacincouldresultinimpairmentofthepatient'sabilitytodriveoroperatemachinery,particularlyin

conjunctionwithalcohol.

4.8Undesirableeffects

Themostfrequentlyreportedadversereactionsarenausea,diarrhoeaandrash.

Thefollowingadversereactionshavebeenobserved:

Effectsonthegastrointestinalsystem

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

alkalinephosphataseincreased,anorexia,flatulence,bilirubinaemia.

Rare(>1/10,000,<1/1,000):moniliasis(oral),jaundice,cholestaticjaundice,pseudomembranouscolitis,dysphagia

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

hepaticfailure),lifethreateningpseudomembranouscolitiswithpossiblefataloutcome,pancreatitis

Effectsonthebodyasawhole

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

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

Effectsonthecardiovascularsystem

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

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

Effectsonthehemicandlymphaticsystem

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

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

thrombocytopenia,thrombocythaemia(thrombocytosis)

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

threatening),bonemarrowdepression(lifethreatening)

Metabolicandnutritionaldisorders

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

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

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

Effectsonthemusculoskeletalsystem

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

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

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

completetendonrupture(predominantlyachillestendon),exacerbationofsymptomsofmyastheniagravis.Treatment

shouldbediscontinuedimmediatelyiftendinitisorcompletetendonruptureoccur.

Effectsonthenervoussystem

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

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

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

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

endangeringbehaviour),intracranialhypertension,ataxia,hyperesthesia,hypertonia,twitching

Effectsontherespiratorysystem

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

Effectsontheskinandappendages

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

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

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

epidermalnecrolysis(Lyell-Syndrome),fixeddrugreaction

Effectsonspecialsenses

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

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

disturbances),diplopia,chromatopsia,tasteloss(impairedtaste)

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

Hypersensitivityreactions

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

Veryrare(<1/10,000):shock(anaphylactic/anaphylactoidreactionsprogressinginveryrarecasestolifethreatening

shock),pruriticrash,serumsicknesslikereaction,angioedema

Effectsontheurogenitalsystem

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

crystalluria,interstitialnephritis

4.9Overdose

Basedonthelimitedinformationavailableintwocasesofingestionofover18gofciprofloxacin,reversiblerenal

toxicityhasoccurred.Therefore,apartfromroutineemergencymeasures,itisrecommendedtomonitorrenalfunction,

includingurinarypHandacidify,ifrequired,topreventcrystalluria.Patientsmustbekeptwellhydrated,andinthe

caseofrenaldamageresultinginprolongedoliguria,dialysisshouldbeinitiated.

CalciumormagnesiumantacidsmaybeadministeredassoonaspossibleafteringestionofCiproxinTabletsinorderto

reducetheabsorptionofciprofloxacin.

Serumlevelsofciprofloxacinarereducedbydialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATCCodeJ01MA02

Ciprofloxacinisasynthetic4-quinolonederivative,withbactericidalactivity.ItactsviainhibitionofbacterialDNA

gyrase,ultimatelyresultingininterferencewithDNAfunction.Ciprofloxacinishighlyactiveagainstawiderangeof

Gram-positiveandGram-negativeorganismsandhasshownactivityagainstsomeanaerobes,Chlamydia

spp.andMycoplasmaspp.Killingcurvesdemonstratetherapidbactericidaleffectagainstsensitiveorganismsanditis

oftenfoundthatminimumbactericidalconcentrationsareintherangeofminimuminhibitoryconcentrations.

CiprofloxacinhasbeenshowntohavenoactivityagainstTreponemapallidumandUreaplasmaurealyticum,Nocardia

asteroides,andEnterococcusfaeciumareresistant.

Breakpoints

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Susceptibility

Theprevalenceofresistancemayvarygeographicallyandwithtimeforselectedspeciesandlocalareainformationon

resistanceisdesirable,particularlywhentreatingsevereinfections.Thisinformationgivesonlyanapproximate

guidanceonprobabilitieswhethermicro-organismswillbesusceptibletociprofloxacinornot.

Organism Prevalenceof

Resistance

Sensitive:

Gram-positivebacteria

Corynebacteriumdiphtheriae 0%

Corynebacteriumspp. -

Staphylococcusaureus(methicillinsensitive) 0-14%

Staphylococcusaureus(methicillinresistant) 48-90%

Streptococcusagalactiae 0–17%

Bacillusanthracis -

Gram-negativebacteria

Acinetobacterbaumanii 6-93%

Acinetobacterspp. 14–70%

Aeromonashydrophilia 0%

Aeromonasspp. -

Bordetellapertussis 0%

Brucellamelitensis 0%

Campylobacterjejuni/coli 0–82%

Campylobacterspp. 0%

Citrobacterfreundii 0–4%

Citrobacterspp. 0%

Edwardsiellatarda 0%

Enterobacteraerogenes 0%

Enterobactercloacae 0-3%

Enterobacterspp. 3-13%

Escherichiacoli 2-7%

Escherichiacoli,EHECandEPEC -

Haemophilusinfluenzae 0–1%

Haemophilusinfluenzae((-lactamnegative) 0%

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Haemophilusparainfluenzae 0%

Hafniaalvei 0%

Klebsiellaoxytoca 0%

Klebsiellapneumoniae 2–5.8%

Klebsiellaspp. 2–21%

Legionellapneumophila 0%

Legionellaspp. 0%

Moraxellacatarrhalis 0%

Morganellamorganii 1–2%

Neisseriagonorrhoeae 0%

Neisseriagonorrhoeae,-lactamase 0%

Neisseriagonorrhoeae,-lactamasepositive 0%

Neisseriameningitidis 0%

Neisseriameningitidis,-lactamasenegative 0%

Plesiomonasshigelloides 0%

Proteusmirabilis 0–10%

Proteusvulgaris 4%

Providenciarettgeri -

Providenciaspp. 4%

Providenciastuartii -

Pseudomonasaeruginosa 1–28%

Salmonellaspp. 0%

Salmonellatyphi 0-2%

Serratialiquefaciens -

Serratiamarcescens 23%

Serratiaspp. 0–21%

Shigellaspp. 0%

Vibriocholerae 0%

Vibrioparahaemolyticus 0%

Vibriospp. 0%

Yersiniaenterocolitica 0%

Anaerobes

Bacteroidesureolyticus 0%

Clostridiumperfringens -

Peptococcusspp. 0%

Peptostreptococcusspp. -

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Veillonellaparvula 0%

Otherpathogens

Chlamydiaspp. -

Helicobacterpylori -

Mycobacteriumfortuitum 0%

Mycobacteriumtuberculosis 0%

Mycoplasmahominis 16%

Intermediate

Gram-positiveaerobes

Enterococci 5%

Enterococcusfaecalis 9–34%

Staphylococcusepidermis,methicillinsensitive 10-16%

Staphylococcusepidermis,methicillinresistant 26-56%

Staphylococcushaemolyticus -

Staphylococcushaemolyticus,methicillinsensitive 8%

Staphylococcushaemolyticus,methicillinresistant 73%

Streptococcusanginosus 9%

Streptococcusbovis -

Streptococcusmilleri 5%

Streptococcusmitis -

Streptococcuspneumoniae,penicillinsensitive 0–1%

Streptococcuspneumoniae,penicillinintermediate -

Streptococcuspneumoniae,penicillinintermediateandresistant 2.8%

Streptococcuspneumoniae,penicillinresistant -

Streptococcuspyogenes 0-28%

Streptococcus,viridansgroup -

Streptococcusviridans,penicillinsensitive -

Streptococcusviridans,penicillinresistant -

Streptococcus,-haemolyticgroupsA,C,andG 0%

Gram-negativeaerobes

Alcaligenesspp. -

Listeriamonocytogenes 0%

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Resistance

Plasmid-relatedtransferofresistancehasnotbeenobservedwithciprofloxacinandtheoverallfrequencyof

developmentofresistanceislow(10 -9

-10 -7

).Cross-resistancetopenicillins,cephalosporins,aminoglycosidesand

tetracyclineshasnotbeenobservedandorganismsresistanttotheseantibioticsaregenerallysensitivetociprofloxacin.

Ciprofloxacinisalsosuitableforuseincombinationwiththeseantibiotics,andadditivebehaviourisusuallyobserved.

5.2Pharmacokineticproperties

Absorptionoforaldosesofciprofloxacintabletformulationoccursrapidly,mainlyfromthesmallintestine,thehalf-

lifeofabsorptionbeing2-15minutes.Plasmalevelsaredose-relatedandpeak0.5-2.0hoursafterdosing.TheAUC

alsoincreasesdoseproportionatelyafteradministrationofbothsingleandrepeatedoral(tablet)andintravenousdoses.

Plasmalevelspeakapproximately1.5-2.5hoursafterdosingandtheAUC

isintherangeof5-12mg.h/l.The

absolutebioavailabilityisreportedtobe52-83%andciprofloxacinissubjecttoonlyslightfirstpassmetabolism.The

Anaerobes

Fusobacteriumspp. -

Gardnerellavaginalis 0%

Prevotellaspp. -

Otherpathogens

Ureaplasmaurealyticum 11%

Resistant

Gram-positiveaerobes

Enterococcusfaecium -

Stenotrophomonasmaltophilia 94%

Streptococcussanguis -

Gram-negativeaerobes

Flavobacteriummeningosepticum -

Nocardiaasteroides -

Anaerobes

Bacteroidesfragilis -

Bacteroidesthetaiotaomicron -

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Theintakeoffoodatthesametimeasadministrationoforalciprofloxacinhasamarginalbutclinicallynotrelevant

effectonthepharmacokineticparametersC

andAUC.Nospecificrecommendationsarenecessarywithregardto

timeofadministrationoforalciprofloxacinrelativetofoodintake.

Distributionofciprofloxacinwithintissuesiswideandthevolumeofdistributionhigh,thoughslightlylowerinthe

elderly.Proteinbindingislow(between19-40%).

Only10-20%ofasingleoralorintravenousdoseiseliminatedasmetabolites(whichexhibitloweractivitythanthe

parentdrug).Fourdifferentantimicrobiallyactivemetaboliteshavebeenreported,desethyleneciprofloxacin(M1),

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

eachofmetabolisedsubstanceandM1isfoundinsmallamounts(1.3-2.6%ofthedose).M4hasbeenfoundinvery

smallquantities(<0.1%ofthedose).M1-M3haveantimicrobialactivitycomparabletonalidixicacidandM4foundin

thesmallestquantityhasantimicrobialactivitysimilartothatofnorfloxacin.

Eliminationofciprofloxacinanditsmetabolitesoccursrapidly,primarilybythekidney.Aftersingleoraland

intravenousdosesofciprofloxacin,55%and75%respectivelyareeliminatedbythekidneyand39%and14%inthe

faeceswithin5days.Renaleliminationtakesplacemainlyduringthefirst12hoursafterdosingandrenalclearance

levelssuggestthatactivesecretionbytherenaltubulesoccursinadditiontonormalglomerularfiltration.Renal

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

ciprofloxacindoseisexcretedviathebiliaryroute.

Theeliminationkineticsarelinearandafterrepeateddosingat12hourlyintervals,nofurtheraccumulationisdetected

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

overaperiodof24-48hourspost-doseis3.1-5.1hours.

Somestudiescarriedoutwithciprofloxacininseverelyrenallyimpairedpatients(serumcreatinine>265micromole/lor

creatinineclearance<20ml/minute)demonstratedeitheradoublingoftheeliminationhalf-life,orfluctuationsinhalf-

lifeincomparisonwithhealthyvolunteers,whereasotherstudiesshowednosignificantcorrelationbetween

eliminationhalf-lifeandcreatinineclearance.However,itisrecommendedthatinseverelyrenallyimpairedpatients,

thetotaldailydoseshouldbereducedbyhalf,althoughmonitoringofdrugserumlevelsprovidesthemostreliable

basisfordoseadjustmentasnecessary.

Resultsofpharmacokineticstudiesinpaediatriccysticfibrosispatientshaveshowndosagesof20mg/kgorallytwice

dailyor10mg/kgivthreetimesdailyarerecommendedtoachieveplasmaconcentration/timeprofilescomparableto

thoseachievedintheadultpopulationatthecurrentlyrecommendeddosageregimen.

Inhalationanthrax:Ciprofloxacinserumconcentrationsachievedinhumansserveasasurrogateendpointreasonably

likelytopredictclinicalbenefitandprovidethebasisfortherecommendeddoses.

5.3Preclinicalsafetydata

Followingextensiveoralandintravenoustoxicologytestingwithciprofloxacin,onlytwofindingswhichmaybe

consideredrelevanttotheuseofciprofloxacininmanwereobserved.Crystalluriawasnotedinthosespeciesof

animalswhichhadanormallyalkalineurine.

Kidneydamagewithoutthepresenceofcrystalluriawasnotobserved.Thiseffectisconsideredasecondary

inflammatoryforeign-bodyreaction,duetotheprecipitationofacrystallinecomplexofciprofloxacin,magnesiumand

proteininthedistaltubulesystemofthekidneys.Thisisconsiderednottobeaprobleminman,becausetheurineis

normallyacidic.However,toavoidtheoccurrenceofcrystalluria,patientsshouldbewellhydratedandexcessive

alkalinityoftheurineavoided.

Aswithotherquinolones,damagetotheweight-bearingjointsofonlyjuvenileratsanddogstreatedwithciprofloxacin

wasnotedinrepeatdosetoxicitytesting.Thiswasmorenoticeableinthedog.Althoughtherelevanceofthistomanis

unknown,theuseofciprofloxacininchildrenandgrowingadolescentsisnotrecommended,(withtheexceptionof

treatmentofcysticfibrosisandinhalationanthrax),unlessthebenefitsareconsideredtooutweighthepotentialrisks.

Additionally,becauseofthepotentialofarthropathy,theuseofciprofloxacinduringpregnancy,inwomencapableof

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Eachtabletcorecontains:

microcrystallinecellulose,

maizestarch,

crospovidone,

colloidalanhydroussilica,

magnesiumstearate.

Thetabletfilm-coatconsistsofamixtureof:

hypromellose

Macrogol,

Titaniumdioxide(E171).

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Nospecialstorageprecautionsarenecessary.

6.5Natureandcontentsofcontainer

Blisterstripsincardboardouters

Packsize10tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7ParallelProductAuthorisationHolder

B&SHealthcare

Unit4

BradfieldRoad

Ruislip

MiddlesexHA40NU

UnitedKingdom

8ParallelProductAuthorisationNumber

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation13 th

April2007.

Irish Medicines Board

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