BIOFLOXCIN

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1063/002/001
  • Authorization date:
  • 07-10-2005
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

BioFloxcin250mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontainsciprofloxacinhydrochlorideequivalentto250mgciprofloxacin.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

Round,white,film-coatedtabletswithascorelineononeside.

Thetabletcanbedividedintoequalhalves

4CLINICALPARTICULARS

4.1TherapeuticIndications

Ciprofloxacinisasynthetic,4-quinolonederivativewithbactericidalactivityagainstawiderangeofGram-negative

andGram-positiveorganisms.

Ciprofloxacinisindicatedforthetreatmentofsingleinfectionsormixedinfectionscausedbytwoormoresusceptible

organisms.Itmaybeusedforinfectionscausedbyorganismsresistanttootherantibiotics,includingaminoglycosides,

penicillinsandcephalosporins.

Theextensivetissuepenetrationofciprofloxacincombinedwithitsenhancedantibacterialactivity(including

antipseudomonalactivity),enablesciprofloxacintobeusedalone(pendingsensitivityresults)orincombinationwith

anaminoglycosideorwithbeta-lactamantibiotics,forinstancewhensevereneutropeniaispresent,orwithanantibiotic

activeagainstanaerobeswherethepresenceofBacteroidesfragilisissuspected.

Ciprofloxacinisindicatedforthetreatmentofthefollowinginfectionscausedbysensitivebacteria:

Respiratorytractinfections:e.g.lobarandbronchopneumonia,acuteandchronicbronchitis,acuteexacerbationof

cysticfibrosis,bronchiectasis,empyema.Ciprofloxacinisnotrecommendedasfirstlinetherapyforthetreatmentof

pneumococcalpneumonia(seeSection4.4,WarningsandPrecautionssection).Incircumstanceswhereaphysician

considersitappropriatetouseciprofloxacininpatientswithpneumococcalpneumonia,anoraldoseof750mgtwice

dailyshouldbeused.(seeSection4.2,PosologyandMethodofAdministrationSection).Ciprofloxacinmaybeused

fortreatingGram-negativepneumonia.

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

epididymitis.

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

Gonorrhoea:includingurethral,rectalandpharyngealgonorrhoeacausedbybeta-lactamaseproducingorganismsor

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Childrenandadolescents:

Ciprofloxacinmaybeusedforthe2 nd

and3 rd

linetreatmentofcomplicatedurinarytractinfectionsandpyelonephritis

inchildrenandadolescents1-17yearsofageandforthetreatmentofacutepulmonaryexacerbationofcysticfibrosis

associatedwithP.aeruginosainfectioninchildrenandaolescents5-17yearsofage.TheuseofBioFloxcinin

paediatricpatientswithcomplicatedurinarytractinfectionsandpyelonephritisshouldberestrictedtoinfectionscaused

byorganisms,basedontheresultsofantimicrobialsusceptibilitytesting.Treatmentshouldbeinitiatedbyaphysician,

whoisexperiencedinthetreatmentofsevereinfectionsinchildrenandadolescentsandaftercarefulbenefit/risk

evaluation,duetopossibleadverseeventsrelatedtojointsand/orsurroundingtissues(see4.4.and5.1.).

InhalationAnthraxinAdultsandChildren:Toreducetheincidenceorprogressionofdiseasefollowingconfirmed

orsuspectedexposuretoaerosolisedBacillusanthracis.

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantibacterialagents.

4.2Posologyandmethodofadministration

Generaldosagerecommendations:thedosageofciprofloxacintabletsisdeterminedbytheseverityandtypeof

infection,thesensitivityofthecausativeorganism(s)andtheage,weightandrenalfunctionofthepatient.BioFloxcin

Tabletsshouldbeswallowedwholewithanadequateamountofliquid.

Tabletscanbetakenindependentofmealtimes.IfBioFloxcinTabletsaretakenonanemptystomach,theactive

substanceisabsorbedmorerapidly.Inthiscase,thetabletsshouldnotbetakenconcurrentlywithdairyproductsor

withmineralfortifieddrinksalone(e.g.milk,yoghurt,calciumfortifiedorangejuice).However,anormaldietthatwill

containsmallamountsofcalcium,doesnotsignificantlyaffectciprofloxacinabsorption.

Adults

Thedosagerangeforadultsis100-750mgtwicedaily.Thefollowingdosagesforspecifictypesofinfectionare

recommended:

Table1:RecommendedAdultDosage(refertoSection5.1)

*Asthepharmacokineticsofciprofloxacinremainunchangedinpatientswithcysticfibrosis,thelowbodyweightof

Indication Dosage

(mgciprofloxacin)

Treatment

Gonorrhoea 250mgsingledose

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

Upperandlowerurinarytractinfections

(dependingonseverity) 250-500mgb.d.

Upperandlowerrespiratorytractinfections

(dependingonseverity) 250-750mgb.d.

Pneumococcalpneumonia(second-linewhere

physicianconsidersitappropriate) 750mgb.d.

Cysticfibrosispatientswithpseudomonal

lowerRTI* 750mgb.d.

Otherinfections 500-750mgb.d.

Severeinfections,particularlydueto

Pseudomonas,staphylococciandstreptococci 750mgb.d.

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**Bothdosesareequallyeffectiveintreatingacute,uncomplicatedcystitis.

ImpairedRenalFunction

Wherecreatinineclearanceisbetween31and60ml/min/1.73m 2

orwheretheserumcreatinineconcentrationis

between1.4and1.9mg/100mlthemaximumdailydoseshouldbe1000mgperdayfororaladministration.

Wherecreatinineclearanceisequalorislessthan30ml/min/1.73m 2

orwheretheserumcreatinineconcentrationis

equalorhigherthan2.0mg/100mlthemaximumdailydoseshouldbe500mgperdayfororaladministration.

Forpatientswithimpairedrenalfunctionundergoinghaemodialysisthemaximumdailydoseshouldbe500mgper

day.Ciprofloxacinshouldbeadministeredondialysisdaysafterdialysis.

Forpatientswithimpairedrenalfunctionandoncontinuousambulatoryperitonealdialysis(CAPD),thedoseshouldbe

1x500mgfilmcoatedtablet(or2x250mgfilmcoatedtablets).

Impairedhepaticfunction

Noadjustmentofdosageisnecessary.Incasesofimpairedrenalandliverfunctionfollowinstructionsasforrenal

impairmentfunction.

Elderly

Elderlypatientsshouldreceiveadoseaslowaspossibledependingontheseverityoftheirillnessandthecreatinine

clearance.

Childrenandadolescents

Cysticfibrosis

Clinicalandpharmacokineticdatasupporttheuseofciprofloxacininpaediatriccysticfibrosispatients(aged5-17

years)withacutepulmonaryexacerbationassociatedwithP.aeruginosainfection,atadoseof20mg/kgorallytwice

daily(maximumdailydose1500mg).

Complicatedurinarytractinfectionsandpyelonephritis

Forcomplicatedurinarytractinfectionsorpyelonephritisthedoseis10to20mg/kgorallyevery12hourswitha

maximumof750mgperdose.

Inhalationanthrax

Fortheindicationofinhalationanthrax,therisk-benefitassessmentindicatesthatadministrationofciprofloxacinto

paediatricpatientsatadoseof15mg/kgorallytwicedaily(maximumdailydoseof1000mg)isappropriate.

Dosinginchildrenwithimpairedrenaland/orhepaticfunctionhasnotbeenstudied.

DurationofTreatment

Thedurationoftreatmentdependsupontheseverityofinfection,clinicalresponseandbacteriologicalfindings.

Inacute,uncomplicatedcystitisthetreatmentperiodisthreedayswithBioFloxcin100mgTabletsorBioFloxcin

250mgTablets.

Inotheracuteinfectionstheusualtreatmentperiodis5to10dayswithBioFloxcinTablets.Generally,treatment

shouldbecontinuedforatleastthreedaysafterthesignsandsymptomsoftheinfectionhavedisappeared.

Prolongedtreatmentoruseinchronicconditionsshouldonlybeinitiatedunderconsultantdirectionwithregular

surveillance.

ForacutepulmonaryexacerbationofcysticfibrosisassociatedwithP.aeruginosainfectioninpaediatricpatients(aged

5–17years),thedurationoftreatmentis10-14days.

Forcomplicatedurinarytractinfectionsandpyelonephritisinpaediatricpatientsthedurationoftreatmentis10-21

days.

Forinhalationanthrax,drugadministrationshouldbeginassoonaspossibleafterconfirmedorsuspectedexposureand

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4.3Contraindications

Ciprofloxaciniscontra-indicatedinpatientswhohaveshownhypersensitivitytociprofloxacinoranyoftheexcipients,

orotherquinoloneanti-infectives,orwhohaveahistoryofquinolone-inducedtendondisorder.

Concurrentadministrationofciprofloxacinandtizanidineiscontraindicatedsinceanundesirableincreaseinserum

tizanidineconcentrationsassociatedwithclinicallyrelevanttizanidine-inducedside-effects(hypotension,somnolence)

canoccur.

4.4Specialwarningsandprecautionsforuse

Intheeventofhypersensitivity,whichinsomecasescanoccurafterthefirstadministration,therapyshouldbe

discontinued.

Ciprofloxacinshouldbeusedwithcautioninepilepticsandpatientswithexistingcentralnervoussystemdisordersora

historyofconvulsivedisordersandonlyifthebenefitsoftreatmentareconsideredtooutweightheriskofpossible

CNSsideeffects.CNSside-effectshavebeenreportedafterfirstadministrationofciprofloxacininsomepatients.

Treatmentshouldbediscontinuediftheside-effects,depressionorpsychosesleadtoself-endangeringbehaviour(see

alsoSection4.8).

Crystalluriarelatedtotheuseofciprofloxacinhasbeenreported.Patientsreceivingciprofloxacinshouldbewell

hydratedandexcessivealkalinityoftheurineshouldbeavoided.

Patientswithafamilyhistoryoractualdefectsinglucose-6-phosphatedehydrogenaseactivityarepronetohaemolytic

reactionswithquinoloneantibacterialsandsociprofloxacinshouldbeusedwithcautioninthesepatients.

Ciprofloxacinisnotrecommendedasfirst-linetherapyforthetreatmentofpneumococcalpneumonia.Streptococcus

pneumoniaeisthemostfrequentpathogenresponsibleforcommunityacquiredpneumonia.

Tendoninflammationandrupturemayoccurwithquinoloneantibiotics.Suchreactionshavebeenobserved

particularlyinolderpatientsandthosetreatedconcurrentlywithcorticosteroids.Atthefirstsignofpainor

inflammation,patientsshoulddiscontinueBioFloxcinandresttheaffectedlimbs.

Patientswithpre-existentsignificantrenalorhepaticdisordersshouldbecarefullymonitoredtodetectany

deteriorationinfunction.Itshouldonlybeadministeredwithgreatcautiontopersonswithrenalinsufficiency,or

severedehydration.

Thereisariskofpseudomembranouscolitiswithbroad-spectrumantibioticspossiblyleadingtoafataloutcome.Itis

importanttoconsiderthisinpatientssufferingfromsevere,persistentdiarrhoea.Withciprofloxacinthiseffecthasbeen

reportedrarely.Ifpseudomembranouscolitisissuspectedtreatmentwithciprofloxacinshouldbestoppedand

appropriatetreatmentgiven(e.g.oralvancomycin).Drugsthatinhibitperistalsismustnotbegiven.

Ciprofloxacinhasbeenshowntoproducephotosensitivityreactions.Patientstakingciprofloxacinshouldavoiddirect

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

skinreactions)occur.

Laboratorytestsmaygiveabnormalfindingsifperformedwhilstpatientsarereceivingciprofloxacine.g.increased

alkalinephosphatase;increasesinliverfunctiontestse.g.transaminasesandcholestaticjaundice,especiallyinpatients

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EradicationofinfectionduetoPseudomonasinpersonswithcysticfibrosisonlyoccursinaminorityofcases,

particularlyafterrepeatcoursesoftreatmentwithciprofloxacin.Cyclicaloralternatingantibacterialtherapiesmayhelp

reducethenumberofresistantstrains.

Childrenandadolescents

Ciprofloxacinhasbeenshowntocausearthropathyinweight-bearingjointsofimmatureanimals.Safetydatafroma

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

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

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

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

arthropathyoverthetimewasnotstatisticallysignificantbetweengroups.Treatmentshouldonlybeinitiatedaftera

carefulbenefit/riskevaluation,duetopossibleadverseeventsrelatedtojointsand/orsurroundingtissue.

Theuseofciprofloxacinforindicationsotherthanthetreatmentofacutepulmonaryexacerbationofcysticfibrosis

causedbyP.aeruginosainfection(childrenaged5–17years),complicatedurinarytractinfectionsandpyelonephritis

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

trialsandtheclinicalexperienceislimited.Theuseofciprofloxacinshouldfollowtheofficialguidance.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Thesimultaneousadministrationofciprofloxacin(oral)andmultivalentcationicdrugsandmineralsupplements(e.g.

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

buffereddrugs(e.g.didanosinetablets),containingmagnesium,aluminiumorcalciumreducetheabsorptionof

ciprofloxacin.Consequently,ciprofloxacinshouldbeadministeredeither1-2hoursbefore,oratleast4hoursafter

thesepreparations.TherestrictiondoesnotapplytoantacidsbelongingtotheclassofH2receptorblockers.

Theconcurrentadministrationofdairyproductsorfortifieddrinksalone(e.g.milk,yoghurt,calciumfortifiedorange

juice)andciprofloxacinshouldbeavoidedbecauseabsorptionofciprofloxacinmaybereduced.Howeveranormal

diet,thatwillcontainsmallamountsofcalcium,doesnotsignificantlyaffectciprofloxacinabsorption.

Concomitantusewithprobenecidreducestherenalclearanceofciprofloxacin,resultinginincreasedquinoloneplasma

levels.

Theuseofmetoclopramidewithciprofloxacinmayacceleratetheabsorptionofciprofloxacin.

ConcomitantadministrationofciprofloxacinandomeprazoleresultsinaslightreductioninCmaxandAUCof

ciprofloxacin.

Inacrossoverstudy,10healthysubjectsweregivenciprofloxacin500mgorplacebotwicedailyforthreedays,atthe

endofwhichasingledoseoftizanidine4mgwasgiven.Therewasanincreaseintizanidineserumconcentrations

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

withciprofloxacincomparedtoplacebo.Associatedwiththeincreasedserumconcentrationswasapotentiated

hypotensiveandsedativeeffect.Tizanidinemustnotbeadministeredtogetherwithciprofloxacin(refertoSection4.3).

Increasedplasmalevelsoftheophyllinehavebeenobservedfollowingconcurrentadministrationwithciprofloxacin.It

isrecommendedthatthedoseoftheophyllineshouldbereducedandplasmalevelsoftheophyllinemonitored.The

reactionbetweentheophyllineandciprofloxacinispotentiallylifethreatening.Therefore,wheremonitoringofplasma

levelsisnotpossible,theuseofciprofloxacinshouldbeavoidedinpatientsreceivingtheophylline.Particularcautionis

advisedinthosepatientswithconvulsivedisorders.

Renaltubulartransportofmethotrexatemaybeinhibitedbyconcomitantadministrationofciprofloxacinpotentially

leadingtoincreasedplasmalevelsofmethotrexate.Thismayincreasetheriskofmethotrexateassociatedtoxic

reactions.Therefore,patientsreceivingmethotrexatetherapyshouldbecarefullymonitoredwhenconcomitant

ciprofloxacintherapyisindicated.

Animaldatahaveshownthathighdosesofquinolonesincombinationwithsomenon-steroidalanti-inflammatory

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

Transientincreasesinserumcreatininehavebeenseenfollowingconcomitantadministrationofciprofloxacinand

ciclosporin.Therefore,monitoringofserumcreatininelevelsisadvisable(twiceaweek).

Prolongationofbleedingtimehasbeenreportedduringconcomitantadministrationofciprofloxacinandoralanti-

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Thesimultaneousadministrationofquinolonesandglibenclamidecanonoccasionpotentiatetheeffectof

glibenclamideresultinginhypoglycaemia.

InclinicalstudiesitwasdemonstratedthatconcomitantuseofduloxetinewithstronginhibitorsoftheCYP4501A2

isozymesuchasfluvoxamine,mayresultinanincreaseofAUCandCmaxofduloxetine.Althoughnoclinicaldataare

availableonapossibleinteractionwithciprofloxacin,similareffectscanbeexpecteduponconcomitantadministration.

CiprofloxacininhibitsCYP1A2andthusmaycauseincreasedserumconcentrationofconcomitantlyadministered

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

Therefore,patientstakingthesesubstancesconcomitantlywithciprofloxacinshouldbemonitoredcloselyforclinical

signsofoverdose,anddeterminationofserumconcentrations,especiallyoftheophylline,maybenecessary.

PhenytoinlevelsmaybealteredwhenBioFloxcinisusedconcomitantly.

Ciprofloxacinmayinterferewithestimationsofurinary17-ketosteroids,orvanillylmandelicacid.

Concomitantusewithsomephenylpropionicacid-derivednon-steroidalanti-inflammatorydrugsmayleadtotoxicity

possiblybecauseofrenaleffects.

Ciprofloxacinmayinterferewithestimationsofurinary17-ketosteroids,orvanillylmandelicacid.

4.6Fertility,pregnancyandlactation

Ciprofloxacinshouldnotbeusedduringpregnancy,orinwomenatriskofpregnancynorduringlactation.

Reproductionstudiesperformedinmice,ratsandrabbitsusingparenteralandoraladministrationdidnotrevealany

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

otherquinolones,ciprofloxacinhasbeenshowntocausearthropathyinimmatureanimalsandthereforeitsuseduring

pregnancyorinwomencapableofchildbearingisnotrecommended.Studieshaveindicatedthatciprofloxacinis

secretedinbreastmilk.Administrationtonursingmothersisthusnotrecommended.

4.7Effectsonabilitytodriveandusemachines

Ciprofloxacincouldresultinanimpairmentofthepatient’sabilitytodriveroroperatemachinery,particularlyin

conjunctionwithalcohol.

4.8Undesirableeffects

Adversedrugreactionsbasedonallclinicalstudieswithciprofloxacin(oral,parenteral)sortedbyCIOMSIII

categoriesoffrequencyusingMedDRAterminologyarelistedbelow.Themostfrequentlyreportedadversereactions

arenausea,diarrhoeaandinjectionandinfusionsitereactions(intravenousadministrationonly).

Adversedrugreactionsderivedfrompost-marketingreportsareincludedinthecolumnfrequency“notknown”.

Common

1%to<10% Uncommon

0.1%to<1% Rare

0.01%to<0.1% Veryrare

<0.01% Notknown

InfectionsandInfestations

Candida

infections Antibioticassociated

colitis(veryrarely

withpossiblefatal

outcome,referto

Section4.4)

BloodandLymphaticSystemDisorders

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Anaemia

Neutropenia

Leukocytosis

Thrombocytopenia

Thrombocythaemia anaemia

Agranulocytosis

Pancytopenia

(life-threatening)

Bonemarrow

depression(life-

threatening)

ImmuneSystemDisorders

Allergicreaction

Allergicoedema/

angiooedema Anaphylactic

reaction

Anaphylactic

shock(life-

threatening) Serumsickness-

likereaction

MetabolismandNutritionDisorders

Anorexia Hyperglycaemia

PsychiatricDisorders

Psychomotor

hyperactivity/

agitation Confusionand

disorientation

Anxietyreaction

Abnormaldreams

Depression

Hallucinations Psychotic

reactions(which

mayprogressto

self-endangering

behaviour)

NervousSystemDisorders

Headache

Dizziness

Sleepdisorders

Tastedisorders

(usually

reversibleupon

discontinuation

Par-andDysaesthesia

Hypoaesthesia

Tremor

Seizures

Vertigo

Somnolence Migraine

Disturbed

coordination

Smelldisorders Hyperaesthesia

Intracranial

hypertension

EyeDisorders

Visualdisturbances Visualcolour

distortions

EarandLabyrinthDisorders

Tinnitus

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CardiacDisorders

Tachycardia

VascularDisorders

Vasodilatation

Hypotension

Syncope Vasculitis

Respiratory,ThoracicandMediastinalDisorders

Dyspnoea(including

asthmaticcondition)

GastrointestinalDisorders

Nausea

Diarrhoea Vomiting

Gastrointestinal

andabdominal

pains

Dyspepsia

Flatulence Dysphagia Pancreatitis

Hepato-biliaryDisorders

Transient

increasein

transaminases

Increased

bilirubin Transienthepatic

impairment

Jaundice

Hepatitis(non

infective) Livernecrosis

(veryrarely

progressingto

life-threatening

hepaticfailure)

SkinandSubcutaneousTissueDisorders

Rash

Pruritus

Urticaria Photosensitivity

reactions

Unspecificblistering Petechiae

Erythema

multiformeminor Erythema

nodosum

Stevens-Johnson

syndrome

Toxicepidermal

necrolysis.

Musculoskeletal,ConnectiveTissueandBoneDisorders

Arthralgia Myalgia

Arthritis

Increasedmuscletone

andcramping Muscular

weakness

Tendonitis

Tendonrupture

(predominantly Exacerbationof

symptomsof

myasthenia

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Theincidenceofarthropathy,mentionedabove,isreferringtodatacollectedinstudieswithadults.Inchildren

arthropathyisreportedtooccurmorecommonly(Seealso4.4Specialwarningandprecautionsforuse).

4.9Overdose

Basedonthelimitedinformationavailable,intwocasesiningestionofover18gofciprofloxacin,reversiblerenal

toxicityhasoccurred.Therefore,apartfromroutineemergencymeasures,itisrecommendedtomonitorrenalfunction,

includingurinarypHandacidify,ifrequired,topreventcrystalluria.Patientsmustbekeptwellhydratedandinthecase

ofrenaldamageresultinginprolongedoliguria,dialysisshouldbeinitiated.

CalciumormagnesiumantacidsmaybeadministeredassoonaspossibleafteringestionofBioFloxcintabletsinorder

toreducetheabsorptionofciprofloxacin.

Serumlevelsofciprofloxacinarereducedbydialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

PharmacotherapeuticGroup:Fluoroquinoloneantibacterials

ATCCode:J01MA02.

Mechanismofaction

Asafluoroquinoloneantibacterialagent,ciprofloxacinactsonthebacterialenzymesDNA-gyraseandtopoisomerase

Achillestendon,

refertoSection

4.4)

RenalandUrinaryDisorders

Renal

impairment Renalfailure

Haematuria

Crystalluria

Tubulointerstitial

nephritis

GeneralDisordersandAdministrationSiteConditions

Injectionand

infusionsite

reactions(only

intravenous

administration) Unspecificpain

Feelingunwell

Fever Oedema

Sweating

(hyperhidrosis) Gaitdisturbance

Investigations

Transient

increasein

bloodalkaline

phosphatase Prothrombinlevel

abnormal

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Mechanismofresistance

Invitroinvestigationshaveshownthatresistancetociprofloxaciniscommonlyduetomutationsinbacterial

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

fluoroquinolonesmayoccurwhenthemechanismofresistanceisduetomutationsinbacterialgyrases.However,

singlemutationsmaynotresultinclinicalresistance,butmultiplemutationsgenerallydoresultinclinicalresistanceto

allactivesubstanceswithintheclass.Impermeabilityand/oractivesubstanceeffluxpumpmechanismsofresistance

mayhaveavariableeffectonsusceptibilitytofluoroquinolones,whichdependsonthephysiochemicalpropertiesof

thevariousactivesubstanceswithintheclassandtheaffinityoftransportsystemsforeachactivesubstance.Plasmid

mediatedresistanceencodedbyqnr-geneshavebeenreported.Resistancemechanismsthatinactivatepenicillins,

cephalosporins,aminoglycosides,macrolides,andtetracyclinesdonotinterferewiththeantibacterialactivityof

ciprofloxacin.

InvitroSusceptibilityData

InaccordancetotheguidancedocumentCPMP/EWP/558/95rev1EUCASTclinicalMICbreakpointsfor

moxifloxacinarelistedtogetherwithClinicalandLaboratoryStandardsInstitute(CLSI,formerlyNCCLS)

interpretativecriteriaforthesusceptibilitytestingofciprofloxacinwherebreakpointsdiffer.CLSIdiscbreakpointsare

alsoincludedsincethemajorityofsusceptibilitytestinginEuropeisperformedbythismethod.

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

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

Organism Susceptible

(mg/L) Resistant

(mg/L)

Enterobacteriaceae ≤0.5 >1

Pseudomonas ≤0.5 >1

Staphylococcus 1 ≤1 >1

Streptococcuspneumoniae 2 ≤0.125 >2

Haemophilusinfluenzaeand

Moraxellacatarrhalis 3 ≤0.5

>0.5

Neisseriagonorrhoeae ≤0.03 >0.06

Non-speciesrelated

breakpoints 4 ≤0.5 >1

1.Staphylococcusspp.-breakpointsforciprofloxacinandofloxacinrelatetohighdose

therapy.

2.Streptococcuspneumoniae-wild-typeS.pneumoniaearenotconsideredsusceptibleto

ciprofloxacinorofloxacinandarethereforecategorizedasintermediate.

3.StrainswithMICvaluesabovetheS/Ibreakpointareveryrareornotyetreported.The

identificationandantimicrobialsusceptibilitytestsonanysuchisolatemustberepeatedand

iftheresultisconfirmedtheisolatesenttoareferencelaboratory.Untilthereisevidence

regardingclinicalresponseforconfirmedisolateswithMICabovethecurrentresistant

breakpoint(initalics)theyshouldbereportedresistant.Haemophilus/Moraxella-

fluoroquinolonelow-levelresistance(ciprofloxacinMIC:sof0.125-0.5mg/L)mayoccur

inH.influenzae.Thereisnoevidencethatlow-levelresistanceisofclinicalimportancein

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ClinicalandLaboratoryStandardsInstitute™(CLSI),formerlyNCCLSbreakpointsarepresentedinthetablebelow

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

Table3:ClinicalandLaboratoryStandardsInstitute™(CLSI)MIC,(mg/L)anddiscdiffusionbreakpoints

(mm)(M100-S16,2006):

Theprevalenceofacquiredresistancemayvarygeographicallyandwithtimeforselectedspeciesandlocalinformation

ofresistanceisdesirable,particularlywhentreatingsevereinfections.Asnecessary,expertadviceshouldbesought

wherethelocalprevalenceofresistanceissuchthatutilityoftheagentinatleastsometypesofinfectionsis

questionable.

4.Non-speciesrelatedbreakpointshavebeendeterminedmainlyonthebasisofPK/PD

dataandareindependentofMICdistributionsofspecificspecies.Theyareforuseonlyfor

speciesthathavenotbeengivenaspecies-specificbreakpointandnotforthosespecies

wheresusceptibilitytestingisnotrecommended(markedwith--orIEinthetable).

Organism Susceptible Intermediate Resistant

Enterobacteriaceae ≤1 a

≥21 b 2 a

16-20 b ≥4 a

≤15 b

Pseudomonas

aeruginosaandother

non-

Enterobacteriaceae ≤1 a

≥21 b 2 a

16-20 b ≥4 a

≤15 b

Staphylococcusspp. ≤1 a

≥21 b 2 a

16-20 b ≥4 a

≤15 b

Enterococcusspp. ≤1 a

≥21 b 2 a

16-20 b ≥4 a

≤15 b

Haemophilusspp. ≤1 c

≥21 d -

Neisseriagonorrhoeae ≤0.06 e

≥41 e 0.12-0.5 e

28-40 e ≥1 e

≤27 e

ThisinterpretivestandardisapplicableonlytobrothdilutiontestsusingCAMHB

incubatedinambientairat33to35°C(donotexceed35°C)for16-20hours

ThisinterpretivestandardisapplicableonlytodiscdiffusiontestsusingMueller-Hinton

agarincubatedinambientairat33to35°C(donotexceed35°C)for16-18hours

cThisinterpretivestandardisapplicableonlytobrothdilutionsusceptibilitytestswithHaemophilus

influenzaeandHaemophilusparainfluenzaeusingHaemophilustestmedium(HTM)brothincubatedin

ambientairat35°C±2°Cfor20–24hours

dThisinterpretivestandardisapplicableonlytodiscdiffusiontestswithH.influenzaeandH.parainfluenzae

usingHTMincubatedin5%CO

at35°C±2°Cfor16-18hours

eThisinterpretivestandardisapplicableonlytoagarbasedsusceptibilitytestsusingGCagarand1%defined

growthsupplementat36±1°C(nottoexceed37°C)in5%CO

for20-24hours.

Commonlysusceptiblespecies

AerobicGram-positivemicro-organisms

Bacillusanthracis

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5.2Pharmacokineticproperties

Absorptionoforaldosesofciprofloxacintabletformulationoccursrapidly,mainlyfromthesmallintestine,thehalf-

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

alsoincreasesdoseproportionatelyafteradministrationofbothsingleandrepeatedoral(tablet)andintravenousdoses.

Plasmalevelspeakapproximately1.5-2.5hoursafterdosingandtheAUC

0- ∞isintherangeof5-12mg.h/l.The

absolutebioavailabilityisapproximately70-80%andciprofloxacinissubjecttoonlyslightfirstpassmetabolism.

Theintakeoffoodatthesametimeasadministrationoforalciprofloxacinhasamarginalbutclinicallynotrelevant

effectonthepharmacokineticparametersC

andAUC.Nospecificrecommendationsarenecessarywithregardto

Citrobacterfreundii*

Haemophiliusinfluenzae*

Moraxellacatarrhalis*

Shigellaspp.

Speciesforwhichacquiredresistancemaybeaproblem

AerobicGram-positivemicro-organisms

Staphylococcusaureus(methicillin-susceptible)*

Streptococcuspneumoniae*

AerobicGram-negativemicro-organisms

Burkholderiacepacia +

Campylobacterspp. +

*

Enterobacteraerogenes

Enterobactercloacae*

Escherichiacoli*

Klebsiellaoxytoca

Klebsiellapneumoniae*

Morganellamorganii +

*

Neisseriagonorrhoeae*

Proteusmirabilis +

*

Proteusvulgaris*

Providenciaspp.

Pseudomonasaeruginosa +

*

Pseudomonasfluorescens +

Salmonellaspp.*

Serratiamarcescens +

*

Inherentlyresistantorganisms

AerobicGram-positivemicro-organisms

Staphylococcusaureus(methicillin-resistant)

AerobicGram-negativemicro-organisms

Stenotrophomonasmaltophilia

*Clinicalefficacyhasbeendemonstratedforsusceptibleisolatesinapprovedclinical

indications

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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.Theeliminationkineticsarelinearandafterrepeateddosingat12

hourlyintervals,nofurtheraccumulationisdetectedafterthedistributionequilibriumisattained(at4-5half-lives).The

eliminationhalf-lifeofunchangedciprofloxacinoveraperiodof24-48hourspost-doseis3.1-5.1hours.

Somestudiescarriedoutwithciprofloxacininseverelyrenallyimpairedpatients(serumcreatinine>265micromole/l

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

half-lifeincomparisonwithhealthyvolunteers,whereasotherstudiesshowednosignificantcorrelationbetween

eliminationhalf-lifeandcreatinineclearance.However,itisrecommendedthatinseverelyrenallyimpairedpatients,

thetotaldailydoseshouldbereducedbyhalf,althoughmonitoringofdrugserumlevelsprovidesthemostreliable

basisfordoseadjustmentasnecessary.

Childrenandadolescents

Thedataavailabletosubstantiatethepharmacokineticdatainchildrenarelimited.InastudyinchildrenCmaxand

AUCwerenotage-dependent(aboveoneyearofage).NonotableincreaseinCmaxandAUCuponmultipledosing

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

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

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

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

foradultsattherapeuticdoses.Basedonpopulationpharmacokineticanalysisofpaediatricpatientswithvarious

infections,thepredictedmeanhalf-lifeinchildrenisapprox.4–5hoursandthebioavailabilityoftheoralsuspension

rangesfrom50to80%.

Inhalationanthrax:Ciprofloxacinserumconcentrationsachievedinhumansserveasasurrogateendpointreasonably

likelytopredictclinicalbenefitandprovidethebasisfortherecommendeddoses.

5.3Preclinicalsafetydata

Followingextensiveoralandintravenoustoxicologytestingwithciprofloxacin,onlytwofindingswhichmaybe

consideredrelevanttotheuseofciprofloxacininmanwereobserved.Crystalluriawasnotedinthosespeciesof

animalswhichhadanormallyalkalineurine.Kidneydamagewithoutthepresenceofcrystalluriawasnotobserved.

Thiseffectisconsideredasecondaryinflammatoryforeign-bodyreaction,duetotheprecipitationofacrystalline

complexofciprofloxacin,magnesiumandproteininthedistaltubulesystemofthekidneys.Thisisconsiderednotto

beaprobleminman,becausetheurineisnormallyacidic.However,toavoidtheoccurrenceofcrystalluria,patients

shouldbewellhydratedandexcessivealkalinityoftheurineavoided.

Articulartolerabilitystudies

Asreportedforothergyraseinhibitors,ciprofloxacincausesdamagetothelargeweight-bearingjointsinimmature

animals.Theextentofthecartilagedamagevariesaccordingtoage,speciesanddose;thedamagecanbereducedby

takingtheweightoffthejoints.Studieswithmatureanimals(rat,dog)revealednoevidenceofcartilagelesions.Ina

studyinyoungbeagledogsciprofloxacincausedseverearticularchangesattherapeuticdosesaftertwoweeksof

treatment,whichwerestillobservedafter5months.Additionally,becauseofthepotentialofarthropathy,theuseof

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Povidone

Sodiumstarchglycolate

Microcrystallinecellulose

Colloidalanhydroussilica

Croscarmellosesodium

Magnesiumstearate

Coat:

Hypromellose

Talc

Titaniumdioxide[E171]

Propyleneglycol

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

3years.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

Keepintheoriginalcontainer.

6.5Natureandcontentsofcontainer

250µmPVC/PVDCblisterswith20µmheat-sealingaluminiumfoilbackingincardboardcarton

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

NicheGenericsLtd.

1CamCentre

WilburyWay

Hitchin,

HertfordshireSG4OTW

Packsizes: 10,20,30,50and100tablets.

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8MARKETINGAUTHORISATIONNUMBER

PA1063/2/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:07October2005

Dateoflastrenewal:07October2010

10DATEOFREVISIONOFTHETEXT

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Date Printed 07/12/2010 CRN 2092814 page number: 15