CEFOTAXIME

Main information

  • Trade name:
  • CEFOTAXIME Solution for Injection 0.5 Grams
  • Dosage:
  • 0.5 Grams
  • Pharmaceutical form:
  • Solution for Injection
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CEFOTAXIME Solution for Injection 0.5 Grams
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0111/005/001
  • Authorization date:
  • 06-12-2002
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cefotaxime0.5gPowderforSolutionforInjection.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each0.5gvialcontains0.5gcefotaxime(ascefotaximesodium).

Sodiumcontent:24mg/vial.

3PHARMACEUTICALFORM

Powderforsolutionforinjection.

Description:Sterile,crystalline,whitetoslightlyyellowpowderforsolutionforinjection.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Cefotaximeisindicatedforthetreatmentofthefollowingsevereinfectionswhenknownorthoughtverylikelytobe

duetobacteriathataresusceptibletocefotaxime(seesection5.1,Pharmacodynamicproperties):

Bacterialpneumonia;cefotaximeisnotactiveagainstbacteriathatcauseatypicalpneumoniaoragainstseveral

otherbacterialspeciesthatmaycausepneumonia,includingP.aeruginosa(seesection5.1,Pharmacodynamic

properties).

Complicatedinfectionsofthekidneysandupperurinarytract.

Severeinfectionsoftheskinandsofttissue.

Genitalinfectionscausedbygonococci,particularlywhenpenicillinhasfailedorisunsuitable.

Intra-abdominalinfections(Suchasperitonitis).Cefotaximeshouldbeusedincombinationwithanantibiotic

thatisactiveagainstanaerobesinthetreatmentofintra-abdominalinfections.

Acutebacterialmeningitis(particularlyifduetoH.influenzae,N.meningitides,S.pneumoniae,E.coli,Kebsiella

spp.)

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantibacterialagents.

4.2Posologyandmethodofadministration

Cefotaximemaybeadministeredbyintravenousbolusinjection,byintravenousinfusion,orbyintramuscularinjection,

afterreconstitutionofthesolutionaccordingtothedirectionsgivenbelow.Dosageandmodeofadministrationshould

bedeterminedbytheseverityoftheinfection,susceptibilityofthecausativeorganismandthepatient'scondition.

Therapymaybestartedbeforetheresultofsensitivitytestsareknown.

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Adultsandchildrenover12years:

Theusualdoseinadultsis2to6gdaily.Thedailydosageshouldbedivided.However,dosagemaybevaried

accordingtotheseverityoftheinfection,sensitivityofcausativeorganismsandconditionofthepatient.

Guidelinesfordosage

Typicalinfectioninpresence(orsuspicion)ofasensiblemicro-organism:1gevery12hourscorrespondingtoatotal

dailydosageof2gintramuscularlyorintravenously.

Infectioninpresence(orsuspicion)ofsensibleormoderatelysensiblemultiplemicro-organisms:1-2gevery12hours

correspondingtoatotaldailydosageof2-4g.

Severeinfectionbyunidentifiedmicro-organismsorforinfectionsthatcannotbelocalised:2-3gasasingledose

every6to8hoursuptoamaximumdailydosageof12g.

AcombinationofCefotaximeandotherantibioticsisindicatedinsevereinfections.

Infantsandchildren(1monthto12yearsofage):

Theusualdosageforinfantsandchildrenis<50kgis50-150mg/kg/dayin2to4divideddoses.Inverysevere

infectionsupto200mg/kg/dayindivideddosesmayberequired.Ininfantsandchildren>50kgtheusualdosein

adults,withoutexceedingthemaximumdailydoseof12gshouldbegiven.

Newborninfantsandprematureinfants:

Therecommendeddosageis50mg/kg/dayin2to4divideddoses.

Incaseoflife-threateningsituationsitmaybenecessarytoincreasethedailydose.Insevereinfections150–200

mg/kg/dayhavebeengiven:Inthosesituationsthefollowingtablemayserveasaguide,sincetherearedifferencesin

kidneymaturation.

Elderly:

Nodosageadjustmentisrequired,providedthatrenalandhepaticfunctionarenormal.

Otherrecommendations:

Gonorrhoea:

Forgonorrhoea,asingleinjection(intramuscularlyorintravenously)of0.5gto1gCefotaxime.Forcomplicated

infectionsconsiderationshouldbegiventoavailableofficialguidance.Syphilisshouldbeexcludedbeforeinitiatingthe

treatment.

Urinarytractinfections:

DailydoseofCefotaxime

0-7days 50mg/kgevery12h

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Bacterialmeningitis:

Inadultsdailydosesof6to12gandinchildrendailydosesof150to200mg/kgdividedinequaldosesevery6to8

hoursarerecommended.Forthenew-born,50mg/kgofcefotaximecanbegivenevery12htoinfants0-7ofageand

every8htothose7-28daysofage.

Intraabdominalinfections:

IntraabdominalinfectionshouldbetreatedwithCefotaximeincombinationwithotherappropriateantibiotics.

Durationoftherapy:

ThedurationoftherapywithCefotaximedependsontheclinicalconditionofthepatientandvariesaccordingtothe

courseofthedisease.AdministrationofCefotaximeshouldbecontinueduntilsymptomshavesubsidedorevidenceof

bacterialeradicationhasbeenobtained.Treatmentoveratleast10daysisnecessaryininfectionscausedby

Streptococcuspyogenes(Parenteraltherapymaybeswitchedtoanadequateoraltherapybeforetheendofthe10days

period).

Dosageinrenalfunctionalimpairment:

Inadultpatientswithacreatinineclearanceof 5ml/min,theinitialdoseissimilartotherecommendedusualdosebut

themaintenancedoseshouldbehalvedwithoutchangeinthefrequencyofdosing.

Dosageindialysisorperitonealdialysis:

Inpatientsonhemodialysisandperitonealdialysisani.v.injectionof0.5g-2g,givenattheendofeachdialysis

sessionandrepeatedevery24hours,issufficienttotreatmostinfectionsefficaciously.

Methodofadministration:

Inordertopreventanyriskofinfection,thepreparationoftheinfusionshouldbedoneincloseasepticconditions.Do

notdelaytheinfusionafterthepreparationofthesolution.

Cefotaximeandaminoglycosidesshouldnotbemixedinthesamesyringeorperfusionfluid.

Intravenousinfusion:

Forshortintravenousinfusion1gor2gCefotaximeshouldbedissolvedin40-50mlWaterforInjectionsorinanother

compatiblefluid(e.g.glucose10%).Afterpreparationthesolutionshouldbegivenasa20minuteintravenous

infusion.

Forlonglastingintravenousinfusion2gCefotaximeshouldbedissolvedin100mlofasuitablefluide.g.0.9%sodium

chlorideorisotonicglucosesolutionorothercompatiblefluidsforinfusions.Afterpreparation,thesolutionmaybe

givenasa50-60minuteintravenousinfusion.

Intravenousinjection:

ForintravenousinjectionCefotaxime0.5gshouldbedissolvedin2mlWaterforInjections,Cefotaxime1gshouldbe

dissolvedin4mlWaterforInjections,Cefotaxime2gshoulddissolvedin10mlWaterforInjectionsandshouldbe

injectedoveraperiodof3-5minutes.Duringpost-marketingsurveillance,potentiallylife-threateningarrhythmiahas

beenreportedinaveryfewpatientswhoreceivedrapidintravenousadministrationofcefotaximethroughacentral

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Intramuscularinjection:

Cefotaxime0.5gisdissolvedinthe2mlWaterforInjectionsorCefotaxime1.0gisdissolvedinthe4mlWaterfor

Injections.Thesolutionshouldbeadministeredbydeepintramuscularinjection.Inordertopreventpainfrominjection

Cefotaxime0.5gmaybedissolvedinthe2ml1%LidocaineHydrochlorideorCefotaxime1.0gmaybedissolvedin

the4ml1%LidocaineHydrochloride(onlyforadults).Solutionswithlidocainemustnotbeadministered

intravenously.Ifthetotaldailydoseismorethan2g,theintravenousadministrationshouldbechosen.Inthecaseof

severeinfections,intramuscularinjectionisnotrecommended.

Thefollowingtableshowsthevolumeofdilutionforeachvialsize

4.3Contraindications

Cefotaximeshouldnotbeusedinpatientswithaknownorsuspectedhypersensitivitytocefotaximeorcephalosporins.

Allergiccrossreactionscanexistbetweenpenicillinsandcephalosporins(seesection4.4).

4.4Specialwarningsandprecautionsforuse

Serious,includingfatalhypersensitivityreactionshavebeenreportedinpatientsreceivingcefotaxime(see

sections4.3and4.8).Ifahypersensitivityreactionoccurs,treatmentmustbestopped.Specialcareisindicated

inpatientswhohavehadananaphylacticresponsetopenicillin.Preliminaryenquiryabouthypersensitivityto

penicillinandotherlactamantibioticsisnecessarybeforeprescribingcephalosporinssincecrossallergyoccurs

in5-10%ofcases.

CasesofseriousbullousskinreactionslikeStevens-Johnsonsyndromeortoxicepidermalnecrolysishavebeen

reportedwithcefotaxime(seesection4.8).Patientsshouldbeadvisedtocontacttheirdoctorimmediatelyprior

tocontinuingtreatmentifskinand/ormucosalreactionsoccur.

Patientswithsevererenaldysfunctionmayneeddosageadjustment(seesection4.2.).Cautionshouldbe

exercisedifcefotaximeisadministeredtogetherwithaminoglycosidesorothernephrotoxicdrugs(seesection

4.5).Renalfunctionmustbemonitoredinthesepatients,theelderly,andthosewithpre-existingrenal

impairment.

Cefotaximeshouldbeusedwithcautioninpatientswithallergicdiathesisandasthma.

Aswithotherbroad-spectrumantibiotics,prolongedusemayresultintheovergrowthofnonsusceptible

organisms,whichmayrequireinterruptionoftreatment.Ifsuper-infectionoccursduringtreatment,specific

anti-microbialtherapyshouldbeinstitutedifconsideredclinicallynecessary.

Diarrhea,particularlyifsevereand/orpersistent,occurringduringtreatmentorintheinitialweeksfollowing

treatment,maybesymptomaticofClostridiumdifficileassociateddisease(CDAD).

CDADmayrangeinseverityfrommildtolifethreatening,themostsevereformofwhichispseudo-

membranouscolitis.

Thediagnosisofthisrarebutpossiblyfatalconditioncanbeconfirmedbyendoscopyand/orhistology.

Itisimportanttoconsiderthisdiagnosisinpatientswhopresentwithdiarrhoeaduringorsubsequenttothe

Methodofadministration

Vialsize Short

intravenousInfusion Longlasting

intravenousinfusion Intravenous

injection Intramuscular

injection

0.5g - - 2ml 2ml

1g 40-50ml - 4ml 4ml

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Ifadiagnosisofpseudomembranouscolitisissuspected,cefotaximeshouldbestoppedimmediatelyand

appropriatespecificantibiotictherapyshouldbestartedwithoutdelay.

Clostridiumdifficileassociateddiseasecanbefavouredbyfaecalstasis.

Medicinalproductsthatinhibitperistalsisshouldnotbegiven.

Sincehaematologicalabnormalitiesmaydevelopduringtreatmentwithcefotaxime,bloodcountshouldbe

monitorediftreatmentlastsforlongerthan7days.Incaseofneutropenia(<1400neutrophils/mm3),treatment

shouldbeinterrupted.

Somecasesofeosinophiliaandthrombocytopenia,rapidlyreversibleonstroppingtreatement,havebeen

reported.Casesofhaemolyticanemiahavebalsobeenreported(seesection4.8).

Highdosesofbeta-lactamantibiotics,includingcefotaxime,particularlyinpatientswithrenalinsufficiency,may

resultinencephalopathy(e.g.impairmentofconsciousness,abnormalmovementsandconvulsions)(seesection

4.8).

Patientsshouldbeadvisedtocontacttheirdoctorimmediatelypriortocontinuingtreatmentifsuchreactions

occur.

Duringpost-marketingsurveillance,potentiallylife-threateningarrhythmiahasbeenreportedinaveryfew

patientswhoreceivedrapidintravenousadministrationofcefotaximethroughacentralvenouscatheter.The

recommendedtimeforinjectionorinfusionshouldbefollowed(seesection4.2).

Thesodiumcontentofcefotaxime(2.09mmol/g)shouldbetakenintoaccountwhenprescribingtopatients

requiringsodiumretention.

Cefotaximeconstitutedwithlidocaineshouldneverbeused:

bytheintravenousroute

ininfantsunder30months

insubjectswithaknownhistoryofhypersensitivitytolidocaineorotherlocalanestheticsoftheamidetype

inpatientswhohaveunpacedheartblock

inpatientswithsevereheartfailure

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Withothermedicaments:

Concomitantadministrationofprobenecidleadstoanincreaseandaprolongationofserumconcentrationsof

cefotaximebyinhibitionofrenaleliminationofcefotaxime.

Theefficacyoforalcontraceptivesmaybedecreasedduringconcomitantuseofcefotaxime.Thereforeduring

therapywithCefotaximeadditionalcontraceptivemethodsshouldbeused.

Concurrenttreatmentwithhighdosesofcephalosporinsandnephrotoxicdrugssuchasaminoglycosidesor

potentdiuretics(e.g.furosemide)mayadverselyaffectrenalfunction.Themonitoringoftherenalfunctionis

strictlyrecommended.

Cefotaximeshouldnotbecombinedwithbacteriostaticantibiotics(e.g.tetracyclines,erythromycinand

chloramphenicol)sinceanantagonisticeffectispossible.

Otherformsofinteractions:

AswithothercephalosporinsapositiveCoombs'testhasbeenfoundinsomepatientstreatedwithcefotaxime.

Thisphenomenoncaninterferewiththecross-matchingofblood.

Afalse-positivereactiontoglucosemayoccurwithreducingsubstances(Benedict'sorFehling'ssolution,orwith

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4.6Fertility,pregnancyandlactation

Thesafetyofcefotaximehasnotbeenestablishedinhumanpregnancy.

Animalstudiesdonotindicatedirectorindirectharmfuleffectswithrespecttoreproductivetoxicity.Thereare,however,no

adequateandwellcontrolledstudiesinpregnantwomen.

Cefotaximecrossestheplacentalbarrier.Therefore,cefotaximeshouldnotbeusedduringpregnancyunlesstheanticipatedbenefit

outweighsanypotentialrisks.

Cefotaximeisexcretedinhumanmilkinlowconcentrations.Useduringlactationcanleadininfantstoaneffectonthe

physiologicalintestinalflorawithdiarrhoea,toSaccharomycescolonisationandmayalsoleadtosensitisation.Adecisionshould

bemadewhethertodiscontinuenursingordiscontinuetreatmenttakingintoaccounttheimportanceofcefotaximetothenursing

woman.

4.7Effectsonabilitytodriveandusemachines

Thereisnoevidencethatcefotaximedirectlyimpairstheabilitytodriveortooperatemachines.

Highdosesofcefotaxime,particularlyinpatientswithrenalinsufficiency,maycauseencephalopathy(e.g.impairmentof

consciousness,abnormalmovementsandconvulsions)(seesection4.8).Patientsshouldbeadvisednottodriveoroperate

machineryifanysuchsymptomsoccur.

4.8Undesirableeffects

Verycommon(

1/10);Common(

1/100to<1/10);Uncommon(

1/1,000to<1/100);Rare(

1/10,000to<1/1,000);Very

rare(<1/10,000));Notknown*(cannotbeestimatedfromtheavailabledata)

*postmarketingexperience

Infectionsandinfestations

Rare

Prolongedusemayresultintheovergrowthofnon-susceptibleorganisms(seesection4.4).

Bloodandlymphaticsystemdisorders:

Uncommon

Leucopenia,eosinophilia,thrombocytopenia.

Rare

Granulocytopeniaandmorerarelyagranulocytosis,maydevelopduringtreatmentwithcefotaxime,particularlyifgiven

overlongperiods.Afewcasesofneutropeniahavebeenobserved,butthesewerereversiblewhentreatmentwasceased.

Rarecasesofhaemolyticanaemiahavebeenreported.Itisthereforerecommendedthatbloodcountshouldbemonitored

iftreatmentlastsforlongerthan7days.

Immunesystemdisorders:

Uncommon

Jarisch-Herxheimerreaction.

Forthetreatmentofborreliosis,aJarisch-Herxheimerreactionmaydevelopduringthefirstdaysoftreatment.The

occurrenceofoneormoreofthefollowingsymptomshasbeenreportedafterseveralweek'streatmentofborreliosis:skin

rash,itching,fever,leucopenia,increaseinliverenzymes,difficultyofbreathing,jointdiscomfort.

Notknown

Anaphylacticreactions,angioedema,bronchospasm,anaphylacticshock.

Nervoussystemdisorders:

Uncommon

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Rare

Administrationofhighdosesofantibioticsbelongingtothisgroup(particularlyinpatientswithrenalinsufficiency)may

resultinencephalopathy,whichmayresultindizziness,convulsionsandfatigue.

Notknown

Headache,dizziness.

Cardiacdisorders

Veryrare

Averysmallnumberofcasesofarrhythmiashaveoccurredfollowingrapidbolusinfusionthroughacentralvenous

catheter.

Gastrointestinaldisorders:

Common

Commonly,patientsreceivingcefotaximeexperiencegastrointestinaldisturbancesuchascandidiasis,nausea,vomiting,

abdominalpain,diarrhoea.Ifsevereandpersistentdiarrhoeaoccurs,pseudomembranouscolitisshouldbeconsidered.In

casesorsuspicionofpseudomembranouscolitis,treatmentwithCefotaximeshouldbediscontinuedandanappropriate

therapyshouldbeinitiated.

Hepato-biliarydisorders:

Uncommon

Increaseinliverenzymes((ASAT,ALAT,LDH,-GT,alkalinephosphatase)and/orbilirubin. Theselaboratory

abnormalitiesmayrarelyexceedtwicetheupperlimitofthenormalrangeandelicitapatternofliverinjury,usually

cholestaticandmostoftenasymptomatic.

Notknown

Hepatitis(sometimeswithjaundice).

Skinandsubcutaneoustissuedisorders:

Common

Hypersensitivityreactionshavebeenreported,theseincludecutaneousreactionssuchasskinrashes,pruritus,urticaria

Drugfever.

Veryrare

Erythemamultiformeexsudativum,

Stevens-Johnsonsyndrome,

Toxicepidermalnecrolysis,

Anaphylacticshock(seesection4.9).

Inpatientswithallergicdiathesis,hypersensitivityreactionsafteradministrationofCefotaximearemorelikelytooccur.

Renalandurinarydisorders:

Uncommon

Decreaseinrenalfunction/increaseofcreatinine(particularlywhenco-prescribedwithaminoglycosides).

Rare

Theremaybeatemporaryincreaseofureaintheserum.

Veryrare

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Generaldisordersandadministrationsiteconditions:

Verycommon

Painattheinjectionsite.

Common

Transientandlocalpainmaybeexperiencedatthesiteofinjection.Thisismorelikelytooccurwithhigherdoses.

Phlebitis/thrombophlebitishasbeenreportedinpatientsreceivingintravenouscefotaxime.However,thishasrarelybeena

causefordiscontinuationoftreatment.

Uncommon

Fever.

4.9Overdose

Symptomsofintoxication:

Cefotaximehasawidemarginofsafety.Casesofacuteintoxicationwithcefotaximehavenotbeenpublished.Symptomsof

overdosemaylargelycorrespondtotheprofileofsideeffects.

Incasesofoverdosage(particularlyinrenalinsufficiency)thereisariskofreversibleencephalopathy.

Therapyofintoxication:

Incaseofoverdose,cefotaximemustbediscontinued,andsupportivetreatmentinitiated,whichincludesmeasurestoaccelerate

elimination,andsymptomatictreatmentofadversereactions(e.g.convulsions).

Thereisnospecificantidoteforoverdose.Serumlevelsofcefotaximecanbereducedbyhaemodialysisorperitonealdialysis.

Therapyofhypersensitivityreactions:

Anaphylacticshockrequiresimmediatecountermeasures.Uponfirstsignsofhypersensitivityreactions(e.g.cutaneousreactions

suchasskinrashesorurticaria,headache,nausea,restlessness)theadministrationofCefotaximeshouldbediscontinued.Incases

ofseverehypersensitivityreactionsoranaphylacticreactions,emergencytreatmentshouldbeinitiated,suchasadministrationof

epinephrineand/orglucocorticoids.Accordingtotheclinicalseverityadditionaltherapeuticmeasuresmayberequired(e.g.

artificialbreathing,applicationofhistamine-receptorantagonists).Incasesofcirculatorycollapse,resuscitationmustbeinitiated

accordingtothecurrentguidelines.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:

Third-generationcephalosporins,ATCCode:J01DD01

Modeofaction

Thebactericidalactivityofcefotaximeresultsfromtheinhibitionofbacterialcellwallsynthesis(duringtheperiodof

growth)causedbyaninhibitionofpenicillin-bindingproteins(PBPs)liketranspeptidases.

Pharmacokineticsandpharmacodynamicsrelationship

Theextentofthebactericidalactivitydependsontheperiodoftimewhentheserumlevelexceedstheminimal

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Mechanismofresistance

Aresistancetocefotaximemaybecausedbyfollowingmechanisms:

inactivationby -lactamases.Cefotaximecanbehydrolysedbycertain -lactamases,especiallybyextended-

spectrum-lactamases(ESBLs)whichcanbefoundinstrainsofEscherichiacoliorKlebsiellapneumoniae,orby

chromosomalencodedinducibleorconstitutive -lactamasesoftheAmpCtypewhichcanbedetectedin

Enterobactercloacae.Thereforeinfectionscausedbypathogenswithinducible,chromosomalencodedAmpC--

lactamasesshouldnotbetreatedwithcefotaximeevenincaseofprovenin-vitro-susceptibilitybecauseoftherisk

oftheselectionofmutantswithconstitutive,derepressedAmpC--lactamases-expression.

reducedaffinityofPBPsagainstcefotaxime.TheacquiredresistanceofPneumococciandotherStreptococciis

causedbymodificationsofalreadyexistingPBPsasaconsequenceofamutationprocess.Incontrasttothis

concerningthemethicillin-(oxacillin-)resistantStaphylococcus,thecreationofanadditionalPBPwithreduced

affinityagainstcefotaximeisresponsibleforresistance.

inadequatepenetrationofcefotaximethroughtheoutercellmembraneofgram-negativebacteriasothatthe

inhibitionofthePBPsisinsufficient.

thepresenceoftransportmechanism(effluxpumps)beingabletoactivelytransportcefotaximeoutofthecell.

Acompletecrossresistanceofcefotaximeoccurswithceftriaxoneandpartiallywithotherpenicillinsand

cephalosporins.

Breakpoints:

Thefollowingminimalinhibitoryconcentrationsweredefinedforsensitiveandresistantgerms:

EUCAST(EuropeanCommitteeonAntimicrobialSusceptibilityTesting)breakpoints(2009-05-25):

*ForStaphylococcusthetestresultsofoxacillinisused.Oxacillin-resistentStaphylococcusisassessedasresistantagainst

cefotaxime.

**ThesusceptibilityofstreptococcusgroupsA,B,CandGcanbeinferredfromtheirsusceptibilitytobenzylpenicillin.

***Generallybasedonserumpharmacokinetics

Susceptibility

Theprevalenceofacquiredresistancemayvarygeographicallyandwithtimeforselectedspeciesandlocalinformation

onresistanceisdesirable,particularlywhentreatingsevereinfections.Iftheefficacyofcefotaximeisquestionabledue

tothelocalprevalenceofresistance,expertopinionshouldbesoughtregardingthechoiceoftherapy.Inparticularin

thecaseofsevereinfectionsorfailureoftherapyamicrobiologicaldiagnosisincludingaverificationofthegermand

Pathogen Susceptible Resistant

Enterobacteriaceae 1mg/l >2mg/l

Staphylococcusspp. --* --*

Streptococcus(groupA,B,C,G) --** --**

OtherStreptococci 0.5mg/l 0.5mg/l

Streptococcuspneumoniae 0.5mg/l >2mg/l

Haemophilusinfluenzae 0.12mg/l >0.12mg/l

Moraxellacatarrhalis 1mg/l >2mg/l

Neisseriagonorrhoeae 0.12mg/l >0.12mg/l

Neisseriameningitidis 0.12mg/l >0.12mg/l

Notspecies-specific

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Commonlysusceptiblespecies

Gram-positiveaerobes

Staphylococcusaureus(methicillin-susceptible)

Streptococcusagalactiae

Streptococcuspneumoniae(incl.penicillin-resistantstrains)

Streptococcuspyogenes

Gram-negativeaerobes

Borreliaburgdorferi°

Escherichiacoli %

Haemophilusinfluenzae

Klebsiellaoxytoca %

Klebsiellapneumoniae #%

Moraxellacatarrhalis°

Morganellamorganii

Neisseriagonorrhoeae°

Neisseriameningitidis°

Proteusmirabilis %

Speciesforwhichacquiredresistancemaybeaproblem

Gram-positiveaerobes

Staphylococcusaureus

Staphylococcusepidermidis +

Staphylococcushaemolyticus +

Staphylococcushominis +

Gram-negativeaerobes

Citrobacterfreundii

Enterobacteraerogenes

Enterobactercloacae

Proteusvulgaris

Serratiamarcescens

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°Literaturedata,referencebooksandtherapyguidelinessupportsusceptibility.

+Inatleastoneregiontheresistancerateis>50%.

#InIntensiveCareUnitstheresistancerateis10%.

%ExtendedSpectrumBeta-Lactamase(ESBL)producingstrainsarealwaysresistant.

Inthecommunityareatheresistancerateis<10%.

5.2Pharmacokineticproperties

Absorption:

Cefotaximeisforparenteralapplication.Meanpeakconcentrations5minutesafterintravenousinjectionareabout81-

102mg/lfollowinga1gdoseofcefotaximeandabout167-214mg/l8minutesaftera2gdose.Intramuscularinjection

producesmeanpeakplasmaconcentrationsof20mg/lwithin30minutesfollowinga1gdose.

Distribution:

Cefotaximegivesgoodpenetrationintodifferentcompartments.Therapeuticdruglevelsexceedingtheminimum

inhibitorylevelsforcommonpathogenscanrapidlybeachieved.Cerebrospinalfluidconcentrationsarelowwhenthe

meningesarenotinflamedbutcefotaximeusuallypassestheblood-brainbarrierinlevelsabovetheMICofthe

sensitivepathogenswhenthemeningesareinflamed(3-30µg/ml).Cefotaximeconcentrations(0.2-5.4µg/ml),

inhibitoryformostGram-negativebacteria,areattainedinpurulentsputum,bronchialsecretionsandpleuralfluidafter

dosesof1or2g.Concentrationslikelytobeeffectiveagainstmostsensitiveorganismsaresimilarlyattainedinfemale

reproductiveorgans,otitismediaeffusions,prostatictissue,interstitialfluid,peritonealfluidandgallbladderwall,after

Bacteroidesfragilis

Inherentlyresistantspecies

Gram-positiveaerobes

Enterococcusspp.

Listeriamonocytogenes

Staphylococcusaureus(methicillin-resistant)

Gram-negativeaerobes

Acinetobacterbaumannii

Pseudomonasaeruginosa

Stenotrophomonasmaltophilia

Anaerobes

Clostridiumdifficile

Others

Chlamydiaspp.

Chlamydophilaspp.

Legionellapneumophila

Mycoplasmaspp.

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Cefotaximepassestheplacentaandattainshighconcentrationsinfoetalfluidandtissues(upto6mg/kg).Small

amountsofcefotaximediffuseintothebreastmilk.

Proteinbindingforcefotaximeisapproximately25-40%.

Theapparentdistributionvolumeforcefotaximeis21-37lafter1gintravenousinfusionover30minutes.

Biotransformation:

Cefotaximeispartlymetabolisedinhumanbeings.Approximately15-25%ofaparenteraldosearemetabolisedtothe

O-desacetylcefotaximemetabolite,whichalsohasantibioticproperties.

Elimination:

ThemainrouteofexcretionofcefotaximeandO-desacetylcefotaximeisthekidney.Onlyasmallamount(2%)of

cefotaximeisexcretedinthebile.Intheurinecollectedwithin6hours40-60%oftheadministereddoseofcefotaxime

isrecoveredasunchangedcefotaximeand20%isfoundasO-desacetylcefotaxime.Afteradministrationofradioactive

labelledcefotaximemorethan80%canberecoveredintheurine,50-60%ofthisfractionisunchangedcefotaximeand

therestcontainsmetabolites.

Thetotalclearanceofcefotaximeis240-390ml/minandtherenalclearanceis130-150ml/min.

Theserumhalf-livesofcefotaximeandO-desacetylcefotaximearenormallyabout50-80and90minutesrespectively.

Inelderly,theserumhalf-lifeofcefotaximeis120-150min.

Inpatientswithimpairedrenalfunction(creatinineclearance3-10ml/min)theserumhalf-lifeofcefotaximecanbe

increasedto2.5-3.6hours.

Inneonates,thepharmacokineticsareinfluencedbygestationandchronologicalage,thehalf-lifebeingprolongedin

prematureandlowbirthweightneonatesofthesameage.

5.3Preclinicalsafetydata

Preclinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofsafetypharmacology,repeated

dosetoxicity,genotoxicity,andtoxicitytoreproduction.

Cefotaximepassesthroughtheplacenta.Afterintravenousadministrationof1gCefotaximeduringthebirthvaluesof

14µg/mlweremeasuredintheumbilicalcordseruminthefirst90minutesafterapplication,whichdroppedto

approximately2.5µg/mlbytheendofthesecondhourafterapplication.Intheamnioticfluid,thehighest

concentrationof6.9µg/mlwasmeasuredafter3-4hours.ThisvalueexceedstheMICformostgram-negative

bacteria.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

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6.2Incompatibilities

Cefotaximeshouldnotbeaddedwithotherantibiotics,inthesamesyringeorsolutionforinfusion.Thisconcerns

especiallyaminoglycosides.

Cefotaximeshouldnotbemixedwithsolutionscontainingsodiumbicarbonate.

6.3Shelflife

Unopened:

2years.

Opened&Reconstitutedproduct:

Forimmediateuse.

6.4Specialprecautionsforstorage

Unopened:

Donotstoreabove25°C.Keepcontainerintheoutercartoninordertoprotectfromlight.

Forstorageconditionsofthereconstitutedmedicinalproduct,seesection6.3.,Shelflife.

6.5Natureandcontentsofcontainer

Nature

0.5gpowderforsolutionforinjection:

15mlvialsofclearglasshydr.classIIIwithhalogenatedbutylrubberstopper.

Content

1vialpercarton

1vialpercartoninpackof5cartons

1vialpercartoninpackof10cartons

1cartonof10vials

1cartonof25vials

1cartonof50vials

1cartonof100vials

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Aseptictechniquesshouldbeusedtoreconstitutethesolution.Thereconstitutedsolutionshouldbeadministered

immediately.

Cefotaximeiscompatiblewithseveralcommonlyusedintravenousinfusionfluids:

WaterforInjection

0.9%SodiumChloridesolution

5%Glucosesolution

5%Glucose/0.9%SodiumChloridesolution

Ringer-lactatesolution

5%Metronidazolesolution

Dextran40in0.9%SodiumChloridesolution

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Thecompatibilityofcefotaximeinotherinfusionfluidsshouldbecheckedbeforeuse.

Followingreconstitutionthesolutionshouldbeclearandpaleyellowishtobrown-yellowish.Donotuseifany

particulatematterisvisible.Withdrawonlyonedose.

Anyunusedsolutionshouldbediscarded.

Seepoint4.2fortheinstructionsforreconstitution.

7MARKETINGAUTHORISATIONHOLDER

SandozGmbH

Biochemiestrasse10

A-6250Kundl

Austria

8MARKETINGAUTHORISATIONNUMBER

PA0111/005/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation: 06December2002

Dateoflastrenewal: 17December2006

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 23/08/2011 CRN 2097136 page number: 14