CLAFORAN

1

ודילערשואוקדבנונכותותואירבהדרשמי"עעבקנהזןולעטמרופ ינויב 3102

CLAFORAN DATASHEET

1. TRADENAMEOFTHEMEDICINALPRODUCT

Claforan

2 QUALITATIVEANDQUANTITATIVECOMPOSITION

1Claforan1.0g vialcontains 1.048gcefotaximesodium, equivalentto 1g cefotaxime.

For afull listofexcipients,seesection6.1.

3 PHARMACEUTICALFORM

Powder withsolventforsolutionfor injectionor infusion.

Whiteto yellowish-whitepowder and colourless solutionas solvent.

4 CLINICALPARTICULARS

4.1 TherapeuticIndications

Properties:Claforanis abroad-spectrum bactericidalcephalosporinantibiotic.

Claforanis exceptionallyactive invitro againstGram-negativeorganisms sensitiveor

resistantto firstor secondgenerationcephalosporins.Itis similar to other

cephalosporins inactivityagainstGram-positiveorganisms.

Indication:CLAFORANisindicatedinthetreatmentofthefollowing infectionseither before

theinfecting organismhasbeenidentified or whencaused by bacteriaofestablished

sensitivity.

Septicaemias

RespiratoryTractInfections suchas acuteandchronicbronchitis,bacterial

pneumonia, infected bronchiectasis, lung abscess andpost-operativechestinfections.

UrinaryTractInfections suchas acuteandchronicpyelonephritis,cystitis and

asymptomaticbacteriuria.

Soft-TissueInfections suchascellulitis, peritonitisand woundinfections.

BoneandJointInfections suchas osteomyelitis, septicarthritis.

Obstetric andGynaecologicalInfections suchas pelvicinflammatorydisease.

Gonorrhoea particularly whenpenicillinhas failed or is unsuitable.

OtherBacterial Infections meningitis and other sensitiveinfections suitablefor

parenteral antibiotictherapy.

PROPHYLAXIS:

2

TheadministrationofClaforanprophylacticallymayreducetheincidenceofcertain

post-operativeinfections inpatients undergoing surgical procedures thatareclassified

as contaminated or potentiallycontaminated or incleanoperations whereinfection

would haveserious effects.

Protectionis bestensuredby achieving adequatelocaltissueconcentrations atthe

timecontaminationis likelyto occur. Claforanshouldthereforebeadministered

immediatelypriorto surgeryand ifnecessary continued in the immediatepost-

operativeperiod.

Administrationshould usuallybestopped within24hours sincecontinuing useofany

antibioticinthemajorityofsurgical proceduresdoes not reducetheincidenceof

subsequentinfection.

BACTERIOLOGY:

Thefollowing organisms haveshown invitro sensitivityto Claforan.

GRAMPOSITIVE:

Staphylococci, includingcoagulase-positive,coagulase-negativeand penicillinase-

producing strains.

Beta-haemolyticandotherstreptococci suchas Streptococcus mitis ( viridans ) (many

strains ofenterococci, e.g. Streptococcus faecalis , arerelativelyresistant).

Streptococcus ( Diplococcus ) pneumoniae .

Clostridium spp .

GRAMNEGATIVE:

Escherichiacoli .

Haemophilusinfluenzae including ampicillinresistantstrains.

Klebsiella spp.

Proteus spp. (bothindolepositive and indolenegative).

Enterobacter spp.

Neisseria spp. (includingβ-lactamaseproducing strainsof N. gonorrhoea ).

Salmonella spp. (including Sal. typhi ).

Shigella spp.

Providencia spp.

Serratia spp.

Citrobacter spp.

Claforanhasfrequentlyexhibited useful invitro activityagainst Pseudomonas and

Bacteroides species althoughsomestrainsof Bacteroides fragilis areresistant.

Thereis invitro evidenceofsynergy betweenClaforanand aminoglycosideantibiotics

suchas gentamicinagainstsomespecies ofGram-negativebacteriaincludingsome

strains of Pseudomonas . No invitro antagonismhas beennoted. Insevereinfections

caused by Pseudomonas spp. theadditionofanaminoglycosideantibioticmaybe

indicated.

4.2 PosologyandMethodofAdministration

DOSAGE:

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Claforanmaybeadministered intravenously, bybolus injection, byinfusionor

intramuscularly.Thedosage, routeandfrequencyofadministrationshould be

determined by the severityofinfection, thesensitivityofcausativeorganisms and

conditionofthepatient. Therapy maybeinitiated beforetheresults ofsensitivitytests

areknown.

Adults: Therecommended dosagefor mild to moderateinfections is1g 12hourly.

However, dosagemaybevaried according to theseverityoftheinfection, sensitivityof

causativeorganisms andconditionofthepatient. Therapy maybeinitiated beforethe

results ofsensitivitytests areknown.

Insevereinfections dosagemaybeincreasedup to 12g dailygivenin3or 4divided

doses. For infections caused by sensitive Pseudomonas spp. dailydoses ofgreater

than6g willusuallyberequired.

Children: Theusual dosagerangeis 100-150mg/kg/dayin2to 4divided doses.

However, inverysevereinfections doses ofup to200mg/kg/daymayberequired.

Neonates: Therecommended dosageis50mg/kg/dayin2to 4divided doses. In

severeinfections 150-200mg/kg/day, individeddoses,havebeengiven.

DosageinGonorrhoea: A singleinjectionof1g maybeadministered

intramuscularly orintravenously.

DosageinRenalImpairment: Becauseofextra–renal elimination, it isonly

necessary to reducethedosageofClaforaninsevererenal failure(GFR <5ml/min=

serum creatinineapproximately751micromol/l). After aninitial loading doseof1g,

dailydoseshould behalvedwithoutchangeinthefrequencyofdosing, i.e.1g in12

hourlybecomes 0.5g 12hourly,1g 8hourly becomes0.5g8hourly, 2g8hourly

becomes 1g8hourlyetc. As in all otherpatients, dosagemayrequirefurther

adjustmentaccording to thecourseoftheinfectionand thegeneral conditionofthe

patient.

ADMINISTRATION:

IntravenousAdministration:

For I.V. injectionClaforan1.0g shouldbedissolved in atleast4ml water forinjections.

Shakewell until dissolved and thenwithdrawtheentirecontentsofthevial into the

syringeand use immediately.

For intermittentI.V. injections, the solutionmustbeinjected over aperiod of3to5

minutes.During postmarketingsurveillance,potentiallylifethreating arrythmiahas

beenreported in averyfewpatients who received rapid intravenous administrationof

cefotaximethroughacentral venous catheter.

IntravenousInfusion: Claforanmaybeadministered by intravenous infusion. 1-2g

aredissolved in40–100mlofWater for InjectionPhEur or in theinfusionfluids listed

under “Pharmaceutical Particulars”. Theprepared infusionmaybeadministered over

20-60minutes. Toproduceaninfusionusing vials withaninfusionconnector, remove

thesafetycapand directlyconnecttheinfusionbag. Theneedleintheclosurewill

automaticallypierce thevial stopper. Pressing theinfusionbag will transfer solvent

into thevial. Reconstituteby shaking thevial andfinally, transfer thereconstituted

solutionbackto theinfusionbag ready for use.

Intramuscularadministration

For intramascular injectionClaforan1.0gshould bedissolved in4ml water for

injections andthenadministered by deep intragluteal injection. PainonI.M.injection

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canbeavoided bydissolving Claforan1.0in4ml lidocainesolution1%. An

intravascular injectionshould beavoided becauselidocainecan causerestlessness,

tachycardia, conductiondisturbances,vomiting andconvulsions following intravascular

administration.(See4.3contraindications)

Itis advisablenot to injectavolumegreater than4mlononeside. Ifthedailydose

exceeds 2g,or morethantwo dailyinjections arerequired, thedoseshouldbe

administered intravenously.

4.3 Contraindications

-DuetotheriskofanaphylacticshockClaforaniscontra-indicatedinpatientswith

knownhypersensitivityreactionsofimmediatetypeorseverehypersensitivityto

cefotaximeorothercephalosporinsoranaphylaxistopenicillinsorotherbeta-

lactamantibiotics.

-Claforanconstituted withlidocaine mustnever beused:

Administrationbytheintravenous route

ininfantsagedless than30monthsofage

insubjects withknown

historyofhypersensitivityto lidocaineorother local anestheticsofthe

amidetype

inpatients whohavenon-pacedheartblock

inpatients withsevereheartfailure.

4.4 SpecialWarningsandSpecial Precautions forUse

Anaphylactic reactions

Duringcefotaximetherapy,severeacute(andevenfatal)hypersensitivityreactions

mayoccur(e.g.angioedema,bronchospasm,anaphylaxisandevenshock)(see

sections4.3and4.8).Inthesecases,cefotaximemustbediscontinuedand

appropriatetreatmentinitiated (e.g. shocktherapy).

ParticularprecautionforuseofClaforanisrequiredinpatientswithany

hypersensitivitytopenicillinandotherbeta-lactamantibioticsasaparallelallergymay

exist(forcontraindicationsinpatientswithknownhypersensitivityreactions,see

section4.3).Hypersensitivityreactions(anaphylaxis)occurringwiththesetwo

antibioticfamilies maybeserious or evenfatal.

Inpatients withallergic reactivityofanyother kind (e.g. withhayfever or bronchial

asthma), Claforanshould likewisebeused withparticular caution, as thereis an

increased riskofserioushypersensitivityreactions inthesecases.

Severebullousreactions

Severebullous skinreactions, suchas Stevens-Johnsonsyndromeor toxicepidermal

necrolysis,havebeenreported withClaforantherapy(seesection4.8). Patients should

beurged to consultadoctor immediatelyifmucocutaneousreactions occur.

Clostridiumdifficileassociateddisease(e.g.pseudomembranouscolitis)

Severeand persistentdiarrhoeaduring or withinthefirstfewweeks oftreatmentmay

bedue to Clostridium-difficile-associated diseasewhich, inits mostsevereformas

pseudomembranous colitis,mayhaveafatal outcome.Diagnosis canbeconfirmed by

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endoscopic orhistological tests. Atthemeresuspicionofpseudomembranous colitis,

cefotaximetreatmentmustbediscontinued immediatelyand appropriatetreatment

promptlyinstituted (e.g. administrationofspecificantibiotics/chemotherapeuticagents

withclinicallyprovenefficacy). Antiperistalticagentsmustnot betaken. Clostridium-

difficile-associated diseasecan bepromoted bycoprostasis.

Haematologicalreactions

Leukopenia,neutropeniaor,morerarely,agranulocytosismayoccur,especiallyafter

prolongeduse.Bloodcountmonitoringshouldthereforebeperformedincaseswhere

treatmentlastsformorethan7to10days.Treatmentwithcefotaximeshouldbe

discontinued ifneutropeniaoccurs.

A fewcases ofeosinophiliaand thrombocytopenia, rapidly reversibleupon

discontinuationofcefotaxime, havebeenreported, aswell as cases ofhaemolytic

anaemia(seealso section4.8).

Neurotoxicity

Especiallyinpatientswithrenal insufficiency,encephalopathymayoccur afterhigh

doses ofbeta-lactamantibiotics, includingcefotaxime,whichmaylead to conditions

suchas clouded consciousness, movementdisorders and seizures (seesection4.8).

Patients should beurged toconsultadoctor immediatelyattheonsetofsuch

reactions. Ifseizures occur,theusual emergencymeasures areindicated and

treatmentwithClaforanmay, uponconsiderationofthebenefits and risks,haveto be

discontinued.

PatientswithRenalinsufficiency

For patients withseverelyimpaired renal function(glomerularfiltrationratebelow

10ml/min), the doseshould beadjusted tocreatinineclearance(seesection4.2).

Renal functionmustbemonitored ifnephrotoxicmedications (e.g. aminoglycosides)

areco-administered (seealso section4.5). Monitoringofrenalfunctionis also

indicated in elderlypatientsand in thosewithpre-existing impairmentofrenal

function.

Precautionsforuse

Inindividual patients, potentiallylife-threateningcardiacarrhythmiashavebeenreported to

occur after rapid injectionofClaforanviaacentralvenous catheter (CVC). Therecommended

rateofinjectionmustthereforeberespected (seesection4.2).

Monitoring

As withanyuseofantibiotics, administrationofClaforan(especiallyover long periods of

treatment) canlead to aproliferationofpathogens, whichareinsensitiveto themedication

being used. Vigilanceis required forsignsofapossiblesecondaryinfectionwithsuch

pathogens.Secondary infections areto betreated accordingly.

As withother beta-lactamantibiotics, granulocytopeniaand, morerarely, agranulocytosis may

develop during treatmentwithCLAFORAN, particularly ifgivenover long periods. For courses

oftreatmentlasting longerthan10days, bloodcountsshouldthereforebemonitored.

Claforanisnot suitableforthetreatmentofsyphilis.

Thereis insufficientclinicalexperiencewithinfectionscaused by Salmonellatyphi,

paratyphi A and paratyphiB.

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Effectonlaboratorydiagnostictests

As withother cephalosporins, the Coombs’testmayprove positiveinsomepatients

duringcefotaximetreatment. This canalso affectcrossmatching.

Urinaryglucosetests usingnon-specificreducing agents mayyieldfalse-positive

results.This phenomenondoes not occur withtests based onglucoseoxidase.

Sodiumuptake

1bottleofClaforan1.0gcontainsabout2.1mmol(48mg)sodium,.Tobetakeninto

considerationby patients onacontrolled sodium(low-sodium/low-salt) diet.

Formulationcontaininglidocaine

See4.3contraindication

Speedof I.V.Injection

Seesection4.2Posologyand MethodofAdministration.

Neutropenia

For treatmentcourses lasting longer than10days, theblood whitecellcountshould be

monitored and treatmentstopped in the eventofneutropenia.

Other

CLAFORAN,likeother parenteral anti-infectivedrugs,maybelocallyirritating to tissues. In

most cases, perivascular extravasationofCLAFORANresponds tochanging oftheinfusionsite.

Inrareinstances, extensiveperivascular extravasationofCLAFORAN mayresultintissue

damageand requiresurgical treatment. To minimizethepotential fortissueinflammation,

infusionsites should bemonitored regularlyand changed whenappropriate.

4.5 InteractionswithOtherMedicinesandOtherForms ofInteraction

Other antibiotics

Cefotaximeshouldnotbecombinedwithbacteriostaticagents(e.g.tetracyclines,

erythromycin,chloramphenicolorsulphonamide),as,intermsof invitro antibacterial

activity,anantagonisteffecthasbeenobserved.Asynergisticeffectmayoccurwhen

combined withaminoglycosides.

Probenecid

Concomitantadministrationofprobenecidcauseshigher,longer-lastingserum

cefotaximeconcentrations,due to inhibitionofrenal excretion.

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Potentially nephrotoxicmedicationsandloopdiuretics

As withother cephalosporins, cefotaximemaypotentiatethenephrotoxiceffectsof

nephrotoxicdrugs.

Renalfunctionshouldbemonitoredwhencombinedwithpotentiallynephrotoxic

medications(e.g.aminoglycosideantibiotics,polymyxinBandcolistin)orloop

diuretics, as thenephrotoxicityofthesesubstances maybeenhanced.

4.6 PregnancyandLactation

Pregnancy

Thesafeuseofcefotaximeduring pregnancyhasnot beendemonstrated. Animal

studies haveshownno reproductivetoxicity. However,thereareno adequate

controlledstudies inpregnantwomen.

Cefotaximecrosses theplacenta. Hence, cefotaximeshouldnot beused during

pregnancyunless absolutelynecessary.

Breastfeeding

Cefotaximeis excreted intohumanmilk.

Innursing infants, useofClaforanduring lactationcanlead to interferencewiththe

physiological intestinal flora, diarrhoea, colonisationbyyeast-likefungi and possible

sensitisation. A decisionmustbemadeas to whether to discontinuebreast-feeding or

to abstainfromClaforantherapy,taking into accountthebenefitofbreastfeedingfor

thechild and thebenefitoftherapy forthewoman.

4.7 EffectsonAbilitytoDriveandUseMachines

Based onexperienceto date, cefotaximeatlow-to-medium doseshas no influenceon

concentrationand reactionskills.

Very rarely(<1/10,000),cases ofencephalopathy(e.g.withclouded consciousness,

seizures [tonic/clonic] andmovementdisorders)havebeenreportedwiththeuseof

high doses and particularlyinpatients withconcurrentrenal dysfunction. Moreover,

vertigo mayoccur.Under thesecircumstances, patients should refrainfromdriving or

using machines (seealso section4.4).

4.8 UndesirableEffects

Systemorgan

class Very common

(≥1/10) Common

(≥1/100to

<1/10) Uncommon

(≥1/1,000to

<1/100) Notknown

(cannot be

estimated from

theavailable

data)*

Infections and

infestations Superinfections

(seesection

4.4), e.g. oral or

vaginal

candidiasis

Blood and

lymphatic

system Granulocytopeni

a,

leukocytopenia, Neutropenia,

agranulocytosis

(see

8

Systemorgan

class Very common

(≥1/10) Common

(≥1/100to

<1/10) Uncommon

(≥1/1,000to

<1/100) Notknown

(cannot be

estimated from

theavailable

data)*

disorders eosinophilia,

thrombocytopen

ia section4.4),

haemolytic

anaemia

Immunesystem

disorders Jarisch-

Herxheimer

reaction** Anaphylactic

reactions,

angioedema,

bronchospasm,

malaisepossibly

culminating in

shock,

anaphylactic

shock

Nervous system

disorders Seizures (see

section4.4) Headache,

dizziness,

encephalopathy

[e.g. clouded

consciousness,

central nervous

excitation,

myoclonus,

movement

disorders](see

section4.4)

Cardiac

disorders Tachycardia,

arrhythmias

following rapid

bolus

administration

viaaCVC

Gastrointestinal

disorders Diarrhoea,

anorexia,

nausea,

vomiting,

abdominal pain Enterocolitis

(also

haemorrhagic),

pseudomembra

nouscolitis (see

section4.4),

candidiasis

Hepatobiliary

disorders Elevationof

liver enzymes

(ALAT, ASAT,

LDH,gamma-

GTand/or

alkaline

phosphatase)

and/or

bilirubin***

Hepatitis*

(possiblywith

jaundice)

Skinand

subcutaneous

tissuedisorders Rash, pruritus,

urticaria Bullous

eruptions

(Erythema

multiforme),

Stevens-

Johnson

syndrome, toxic

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Systemorgan

class Very common

(≥1/10) Common

(≥1/100to

<1/10) Uncommon

(≥1/1,000to

<1/100) Notknown

(cannot be

estimated from

theavailable

data)*

epidermal

necrolysis(see

section4.4)

Musculoskeleta

l and

connective

tissue

disorders Joint-related

complaints (e.g.

swelling)

Renal and

urinary

disorders Impairmentof

renal function/

elevationof

creatinineand

urea(especially

onco-

medicationwith

amino-

glycosides) Interstitial

nephritis

General

disorders and

administration

siteconditions Painatthe

injectionsite;

IM

administration:

induration

Fever,

inflammatory

reactions atthe

administration

site, including

phlebitis/

thrombo-

phlebitis Rapid IV

injection:hot

flushes and

vomiting.

*Postmarketing experience

**During treatmentofspirochetal infections (e.g.borreliosis), aJarisch-Herxheimer

reactionmaydevelop, withfever,chills, headacheandjoint-related complaints.

After several weeks ofborreliosis treatment, oneormoreofthefollowing symptoms has

beenreported to occur:skinrash, pruritus, fever, leukopenia, liver enzymeelevations,

respiratorycomplaints,joint-related complaints.To someextent, thesephenomenaare

consistentwiththesymptoms oftheunderlying diseaseofthetreated patient.

***Inrarecases,theriseinliver enzymes or bilirubinexceeded theupper limitofnormal

by 2-fold, indicating variousforms ofliver damage(usuallycholestatic, mostly

asymptomatic).

For IMformulations:sincethesolventcontains lidocaine, systemicreactions to

lidocaine mayoccur, especiallyintheeventofinadvertentintravenous injectionor

injectioninto highlyvascularized tissueor intheeventofanoverdose.

4.9 Overdose

Intheeventofanoverdose, measures to accelerateeliminationmayberequiredin

additionto discontinuing themedicinal product(e.g.haemodialysis or peritoneal

dialysis).Thereisnoantidote.

a) Symptomsofanoverdose

Cases ofintoxicationinthestrictestsenseareunknowninhumans. Thesymptoms

largelycorrelateto theadverseeffectprofile. Withcertainrisk constellations and

administrationofveryhighdoses, reversibleencephalopathymayoccur, withcentral

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nervous excitation, myoclonus andseizures, ashas beendescribedfor other beta-

lactams. Theriskfor developing theseadverseeffects is greater in patients with

severelyimpaired renalfunction, epilepsyand meningitis.

b) Emergencymeasures

Centrallymediated seizurescan betreated withdiazepamor phenobarbital, butnot

withphenytoin. Intheeventofanaphylacticreactions,theusual emergencymeasures

areto beinstituted, preferably atthefirstsign ofshock. Otherwise, symptomatic

treatmentofthesideeffects is recommended, ifrequired.

5. PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup

Cefotaximeis aparenteral beta-lactamantibioticbelonging to thecephalosporingroup.

ATC code

J01DD01.

Modeofaction

Themechanismofactionofcefotaximeisbasedonaninhibitionofbacterialcellwallsynthesis(during

thegrowthphase)throughblockadeofthepenicillin-bindingproteins(PBPs),suchastranspeptidases.

This results inabactericidaleffect.

Relationship betweenpharmacokinetics and pharmacodynamics

Theefficacydependsmainlyuponthelengthoftimethattheactivesubstancelevelremainsabovethe

minimuminhibitoryconcentration(MIC)ofthepathogen.

Mechanismofresistance

Resistanceto cefotaximemaybedue to thefollowingmechanisms:

Inactivationthrough beta-lactamases:

Cefotaximecan behydrolysed by certainbeta-lactamases, particularly through extended-

spectrum beta-lactamases (ESBLs), whichoccur instrains suchas Escherichiacoli or Klebsiella

pneumoniae or throughconstitutivelyexpressed beta-lactamases oftheAmpC type, whichhave

beenconfirmed insuchstrains as Enterobactercloacae . Ininfectionscaused bybacteriawith

inducibleAmpC beta-lactamaseand invitro susceptibilityto cefotaxime, thereisarisk that,

during treatment, mutantswithconstitutive(derepressed)AmpC beta-lactamaseexpressionmay

beselected.

Reduced affinityofPBPsforcefotaxime:

Acquired resistanceofpneumococci andotherstreptococci isdue to modificationsofexisting

PBPs as aresultofmutation. However, theformationofanadditional PBPwithreduced affinity

for cefotaximeis responsiblefor resistanceinmethicillin(oxacillin)-resistantstaphylococci.

Insufficientpenetrationofcefotaximethrough theouter cell wall ofGram-negativebacteriacan result

inaninsufficientinhibitionofthePBPs.

Cefotaximecan beactivelytransported outofthecellby efflux pumps.

Thereiscompletecross-resistancebetweencefotaximeandceftriaxoneandpartialcross-resistance

withother penicillins and cephalosporins.

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Breakpoints

Testingofcefotaximeisperformedwiththeusualdilutionseries.Thefollowingminimuminhibitory

concentrationsweredetermined forsusceptibleand resistantmicro-organisms:

EUCAST(EuropeanCommitteeonAntimicrobial SusceptibilityTesting)breakpoints

Pathogen Susceptible Resistant

Enterobacteriaceae 1mg/l >2mg/l

Staphylococcusspp. 1) __1) __1)

Streptococcusspp.

(groups A, B, C,G) 2) _ 2) _ 2)

Streptococcus pneumoniae 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

Non-species-specificbreakpoints* 1mg/l >2mg/l

For Staphylococcus spp.,thetestresultforoxacillinis used. Methicillin(oxacillin)-resistant

staphylococci areconsidered to beresistant, regardless ofthetestresult.

For Streptococcus spp. (group A, B,C, G) thetestresultforpenicillinGisused.

*Mainlybased onserum pharmacokinetics.

PrevalenceofacquiredresistanceinGermany

Theprevalenceofacquiredresistanceinindividualspeciesmayshowlocalandtemporalvariations.

Localinformationontheresistancesituationisthusrequired,particularlyfortheadequatetreatmentof

severeinfections.If,basedonthelocalresistancesituation,theefficacyofcefotaximeisquestionable,

experttherapeuticadviceshould besought.

Particularlyincasesofseriousinfectionorunsuccessfultherapy,amicrobiologicaldiagnosiswith

confirmationofthepathogenand its susceptibilityto cefotaximeshould beundertaken.

PrevalenceofacquiredresistanceinGermanyonthebasisofdatafromthepast5yearsfromnational

resistancemonitoring projects and studies(lastrevisedDecember 2010):

Commonlysusceptiblespecies

Aerobic Gram-positivemicro-organisms

Staphylococcus aureus (methicillin-sensitive)

Streptococcus agalactiae

Streptococcus pneumoniae (including penicillin-resistantstrains)

Streptococcus pyogenes

Aerobic Gram-negativemicro-organisms

Borreliaburgdorferi°

Haemophilusinfluenzae

Moraxellacatarrhalis°

Neisseriagonorrhoeae°

Neisseriameningitidis°

Proteus mirabilis %

Proteus vulgaris

Speciesinwhichacquiredresistancemaypresentaproblemforuse

Aerobic Gram-positivemicro-organisms

Staphylococcus aureus $

Staphylococcus epidermidis +

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Staphylococcus haemolyticus +

Staphylococcus hominis +

Aerobic Gram-negativemicro-organisms

Citrobacter freundii

Enterobacter aerogenes

Enterobacter cloacae

Escherichiacoli %

Klebsiellaoxytoca %

Klebsiellapneumoniae %

Morganellamorganii

Serratiamarcescens

Anaerobicmicro-organisms

Bacteroides fragilis

Inherentlyresistantorganisms

Aerobic Gram-positivemicro-organisms

Enterococcus spp.

Listeriamonocytogenes

Staphylococcus aureus (methicillin-resistant)

Aerobic Gram-negativemicro-organisms

Acinetobacter baumannii

Pseudomonas aeruginosa

Stenotrophomonas maltophilia

Anaerobicmicro-organisms

Clostridium difficile

Othermicro-organisms

Chlamydia spp.

Chlamydophila spp.

Legionellapneumophila

Mycoplasma spp.

Treponemapallidum

°Atthetimeofpublicationofthetable, no currentdatawereavailable. Susceptibilityis assumed in

theprimary literature, standard works and therapy recommendations.

+ Inatleastoneregion, theresistancerateis over50%.

% Strains producing extended-spectrum beta-lactamases (ESBL) arealways resistant.

§ On anout-patientbasis, the resistancerateis<10%.

5.2Pharmacokineticproperties

Cefotaximeisadministeredviatheparenteralroute.Followingintravenousinjectionof1gcefotaxime,

serum concentrations areapproximately81-102mg/lafter5minutes and 46mg/l after 15minutes.

8minutes after IVinjectionof2gcefotaxime, serumconcentrations of167-214mg/l weremeasured.

Followingintramuscularadministration,peakserumconcentrations(approximately20mg/lafter1g)

arereached within30minutes.

Distribution

Cefotaximehasgoodtissuepenetration,crossestheplacentalbarrierandreacheshighconcentrations

infoetaltissue(upto6mg/kg).Onlyasmallpercentageisexcretedinhumanmilk(breastmilk

concentrations:0.4mg/lafter 2g).

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Whenthemeningesareinflamed,cefotaximeanddesacetylcefotaximepenetratethesubarachnoid

space, wheretheysubsequentlyreachtherapeuticallyeffectiveconcentrations (e.g. ininfectionscaused

by Gram-negativebacteriaand pneumococci).

Theapparentvolumeofdistributionrangesbetween21-37l.Serumproteinbindingisapproximately

25-40%.

Metabolism

Cefotaximeisextensivelymetabolisedinhumans.Around15-25%ofaparenteraldoseisexcretedas

O-desacetylcefotaxime.Themetabolitehasgoodantibacterialactivityagainstawiderangeof

pathogens.

Inadditiontodesacetylcefotaxime,therearetwofurtherinactivelactones.Fromdesacetylcefotaxime,

alactoneisformedasanintermediateproductwithashortlife-cycle,whichisnotdetectableineither

theurineorplasma,asitundergoesrapidconversionintoopen-ring(beta-lactamring)lactone

stereoisomers.Thesearealso excreted in theurine.

Excretion

Cefotaximeanddesacetylcefotaximearepredominantlyexcretedviatherenalroute.Asmall

percentage(approximately2%)isexcretedwiththebile.Inurinecollectedafter6hours,40-60%of

adosewasrecoveredinitsunchangedformandapproximately20%wasrecoveredas

desacetylcefotaxime.AfterIVadministrationof radioactively- labelledcefotaxime,justover80%was

recoveredintheurine,ofwhich50-60%wasunchangedparentsubstanceandtheremaindera

mixtureofthreemetabolites.

Thetotal clearanceofcefotaximeis 240-390ml/minand renal clearanceis130-150ml/min.

Theserumhalf-lifeisbetween50-80minutes.Ingeriatricpatients,thehalf-lifewas120-

150minutes.

Incasesofsevererenaldysfunction(creatinineclearance:3-10ml/min),thehalf-lifeofcefotaxime

maybeprolongedto 2.5-10hours.

Unliketheactiveandinactivemetabolites,cefotaximeonlyaccumulatestoasmallextentunderthese

conditions.

Bothcefotaximeand desacetylcefotaximearelargelyremoved fromtheblood byhaemodialysis.

5.3Preclinicalsafetydata

ThetoxicityofClaforanisverylow.Dependingonthespecies,theLD

50 variesafterIVadministrationin

animaltrials.Inmiceandrats,itis9-11g/kgbodyweight.Followingsubcutaneousadministration,

theLD

50 valuesinone-week-oldmiceandratswere6.1to7.4g/kgbodyweightand18.7g/kgbody

weight in femalemice.

Mutagenicpotential

Invivo studiesonthebonemarrowofratsandmicedidnotindicateamutagenicpotentialfor

Claforan.

Reproductivetoxicity

Cefotaximecrossestheplacenta.Followingintravenousadministrationof1gClaforanduringlabour,

valuesof14µg/mlweremeasuredintheumbilicalcordserumwithinthefirst90minutespost-dose,

whichfelltoabout2.5µg/mlbytheendofthesecondhourpost-dose.Intheamnioticfluid,peak

concentrationsof6.9µg/mlweremeasured after 3-4hours;thisvalueexceeds theMIC for most Gram-

negativepathogens.

AnimalstudiesonratsandmicedidnotindicateteratogenicpropertiesforClaforan.Fertilityofthe

exposed animals was not impaired.

14

6 PHARMACEUTICALPARTICULARS

6.1 ListofExcipients

Water for injectionas solvent.

6.2 Incompatibilities

Thefollowing arenot compatiblewithClaforan:

- sodiumhydrogencarbonatesolution,

- solutions for infusionwithapH valueover 7,

- aminoglycosides.

Ifimmiscibilityhasnotbeenproven,Claforanshouldnotbemixedwithothermedicinal

products (forcompatibilitywithsolutionsfor infusion,seesection6.3).

Incompatibilitywithother antibiotics/chemotherapeuticagents

Duetophysical/chemicalincompatibilitywithallaminoglycosides,cefotaximeshouldnotbe

administeredinaninjectionorsolutionforinfusioncontainingaminoglycosides.Thetwo

antibiotics should beinjected atseparatesites using separatedevices.

6.3 Special PrecautionsforStorage

Finished Product:

Do not storeabove25 o C.

Keep thecontainer intheouter carton, inorder toprotectfromlight.

ReconstitutedSolution:

Thechemical andphysicalstabilityofthereconstituted solutionis12hoursat25 0 C.

For microbiological reasons, the solutionshould beadministered immediately. Ifthe

solutionis not usedstraightaway, the useris responsiblefor in-usestoragetimes and

conditions. Evenifreconstitutionhas takenplaceunder controlled andvalidated

conditions, thestoragetimeshouldnotnormallyexceed 24hours at2-8 0 C.

Whilst itis preferableto useonlyfreshlyprepared solutions for bothintravenous and

intramuscular injection, Claforaniscompatiblewithseveral commonlyused

intravenous infusionfluidsand will retainsatisfactorypotencyforup to24hours

refrigerated (2-8 o C)inthefollowing:

Water for Injections Ph.Eur.

Sodium ChlorideInjectionBP.

5% DextroseInjectionBP.

DextroseandSodiumChlorideInjectionBP.

Compound SodiumLactateInjectionBP(Ringer-lactateInjection).

After 24hours anyunusedsolutionshould bediscarded.

Claforanis alsocompatiblewith1%lidocaine,howeverfreshlyprepared solutions

shouldbeused.

Claforanis alsocompatiblewithmetronidazoleinfusion(500mg/100ml) and bothwill

maintainpotencywhenrefrigerated(2-8 o C)forup to24hours. Someincreasein

colour ofprepared solutions mayoccur onstorage. However, provided the

recommended storageconditions areobserved, this does not indicatechangein

potencyor safety.

15

6.4 NatureandContentsofContainer

Eachbox includes:

1vial ofdry powder for thepreparationofasolutionfor injectionor infusion+1

ampouleof4ml water for injection.

6.5 PreparationandHandling

Inordertoavoidsepticcomplicationsoninjection,itisrecommendedthatcareshouldbe

takenduringreconstitutiontoensureaseptichandlingandthatthesolutionshouldbeused

immediatelyafterreconstitition.Aseptichandlingisparticularlyimportantifthesolutionisnot

intended for immediateuse.

7 Manufacturer–PatheonUK Ltd.

8 LicenseHolder–Sanofi-aventisIsraelltd.10BeniGaon,POB8090Netanya.