AUGMENTIN 500/125 Milligram Film Coated Tablet

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
AMOXICILLIN TRIHYDRATE, CLAVULANIC ACID
Available from:
B & S Healthcare
ATC code:
J01CR02
INN (International Name):
AMOXICILLIN TRIHYDRATE, CLAVULANIC ACID
Dosage:
500/125 Milligram
Pharmaceutical form:
Film Coated Tablet
Prescription type:
Product subject to prescription which may not be renewed (A)
Therapeutic area:
Combinations of penicillins, incl. beta-lactamase inhibitors
Authorization status:
Authorised
Authorization number:
PPA1328/050/001
Authorization date:
2009-01-09

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Augmentin500/125mgFilm-CoatedTablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilmcoatedtabletcontainsamoxicillintrihydrateequivalentto500mgamoxicillinandpotassiumclavulanate

equivalentto125mgclavulanicacid.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedTablet

ProductimportedfromGreece:

White,oval,film-coatedtabletswithabreaklineononeside,‘A’ononesideofthelineand‘C’ontheotherandplain

ontheotherside.

ProductimportedfromSpain:

White,capsuleshaped,film-coatedtabletsimprintedwith'A/C'ononesideandplainontheotherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Augmentinisindicatedforthetreatmentofthefollowinginfectionsinadultsandchildren(see

sections4.2,4.4and5.1):

Acutebacterialsinusitis(adequatelydiagnosed)

Acuteotitismedia

Acuteexacerbationsofchronicbronchitis(adequatelydiagnosed)

Communityacquiredpneumonia

Cystitis

Pyelonephritis

Skinandsofttissueinfectionsinparticularcellulitis,animalbites,severedentalabscesswithspreading

cellulitis.

Boneandjointinfections,inparticularosteomyelitis.

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantibacterialagents.

4.2Posologyandmethodofadministration

Dosesareexpressedthroughoutintermsofamoxicillin/clavulanicacidcontentexceptwhendosesarestatedinterms

ofanindividualcomponent.

ThedoseofAugmentinthatisselectedtotreatanindividualinfectionshouldtakeintoaccount:

Theexpectedpathogensandtheirlikelysusceptibilitytoantibacterialagents(seesection4.4)

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Theage,weightandrenalfunctionofthepatientasshownbelow.

TheuseofalternativepresentationsofAugmentin(e.g.thosethatprovidehigherdosesofamoxicillinand/ordifferent

ratiosofamoxicillintoclavulanicacid)shouldbeconsideredasnecessary(see

sections4.4and5.1).

Foradultsandchildren ≥40kg,thisformulationofAugmentinprovidesatotaldailydoseof1500mgamoxicillin/375

mgclavulanicacid,whenadministeredasrecommendedbelow.Forchildren<40kg,thisformulationofAugmentin

providesamaximumdailydoseof2400mgamoxicillin/600mgclavulanicacid,whenadministeredasrecommended

below.Ifitisconsideredthatahigherdailydoseofamoxicillinisrequired,itisrecommendedthatanotherpreparation

ofAugmentinisselectedinordertoavoidadministrationofunnecessarilyhighdailydosesofclavulanicacid(see

sections4.4

and5.1).

Thedurationoftherapyshouldbedeterminedbytheresponseofthepatient.Someinfections(e.g.osteomyelitis)

requirelongerperiodsoftreatment.Treatmentshouldnotbeextendedbeyond14dayswithoutreview(seesection4.4

regardingprolongedtherapy).

Adultsandchildren ≥40kg

One500mg/125mgdosetakenthreetimesaday.

Children<40kg

20mg/5mg/kg/dayto60mg/15mg/kg/daygiveninthreedivideddoses.

ChildrenmaybetreatedwithAugmentintablets,suspensionsorpaediatricsachets.Childrenaged6yearsandbelow

shouldpreferablybetreatedwithAugmentinsuspensionorpaediatricsachets.

NoclinicaldataareavailableondosesofAugmentin4:1formulationshigherthan40mg/10mg/kgperdayinchildren

under2years.

Elderly

Nodoseadjustmentisconsiderednecessary.

Renalimpairment

Doseadjustmentsarebasedonthemaximumrecommendedlevelofamoxicillin.

Noadjustmentindoseisrequiredinpatientswithcreatinineclearance(CrCl)greaterthan30ml/min.

Adultsandchildren40kg

Children<40kg CrCl:10-30ml/min 500mg/125mgtwicedaily

CrCl<10ml/min 500mg/125mgoncedaily

Haemodialysis 500mg/125mgevery24hours,plus500mg/125mgduringdialysis,tobe

repeatedattheendofdialysis(asserumconcentrationsofbothamoxicillin

andclavulanicacidaredecreased)

CrCl:10-30ml/min 15mg/3.75mg/kgtwicedaily(maximum500mg/125mgtwicedaily).

CrCl<10ml/min 15mg/3.75mg/kgasasingledailydose(maximum500mg/125mg).

Haemodialysis 15mg/3.75mg/kgperdayoncedaily.

Priortohaemodialysis15mg/3.75mg/kg.Inordertorestorecirculatingdrug

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Hepaticimpairment

Dosewithcautionandmonitorhepaticfunctionatregularintervals(seesections4.3and4.4).

Methodofadministration

Augmentinisfororaluse.

Administeratthestartofamealtominimisepotentialgastrointestinalintoleranceandoptimiseabsorptionof

amoxicillin/clavulanicacid.

TherapycanbestartedparenterallyaccordingtheSPCoftheIV-formulationandcontinuedwithanoral

preparation.

4.3Contraindications

Hypersensitivitytotheactivesubstances,toanyofthepenicillinsortoanyoftheexcipients.

Historyofasevereimmediatehypersensitivityreaction(e.g.anaphylaxis)toanotherbeta-lactamagent(e.g.a

cephalosporin,carbapenemormonobactam).

Historyofjaundice/hepaticimpairmentduetoamoxicillin/clavulanicacid(seesection4.8).

4.4Specialwarningsandprecautionsforuse

Beforeinitiatingtherapywithamoxicillin/clavulanicacid,carefulenquiryshouldbemadeconcerningprevious

hypersensitivityreactionstopenicillins,cephalosporinsorotherbeta-lactamagents.

Seriousandoccasionallyfatalhypersensitivity(anaphylactoid)reactionshavebeenreportedinpatientsonpenicillin

therapy.Thesereactionsaremorelikelytooccurinindividualswithahistoryofpenicillinhypersensitivityandin

atopicindividuals.Ifanallergicreactionoccurs,amoxicillin/clavulanicacidtherapymustbediscontinuedand

appropriatealternativetherapyinstituted.

Inthecasethataninfectionisproventobeduetoanamoxicillin-susceptibleorganisms(s)thenconsiderationshouldbe

giventoswitchingfromamoxicillin/clavulanicacidtoamoxicillininaccordancewithofficialguidance.

ThispresentationofAugmentinisnotsuitableforusewhenthereisahighriskthatthepresumptivepathogenshave

reducedsusceptibilityorresistancetobeta-lactamagentsthatisnotmediatedbybetalactamasessusceptibleto

inhibitionbyclavulanicacid.Thispresentationshouldnotbeusedtotreatpenicillin-resistantS.pneumoniae.

Convulsionsmayoccurinpatientswithimpairedrenalfunctionorinthosereceivinghighdoses(seesection4.8).

Amoxicillin/clavulanicacidshouldbeavoidedifinfectiousmononucleosisissuspectedsincetheoccurrenceofa

morbilliformrashhasbeenassociatedwiththisconditionfollowingtheuseofamoxicillin.

Concomitantuseofallopurinolduringtreatmentwithamoxicillincanincreasethelikelihoodofallergicskinreactions.

Prolongedusemayoccasionallyresultinovergrowthofnon-susceptibleorganisms.

Theoccurrenceatthetreatmentinitiationofafeverishgeneralisederythemaassociatedwithpustulamaybeasymptom

ofacutegeneralisedexanthemouspustulosis(AGEP)(seeSection4.8).ThisreactionrequiresAugmentin

discontinuationandcontra-indicatesanysubsequentadministrationofamoxicillin.

Amoxicillin/clavulanicacidshouldbeusedwithcautioninpatientswithevidenceofhepaticimpairment(seesection

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Hepaticeventshavebeenreportedpredominantlyinmalesandelderlypatientsandmaybeassociatedwithprolonged

treatment.Theseeventshavebeenveryrarelyreportedinchildren.Inallpopulations,signsandsymptomsusually

occurduringorshortlyaftertreatmentbutinsomecasesmaynotbecomeapparentuntilseveralweeksaftertreatment

hasceased.Theseareusuallyreversible.Hepaticeventsmaybesevereand,inextremelyrarecircumstances,deaths

havebeenreported.Thesehavealmostalwaysoccurredinpatientswithseriousunderlyingdiseaseortaking

concomitant

medicationsknowntohavethepotentialforhepaticeffects(seesection4.8).

Antibiotic-associatedcolitishasbeenreportedwithnearlyallantibacterialagentsandmayrangeinseverityfrommild

tolifethreatening(seesection4.8).Therefore,itisimportanttoconsiderthisdiagnosisinpatientswhopresentwith

diarrhoeaduringorsubsequenttotheadministrationofany

antibiotics.Shouldantibiotic-associatedcolitisoccur,amoxicillin/clavulanicacidshouldimmediatelybediscontinued,

aphysicianbeconsultedandanappropriatetherapyinitiated.Anti-peristalticmedicinalproductsarecontra-indicatedin

thissituation.

Periodicassessmentoforgansystemfunctions,includingrenal,hepaticandhaematopoieticfunctionisadvisable

duringprolongedtherapy.

Prolongationofprothrombintimehasbeenreportedrarelyinpatientsreceivingamoxicillin/clavulanicacid.

Appropriatemonitoringshouldbeundertakenwhenanticoagulantsareprescribedconcomitantly.Adjustmentsinthe

doseoforalanticoagulantsmaybenecessarytomaintainthedesiredlevelofanticoagulation(seesection4.5and4.8).

Inpatientswithrenalimpairment,thedoseshouldbeadjustedaccordingtothedegreeofimpairment(seesection4.2).

Inpatientswithreducedurineoutput,crystalluriahasbeenobservedveryrarely,predominantlywithparenteral

therapy.Duringtheadministrationofhighdosesofamoxicillin,itisadvisabletomaintainadequatefluidintakeand

urinaryoutputinordertoreducethepossibilityofamoxicillincrystalluria.

Inpatientswithbladdercatheters,aregularcheckofpatencyshouldbemaintained(seesection4.9).Duringtreatment

withamoxicillin,enzymaticglucoseoxidasemethodsshouldbeusedwhenevertestingforthepresenceofglucosein

urinebecausefalsepositiveresultsmayoccurwithnonenzymaticmethods.

ThepresenceofClavulanicacidinAugmentinmaycauseanon-specificbindingofIgGandalbuminbyredcell

membranesleadingtoafalsepositiveCoombstest.

TherehavebeenreportsofpositivetestresultsusingtheBio-RadLaboratoriesPlateliaAspergillusEIAtestinpatients

receivingamoxicillin/clavulanicacidwhoweresubsequentlyfoundtobefreeofAspergillusinfection.Cross-reactions

withnon-Aspergilluspolysaccharidesandpolyfuranoseswith

Bio-RadLaboratoriesPlateliaAspergillusEIAtesthavebeenreported.Therefore,positivetestresultsinpatients

receivingamoxicillin/clavulanicacidshouldbeinterpretedcautiouslyandconfirmedbyotherdiagnosticmethods.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Oralanticoagulants

Oralanticoagulantsandpenicillinantibioticshavebeenwidelyusedinpracticewithoutreportsofinteraction.

However,intheliteraturetherearecasesofincreasedinternationalnormalisedratioinpatientsmaintainedon

acenocoumarolorwarfarinandprescribedacourseofamoxicillin.Ifcoadministrationisnecessary,theprothrombin

timeorinternationalnormalisedratioshouldbecarefullymonitoredwiththeadditionorwithdrawalofamoxicillin.

Moreover,adjustmentsinthedoseoforalanticoagulantsmaybenecessary(seesections4.4and4.8).

Methotrexate

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Probenecid

Concomitantuseofprobenecidisnotrecommended.Probeneciddecreasestherenaltubularsecretionofamoxicillin.

Concomitantuseofprobenecidmayresultinincreasedandprolongedbloodlevelsofamoxicillinbutnotofclavulanic

acid.

4.6Fertility,pregnancyandlactation

Pregnancy

Animalstudiesdonotindicatedirectorindirectharmfuleffectswithrespecttopregnancy,embryonal/foetal

development,parturitionorpostnataldevelopment(seesection5.3).Limiteddataontheuseofamoxicillin/clavulanic

acidduringpregnancyinhumansdonotindicateanincreasedriskofcongenitalmalformations.Inasinglestudyin

womenwithpreterm,prematureruptureofthefoetalmembraneitwasreportedthatprophylactictreatmentwith

amoxicillin/clavulanicacidmaybeassociatedwithanincreasedriskofnecrotisingenterocolitisinneonates.Use

shouldbeavoidedduringpregnancy,unlessconsideredessentialbythephysician.

Lactation

Bothsubstancesareexcretedintobreastmilk(nothingisknownoftheeffectsofclavulanicacidonthebreast-fed

infant).Consequently,diarrhoeaandfungusinfectionofthemucousmembranesarepossibleinthebreast-fedinfant,so

thatbreast-feedingmighthavetobediscontinued.

Amoxicillin/clavulanicacidshouldonlybeusedduringbreast-feedingafterbenefit/riskassessmentbythephysicianin

charge.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.However,undesirableeffects

mayoccur(e.g.allergicreactions,dizziness,convulsions),whichmayinfluencetheabilitytodriveandusemachines

(seesection4.8).

4.8Undesirableeffects

Themostcommonlyreportedadversedrugreactions(ADRs)arediarrhea,nauseaandvomiting.

TheADRsderivedfromclinicalstudiesandpost-marketingsurveillancewithAugmentin,sortedby

MedDRASystemOrganClassarelistedbelow.

Thefollowingterminologieshavebeenusedinordertoclassifytheoccurrenceofundesirableeffects.

Verycommon( ≥1/10)

Common( ≥1/100to<1/10)

Uncommon( ≥1/1,000to<1/100)

Rare( ≥1/10,000to<1/1,000)

Veryrare(<1/10,000)

Notknown(cannotbeestimatedfromtheavailabledata)

Infectionsandinfestations

Bloodandlymphaticsystemdisorders Mucocutaneouscandidosis Common

Overgrowthofnon-susceptibleorganisms Notknown

Reversibleleucopenia(including

neutropenia) Rare

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Immunesystemdisorders 10

Nervoussystemdisorders

Gastrointestinaldisorders

Hepatobiliarydisorders

Skinandsubcutaneoustissuedisorders 7

Reversibleagranulocytosis Notknown

Haemolyticanaemia Notknown

Prolongationofbleedingtimeandprothrombin

time 1 Notknown

Angioneuroticoedema Notknown

Anaphylaxis Notknown

Serumsickness-likesyndrome Notknown

Hypersensitivityvasculitis Notknown

Dizziness Uncommon

Headache Uncommon

Reversiblehyperactivity Notknown

Convulsions Notknown

Diarrhoea Verycommon

Nausea 3 Common

Vomiting Common

Indigestion Uncommon

Antibiotic-associatedcolitis 4 Notknown

Blackhairytongue Notknown

RisesinASTand/orALT 5 Uncommon

Hepatitis 6 Notknown

Cholestaticjaundice 6 Notknown

Skinrash Uncommon

Pruritus Uncommon

Urticaria Uncommon

Erythemamultiforme Rare

Stevens-Johnsonsyndrome Notknown

Toxicepidermalnecrolysis Notknown

Bullousexfoliative-dermatitis Notknown

Acutegeneralisedexanthemouspustulosis

(AGEP) 9 Notknown

Interstitialnephritis Notknown

Crystalluria 8 Notknown

Seesection4.4

Seesection4.4

Nauseaismoreoftenassociatedwithhigheroraldoses.Ifgastrointestinalreactionsare

evident,theymaybereducedbytakingAugmentinatthestartofameal.

Includingpseudomembranouscolitisandhaemorrhagiccolitis(seesection4.4)

AmoderateriseinASTand/orALThasbeennotedinpatientstreatedwithbeta-lactam

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4.9Overdose

Symptomsandsignsofoverdose

Gastrointestinalsymptomsanddisturbanceofthefluidandelectrolytebalancesmaybeevident.Amoxicillin

crystalluria,insomecasesleadingtorenalfailure,hasbeenobserved(seesection4.4).

Convulsionsmayoccurinpatientswithimpairedrenalfunctionorinthosereceivinghighdoses.

Amoxicillinhasbeenreportedtoprecipitateinbladdercatheters,predominantlyafterintravenousadministrationof

largedoses.Aregularcheckofpatencyshouldbemaintained(seesection4.4).

Treatmentofintoxication

Gastrointestinalsymptomsmaybetreatedsymptomatically,withattentiontothewater/electrolytebalance.

Amoxicillin/clavulanicacidcanberemovedfromthecirculationbyhaemodialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Combinationsofpenicillins,incl.beta-lactamaseinhibitors;ATCcode:

J01CR02.

Modeofaction

Amoxicillinisasemisyntheticpenicillin(beta-lactamantibiotic)thatinhibitsoneormoreenzymes(oftenreferredtoas

penicillin-bindingproteins,PBPs)inthebiosyntheticpathwayofbacterial

peptidoglycan,whichisanintegralstructuralcomponentofthebacterialcellwall.Inhibitionof

peptidoglycansynthesisleadstoweakeningofthecellwall,whichisusuallyfollowedbycelllysis

anddeath.

Amoxicillinissusceptibletodegradationbybeta-lactamasesproducedbyresistantbacteriaand

thereforethespectrumofactivityofamoxicillinalonedoesnotincludeorganismswhichproduce

theseenzymes.

Clavulanicacidisabeta-lactamstructurallyrelatedtopenicillins.Itinactivatessomebeta-lactamase

enzymestherebypreventinginactivationofamoxicillin.Clavulanicacidalonedoesnotexerta

clinicallyusefulantibacterialeffect.

PK/PDrelationship

Thetimeabovetheminimuminhibitoryconcentration(T>MIC)isconsideredtobethemajordeterminantofefficacy

Theseeventshavebeennotedwithotherpenicillinsandcephalosporins(seesection4.4).

Ifanyhypersensitivitydermatitisreactionoccurs,treatmentshouldbediscontinued(see

section4.4).

Seesection4.9

Seesection4.4

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Mechanismsofresistance

Thetwomainmechanismsofresistancetoamoxicillin/clavulanicacidare:

Inactivationbythosebacterialbeta-lactamasesthatarenotthemselvesinhibitedbyclavulanicacid,includingclass

B,CandD.

AlterationofPBPs,whichreducetheaffinityoftheantibacterialagentforthetarget.

Impermeabilityofbacteriaoreffluxpumpmechanismsmaycauseorcontributetobacterialresistance,particularlyin

Gram-negativebacteria.

Breakpoints

MICbreakpointsforamoxicillin/clavulanicacidarethoseoftheEuropeanCommitteeon

AntimicrobialSusceptibilityTesting(EUCAST)

Theprevalenceofresistancemayvarygeographicallyandwithtimeforselectedspecies,andlocalinformationon

resistanceisdesirable,particularlywhentreatingsevereinfections.Asnecessary,expertadviceshouldbesoughtwhen

Organism SusceptibilityBreakpoints(µg/ml)

Susceptible Intermediate Resistant

Haemophilusinfluenzae 1 ≤1 - >1

Moraxellacatarrhalis 1 ≤1 - >1

Staphylococcusaureus 2 ≤2

>2

Coagulase-negativestaphylococci 2 ≤0.25

>0.25

Enterococcus 1 ≤4

>8

StreptococcusA,B,C,G 5 ≤0.25 - >0.25

Streptococcuspneumoniae 3 ≤0.5 1-2 >2

Enterobacteriaceae 1,4 - - >8

Gram-negativeAnaerobes 1 ≤4

>8

Gram-positiveAnaerobes 1 ≤4

>8

Non-speciesrelated

breakpoints 1 ≤2

4-8 >8

ThereportedvaluesareforAmoxicillinconcentrations.Forsusceptibilitytestingpurposes,the

concentrationofClavulanicacidisfixedat2mg/l.

ThereportedvaluesareOxacillinconcentrations.

BreakpointvaluesinthetablearebasedonAmpicillinbreakpoints.

TheresistantbreakpointofR>8mg/lensuresthatallisolateswithresistancemechanismsarereported

resistant.

BreakpointvaluesinthetablearebasedonBenzylpenicillinbreakpoints.

Commonlysusceptiblespecies

AerobicGram-positivemicro-organisms

Enterococcusfaecalis

Gardnerellavaginalis

Staphylococcusaureus(methicillin-susceptible)£

Coagulase-negativestaphylococci(methicillin-susceptible)

Streptococcusagalactiae

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Streptococcuspyogenesandotherbeta-haemolyticstreptococci

Streptococcusviridansgroup

AerobicGram-negativemicro-organisms

Capnocytophagaspp.

Eikenellacorrodens

Haemophilusinfluenzae 2

Moraxellacatarrhalis

Pasteurellamultocida

Anaerobicmicro-organisms

Bacteroidesfragilis

Fusobacteriumnucleatum

Prevotellaspp.

Speciesforwhichacquiredresistancemaybeaproblem

AerobicGram-positivemicro-organisms

Enterococcusfaecium$

AerobicGram-negativemicro-organisms

Escherichiacoli

Klebsiellaoxytoca

Klebsiellapneumoniae

Proteusmirabilis

Proteusvulgaris

Inherentlyresistantorganisms

AerobicGram-negativemicro-organisms

Acinetobactersp.

Citrobacterfreundii

Enterobactersp.

Legionellapneumophila

Morganellamorganii

Providenciaspp.

Pseudomonassp.

Serratiasp.

Stenotrophomonasmaltophilia

Othermicro-organisms

Chlamydophilapneumoniae

Chlamydophilapsittaci

Coxiellaburnetti

Mycoplasmapneumoniae

$Naturalintermediatesusceptibilityintheabsenceofacquiredmechanismofresistance.

£Allmethicillin-resistantstaphylococciareresistanttoamoxicillin/clavulanicacid

Streptococcuspneumoniaethatareresistanttopenicillinshouldnotbetreatedwiththispresentationof

amoxicillin/clavulanicacid(seesections4.2and4.4).

StrainswithdecreasedsusceptibilityhavebeenreportedinsomecountriesintheEUwithafrequency

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5.2Pharmacokineticproperties

Absorption

Amoxicillinandclavulanicacid,arefullydissociatedinaqueoussolutionatphysiologicalpH.Bothcomponentsare

rapidlyandwellabsorbedbytheoralrouteofadministration.Absorptionofamoxicillin/clavulanicacidisoptimised

whentakenatthestartofameal.Followingoraladministration,amoxicillinandclavulanicacidareapproximately

70%bioavailable.Theplasmaprofilesofbothcomponentsaresimilarandthetimetopeakplasmaconcentration

(Tmax)ineachcaseisapproximatelyonehour.

Thepharmacokineticresultsforastudy,inwhichamoxicillin/clavulanicacid(500mg/125mgtabletsthreetimesdaily)

wasadministeredinthefastingstatetogroupsofhealthyvolunteersarepresentedbelow.

Amoxicillinandclavulanicacidserumconcentrationsachievedwithamoxicillin/clavulanicacidaresimilartothose

producedbytheoraladministrationofequivalentdosesofamoxicillinorclavulanicacidalone.

Distribution

About25%oftotalplasmaclavulanicacidand18%oftotalplasmaamoxicillinisboundtoprotein.Theapparent

volumeofdistributionisaround0.3-0.4l/kgforamoxicillinandaround0.2l/kgforclavulanicacid.

Followingintravenousadministration,bothamoxicillinandclavulanicacidhavebeenfoundingallbladder,abdominal

tissue,skin,fat,muscletissues,synovialandperitonealfluids,bileandpus.Amoxicillindoesnotadequatelydistribute

intothecerebrospinalfluid.

Fromanimalstudiesthereisnoevidenceforsignificanttissueretentionofdrug-derivedmaterialforeithercomponent.

Amoxicillin,likemostpenicillins,canbedetectedinbreastmilk.Tracequantitiesofclavulanicacidcanalsobe

detectedinbreastmilk(seesection4.6).

Bothamoxicillinandclavulanicacidhavebeenshowntocrosstheplacentalbarrier(seesection4.6).

Biotransformation

Amoxicillinispartlyexcretedintheurineastheinactivepenicilloicacidinquantitiesequivalenttoupto10to25%of

theinitialdose.Clavulanicacidisextensivelymetabolizedinmanandeliminatedinurineandfaecesandascarbon

dioxideinexpiredair.

Elimination

Themajorrouteofeliminationforamoxicillinisviathekidney,whereasforclavulanicaciditisbybothrenalandnon-

renalmechanisms.

Mean(±SD)pharmacokineticparameters

Activesubstance(s)

administered Dose Cmax Tmax* AUC(0-24h) T1/2

(mg) (µg/ml) (h) ((µg.h)/ml) (h)

Amoxicillin

AMX/CA

500/125mg 500 7.19

±2.26 1.5

(1.0-2.5) 53.5

±8.87 1.15

±0.20

Clavulanicacid

AMX/CA

500mg/125mg 125 2.40

±0.83 1.5

(1.0-2.0) 15.72

±3.86 0.98

±0.12

AMX–amoxicillin,CA–clavulanicacid

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approximately25l/hinhealthysubjects.Approximately60to70%oftheamoxicillinandapproximately40to65%of

theclavulanicacidareexcretedunchangedinurineduringthefirst6hafteradministrationofsingleAugmentin250

mg/125mgor500mg/125mgtablets.Variousstudieshavefoundtheurinaryexcretiontobe50-85%foramoxicillin

andbetween27-60%forclavulanicacidovera24hourperiod.Inthecaseofclavulanicacid,thelargestamountof

drugisexcretedduringthefirst2hoursafteradministration.

Concomitantuseofprobeneciddelaysamoxicillinexcretionbutdoesnotdelayrenalexcretionofclavulanicacid(see

section4.5).

Theeliminationhalf-lifeofamoxicillinissimilarforchildrenagedaround3monthsto2yearsandolderchildrenand

adults.Forveryyoungchildren(includingpretermnewborns)inthefirstweekoflifetheintervalofadministration

shouldnotexceedtwicedailyadministrationduetoimmaturityoftherenalpathwayofelimination.Becauseelderly

patientsaremorelikelytohavedecreasedrenalfunction,careshouldbetakenindoseselection,anditmaybeusefulto

monitorrenalfunction.

Gender

Followingoraladministrationofamoxicillin/clavulanicacidtohealthymalesandfemalesubjects,genderhasno

significantimpactonthepharmacokineticsofeitheramoxicillinorclavulanicacid.

Renalimpairment

Thetotalserumclearanceofamoxicillin/clavulanicaciddecreasesproportionatelywithdecreasingrenalfunction.The

reductionindrugclearanceismorepronouncedforamoxicillinthanforclavulanicacid,asahigherproportionof

amoxicillinisexcretedviatherenalroute.Dosesinrenalimpairmentmustthereforepreventundueaccumulationof

amoxicillinwhilemaintainingadequatelevelsofclavulanicacid(seesection4.2).

Hepaticimpairment

Hepaticallyimpairedpatientsshouldbedosedwithcautionandhepaticfunctionmonitoredatregularintervals.

5.3Preclinicalsafetydata

Nonclinicaldatarevealnospecialhazardforhumansbasedonstudiesofsafetypharmacology,

genotoxicityandtoxicitytoreproduction.

Repeatdosetoxicitystudiesperformedindogswithamoxicillin/clavulanicaciddemonstrategastricirritancyand

vomiting,anddiscolouredtongue.

CarcinogenicitystudieshavenotbeenconductedwithAugmentinoritscomponents.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

ProductimportedfromGreece:

Magnesiumstearate(E572)

Crospovidone

Colloidalhydratedsilca

Colloidalsilicondioxide

Lowsubstitutedhypromellose

Titaniumdioxide(E171)

Hypromellose(E464)

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Macrogol6000

ProductimportedfromSpain:

Crospovidone

Hydratedcolloidalsilica

Lowsubstitutedhypromellose

Magnesiumstearate

Macrogol4000

Macrogol6000

Hypromellose

Titaniumdioxide(E171)

Dimeticone500

6.2Incompatibilities

Notapplicable

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

Blisterpackscontaining4film-coatedtablets.Theblistersarepackagedinacartonwhichcontains3blisterstrips(12

tablets).

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Thetabletsshouldnotbebroken.

7PARALLELPRODUCTAUTHORISATIONHOLDER

B&SHealthcare

Unit4

BradfieldRoad

Ruislip

MiddlesexHA40NU

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1328/50/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 27/01/2011 CRN 2094037 page number: 12

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 27/01/2011 CRN 2094037 page number: 13

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