AUGMENTIN

Main information

  • Trade name:
  • AUGMENTIN Film Coated Tablet 875/125mg Milligram
  • Dosage:
  • 875/125mg Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • AUGMENTIN Film Coated Tablet 875/125mg Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0678/012/006
  • Authorization date:
  • 12-11-2004
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Augumentin875/125mgfilmcoatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Augumentin875/125mgfilm-coatedtabletscontainAmoxicillintrihydrateequivalentto

875mgamoxicillinandpotassiumclavulanateequivalentto125mgclavulanicacid

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Filmcoatedtablet

WhitetooffwhiteovalfilmcoatedtabletsdebossedwiththelettersAConbothsidesandwithascorelineononeside.

Thepruposeofthescorelineistoaidswallowingandnottoenablethetablettobedividedintotwoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Augmentinisindicatedforthetreatmentofthefollowinginfectionsinadultsandchildren(seesections4.2,4.4and

5.1):

Acutebacterialsinusitis(adequatelydiagnosed)

Acuteotitismedia

Acuteexacerbationsofchronicbronchitis(adequatelydiagnosed)

Communityacquiredpneumonia

Cystitis

Pyelonephritis

Skinandsofttissueinfectionsinparticularcellulitis,animalbites,severedentalabscesswithspreading

cellulitis.

Boneandjointinfections,inparticularosteomyelitis.

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantibacterialagents.

4.2Posologyandmethodofadministration

Dosesareexpressedthroughoutintermsofamoxicillin/clavulanicacidcontentexceptwhendosesarestatedinterms

ofanindividualcomponent.

ThedoseofAugmentinthatisselectedtotreatanindividualinfectionshouldtakeintoaccount:

Theexpectedpathogensandtheirlikelysusceptibilitytoantibacterialagents(seesection4.4)

Theseverityandthesiteoftheinfection

Theage,weightandrenalfunctionofthepatientasshownbelow.

TheuseofalternativepresentationsofAugmentin(e.g.thosethatprovidehigherdosesofamoxicillinand/ordifferent

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Foradultsandchildren 40kg,thisformulationofAugmentinprovidesatotaldailydoseof1750mgamoxicillin/250

mgclavulanicacidwithtwicedailydosingand2625mgamoxicillin/375mgclavulanicacidwiththreetimesdaily

dosing,whenadministeredasrecommendedbelow.Forchildren<40kg,thisformulationofAugmentinprovidesa

maximumdailydoseof1000-2800mgamoxicillin/143-400mgclavulanicacid,whenadministeredasrecommended

below.Ifitisconsideredthatahigherdailydoseofamoxicillinisrequired,itisrecommendedthatanotherpreparation

ofAugmentinisselectedinordertoavoidadministrationofunnecessarilyhighdailydosesofclavulanicacid(see

sections4.4and5.1).

Thedurationoftherapyshouldbedeterminedbytheresponseofthepatient.Someinfections(e.g.osteomyelitis)

requirelongerperiodsoftreatment.Treatmentshouldnotbeextendedbeyond14dayswithoutreview(seesection4.4

regardingprolongedtherapy).

Adultsandchildren 40kg

Recommendeddoses:

standarddose:(forallindications)875mg/125mgtwotimesaday;

higherdose-(particularlyforinfectionssuchasotitismedia,sinusitis,lowerrespiratorytractinfectionsand

urinarytractinfections):875mg/125mgthreetimesaday.

Children<40kg

ChildrenmaybetreatedwithAugmentintablets,suspensionsorpaediatricsachets.

Recommendeddoses:

25mg/3.6mg/kg/dayto45mg/6.4mg/kg/daygivenastwodivideddoses;

upto70mg/10mg/kg/daygivenastwodivideddosesmaybeconsideredforsomeinfections(suchasotitis

media,sinusitisandlowerrespiratorytractinfections).

NoclinicaldataareavailableforAugmentin7:1formulationsregardingdoseshigherthan45mg/6.4mgperkgperday

inchildrenunder2years

TherearenoclinicaldataforAugmentin7:1formulationsforpatientsunder2monthsofage.Dosing

recommendationsinthispopulationthereforecannotbemade.

Elderly

Nodoseadjustmentisconsiderednecessary.

Renalimpairment

Nodoseadjustmentisrequiredinpatientswithcreatinineclearance(CrCl)greaterthan30ml/min.

Inpatientswithcreatinineclearancelessthan30ml/min,theuseofAugmentinpresentationswithanamoxicillinto

clavulanicacidratioof7:1isnotrecommended,asnorecommendationsfordoseadjustmentsareavailable.

Hepaticimpairment

Dosewithcautionandmonitorhepaticfunctionatregularintervals(seesections4.3and4.4).

Methodofadministration

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Administeratthestartofamealtominimisepotentialgastrointestinalintoleranceandoptimiseabsorptionof

amoxicillin/clavulanicacid.

TherapycanbestartedparenterallyaccordingtotheSmPCoftheIV-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(seesections4.3and4.8).

Seriousandoccasionallyfatalhypersensitivity(anaphylactoid)reactionshavebeenreportedinpatientsonpenicillin

therapy.Thesereactionsaremorelikelytooccurinindividualswithahistoryofpenicillinhypersensitivityandin

atopicindividuals.Ifanallergicreactionoccurs,amoxicillin/clavulanicacidtherapymustbediscontinuedand

appropriatealternativetherapyinstituted.

Inthecasethataninfectionisproventobeduetoanamoxicillin-susceptibleorganisms(s)thenconsiderationshouldbe

giventoswitchingfromamoxicillin/clavulanicacidtoamoxicillininaccordancewithofficialguidance.

ThispresentationofAugmentinisnotsuitableforusewhenthereisahighriskthatthepresumptivepathogenshave

resistancetobeta-lactamagentsthatisnotmediatedbybeta-lactamasessusceptibletoinhibitionbyclavulanicacid.

Thispresentationshouldnotbeusedtotreatpenicillin-resistantS.pneumoniae.

Convulsionsmayoccurinpatientswithimpairedrenalfunctionorinthosereceivinghighdoses(see4.8).

Amoxicillin/clavulanicacidshouldbeavoidedifinfectiousmononucleosisissuspectedsincetheoccurrenceofa

morbilliformrashhasbeenassociatedwiththisconditionfollowingtheuseofamoxicillin.

Concomitantuseofallopurinolduringtreatmentwithamoxicillincanincreasethelikelihoodofallergicskinreactions.

Prolongedusemayoccasionallyresultinovergrowthofnon-susceptibleorganisms.

Theoccurrenceatthetreatmentinitiationofafeverishgeneralisederythemaassociatedwithpustulamaybeasymptom

ofacutegeneralisedexanthemouspustulosis(AGEP)(seeSection4.8).ThisreactionrequiresAugmentin

discontinuationandcontra-indicatesanysubsequentadministrationofamoxicillin.

Amoxicillin/clavulanicacidshouldbeusedwithcautioninpatientswithevidenceofhepaticimpairment(seesections

4.2,4.3and4.8).

Hepaticeventshavebeenreportedpredominantlyinmalesandelderlypatientsandmaybeassociatedwithprolonged

treatment.Theseeventshavebeenveryrarelyreportedinchildren.Inallpopulations,signsandsymptomsusually

occurduringorshortlyaftertreatmentbutinsomecasesmaynotbecomeapparentuntilseveralweeksaftertreatment

hasceased.Theseareusuallyreversible.Hepaticeventsmaybesevereandinextremelyrarecircumstances,deaths

havebeenreported.Thesehavealmostalwaysoccurredinpatientswithseriousunderlyingdiseaseortaking

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Antibiotic-associatedcolitishasbeenreportedwithnearlyallantibacterialagentsincludingamoxicillinandmayrange

inseverityfrommildtolifethreatening(seesection4.8).Therefore,itisimportanttoconsiderthisdiagnosisin

patientswhopresentwithdiarrhoeaduringorsubsequenttotheadministrationofanyantibiotics.Shouldantibiotic-

associatedcolitisoccur,Augmentinshouldimmediatelybediscontinued,aphysicianbeconsultedandanappropriate

therapyinitiated.Anti-peristalticdrugsarecontra-indicatedinthissituation.

Periodicassessmentoforgansystemfunctions,includingrenal,hepaticandhaematopoieticfunctionisadvisable

duringprolongedtherapy.

Prolongationofprothrombintimehasbeenreportedrarelyinpatientsreceivingamoxicillin/clavulanicacid.

Appropriatemonitoringshouldbeundertakenwhenanticoagulantsareprescribedconcomitantly.Adjustmentsinthe

doseoforalanticoagulantsmaybenecessarytomaintainthedesiredlevelofanticoagulation(seesection4.5and4.8).

Inpatientswithrenalimpairment,thedoseshouldbeadjustedaccordingtothedegreeofimpairment(seesection4.2).

Inpatientswithreducedurineoutput,crystalluriahasbeenobservedveryrarely,predominantlywithparenteral

therapy.Duringtheadministrationofhighdosesofamoxicillin,itisadvisabletomaintainadequatefluidintakeand

urinaryoutputinordertoreducethepossibilityofamoxicillincrystalluria.Inpatientswithbladdercatheters,aregular

checkofpatencyshouldbemaintained(seesection4.9).

Duringtreatmentwithamoxicillin,enzymaticglucoseoxidasemethodsshouldbeusedwhenevertestingforthe

presenceofglucoseinurinebecausefalsepositiveresultsmayoccurwithnon-enzymaticmethods.

ThepresenceofclavulanicacidinAugmentinmaycauseanon-specificbindingofIgGandalbuminbyredcell

membranesleadingtoafalsepositiveCoombstest.

TherehavebeenreportsofpositivetestresultsusingtheBio-RadLaboratoriesPlateliaAspergillusEIAtestinpatients

receivingamoxicillin/clavulanicacidwhoweresubsequentlyfoundtobefreeofAspergillusinfection.Cross-reactions

withnon-AspergilluspolysaccharidesandpolyfuranoseswithBio-RadLaboratoriesPlateliaAspergillusEIAtesthave

beenreported.Therefore,positivetestresultsinpatientsreceivingamoxicillin/clavulanicacidshouldbeinterpreted

cautiouslyandconfirmedbyotherdiagnosticmethods.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Oralanticoagulants

Oralanticoagulantsandpenicillinantibioticshavebeenwidelyusedinpracticewithoutreportsofinteraction.

However,intheliteraturetherearecasesofincreasedinternationalnormalisedratioinpatientsmaintainedon

acenocoumarolorwarfarinandprescribedacourseofamoxicillin.Ifco-administrationisnecessary,theprothrombin

timeorinternationalnormalisedratioshouldbecarefullymonitoredwiththeadditionorwithdrawalofamoxicillin.

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

Methotrexate

Penicillinsmayreducetheexcretionofmethotrexatecausingapotentialincreaseintoxicity.

Probenecid

Concomitantuseofprobenecidisnotrecommended.Probeneciddecreasestherenaltubularsecretionofamoxicillin.

Concomitantuseofprobenecidmayresultinincreasedandprolongedbloodlevelsofamoxicillinbutnotofclavulanic

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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,

sothatbreast-feedingmighthavetobediscontinued.Amoxicillin/clavulanicacidshouldonlybeusedduringbreast-

feedingafterbenefit/riskassessmentbythephysicianincharge.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.However,undesirableeffects

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

(seesection4.8).

4.8Undesirableeffects

Themostcommonlyreportedadversedrugreactions(ADRs)arediarrhoea,nauseaandvomiting.

TheADRsderivedfromclinicalstudiesandpost-marketingsurveillancewithAugmentin,sortedbyMedDRASystem

OrganClassarelistedbelow.

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

Mucocutaneouscandidosis Common

Overgrowthofnon-susceptibleorganisms Notknown

Bloodandlymphaticsystemdisorders

Reversibleleucopenia(including

neutropenia) Rare

Thrombocytopenia Rare

Reversibleagranulocytosis Notknown

Haemolyticanaemia Notknown

Prolongationofbleedingtimeand

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Immunesystemdisorders 10

Angioneuroticoedema Notknown

Anaphylaxis Notknown

Serumsickness-likesyndrome Notknown

Hypersensitivityvasculitis Notknown

Nervoussystemdisorders

Dizziness Uncommon

Headache Uncommon

Reversiblehyperactivity Notknown

Convulsions 2 Notknown

Gastrointestinaldisorders

Diarrhoea Verycommon

Nausea 3 Common

Vomiting Common

Indigestion Uncommon

Antibiotic-associatedcolitis 4 Notknown

Blackhairytongue Notknown

Hepatobiliarydisorders

RisesinASTand/orALT 5 Uncommon

Hepatitis 6 Notknown

Cholestaticjaundice 6 Notknown

Skinandsubcutaneoustissuedisorders 7

Skinrash Uncommon

Pruritus Uncommon

Urticaria Uncommon

Erythemamultiforme Rare

Stevens-Johnsonsyndrome Notknown

Toxicepidermalnecrolysis Notknown

Bullousexfoliative-dermatitis Notknown

Acutegeneralisedexanthemouspustulosis

(AGEP) 9 Notknown

Renalandurinarydisorders

Interstitialnephritis Notknown

Crystalluria 8 Notknown

Seesection4.4

Seesection4.4

Nauseaismoreoftenassociatedwithhigheroraldoses.Ifgastrointestinalreactions

areevident,theymaybereducedbytakingAugmentinatthestartofameal.

Includingpseudomembranouscolitisandhaemorrhagiccolitis(seesection4.4)

AmoderateriseinASTand/orALThasbeennotedinpatientstreatedwithbeta-

lactamclassantibiotics,butthesignificanceofthesefindingsisunknown.

Theseeventshavebeennotedwithotherpenicillinsandcephalosporins(seesection

4.4).

Ifanyhypersensitivitydermatitisreactionoccurs,treatmentshouldbediscontinued

(seesection4.4).

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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)inthebiosyntheticpathwayofbacterialpeptidoglycan,whichisanintegral

structuralcomponentofthebacterialcellwall.Inhibitionofpeptidoglycansynthesisleadstoweakeningofthecell

wall,whichisusuallyfollowedbycelllysisanddeath.

Amoxicillinissusceptibletodegradationbybeta-lactamasesproducedbyresistantbacteriaandthereforethespectrum

ofactivityofamoxicillinalonedoesnotincludeorganismswhichproducetheseenzymes.

Clavulanicacidisabeta-lactamstructurallyrelatedtopenicillins.Itinactivatessomebeta-lactamaseenzymesthereby

preventinginactivationofamoxicillin.Clavulanicacidalonedoesnotexertaclinicallyusefulantibacterialeffect.

PK/PDrelationship

Thetimeabovetheminimuminhibitoryconcentration(T>MIC)isconsideredtobethemajordeterminantofefficacy

foramoxicillin.

Mechanismsofresistance

Thetwomainmechanismsofresistancetoamoxicillin/clavulanicacidare:

Inactivationbythosebacterialbeta-lactamasesthatarenotthemselvesinhibitedbyclavulanicacid,including

classB,CandD.

AlterationofPBPs,whichreducetheaffinityoftheantibacterialagentforthetarget.

Impermeabilityofbacteriaoreffluxpumpmechanismsmaycauseorcontributetobacterialresistance,particularlyin

Seesection4.3

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Breakpoints

MICbreakpointsforamoxicillin/clavulanicacidarethoseoftheEuropeanCommitteeonAntimicrobialSusceptibility

Testing(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-negative

staphylococci 2 ≤0.25 >0.25

Enterococcus 1 ≤4 8 >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 >8

Non-speciesrelated

breakpoints 1 ≤2 4-8 >8

ThereportedvaluesareforAmoxicillinconcentrations.Forsusceptibilitytestingpurposes,

theconcentrationofClavulanicacidisfixedat2mg/l.

ThereportedvaluesareOxacillinconcentrations.

BreakpointvaluesinthetablearebasedonAmpicillinbreakpoints.

TheresistantbreakpointofR>8mg/lensuresthatallisolateswithresistancemechanismsare

reportedresistant.

BreakpointvaluesinthetablearebasedonBenzylpenicillinbreakpoints.

Commonlysusceptiblespecies

AerobicGram-positivemicro-organisms

Enterococcusfaecalis

Gardnerellavaginalis

Staphylococcusaureus(methicillin-susceptible)

Streptococcusagalactiae

Streptococcuspneumoniae 1

Streptococcuspyogenesandotherbeta-haemolyticstreptococci

Streptococcusviridansgroup

AerobicGram-negativemicro-organisms

Capnocytophagaspp.

Eikenellacorrodens

Haemophilusinfluenzae 2

Moraxellacatarrhalis

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5.2Pharmacokineticproperties

Absorption

Amoxicillinandclavulanicacid,arefullydissociatedinaqueoussolutionatphysiologicalpH.Bothcomponentsare

rapidlyandwellabsorbedbytheoralrouteofadministration.Absorptionofamoxicillin/clavulanicacidisoptimised

whentakenatthestartofameal.Followingoraladministration,amoxicillinandclavulanicacidareapproximately

70%bioavailable.Theplasmaprofilesofbothcomponentsaresimilarandthetimetopeakplasmaconcentration

)ineachcaseisapproximatelyonehour.

Thepharmacokineticresultsforastudy,inwhichamoxicillin/clavulanicacid(875mg/125mgtabletsgiventwice

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

$Naturalintermediatesusceptibilityintheabsenceofacquiredmechanismof

resistance.

Allmethicillin-resistantstaphylococciareresistanttoamoxicillin/clavulanicacid

Streptococcuspneumoniaethatareresistanttopenicillinshouldnotbetreatedwith

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

StrainswithdecreasedsusceptibilityhavebeenreportedinsomecountriesintheEU

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Amoxicillinandclavulanicacidserumconcentrationsachievedwithamoxicillin/clavulanicacidaresimilartothose

producedbytheoraladministrationofequivalentdosesofamoxicillinorclavulanicacidalone.

Distribution

About25%oftotalplasmaclavulanicacidand18%oftotalplasmaamoxicillinisboundtoprotein.Theapparent

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

Followingintravenousadministration,bothamoxicillinandclavulanicacidhavebeenfoundingallbladder,abdominal

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

distributeintothecerebrospinalfluid.

Fromanimalstudiesthereisnoevidenceforsignificanttissueretentionofdrug-derivedmaterialforeithercomponent.

Amoxicillin,likemostpenicillins,canbedetectedinbreastmilk.Tracequantitiesofclavulanicacidcanalsobe

detectedinbreastmilk(seesection4.6).

Bothamoxicillinandclavulanicacidhavebeenshowntocrosstheplacentalbarrier(seesection4.6).

Biotransformation

Amoxicillinispartlyexcretedintheurineastheinactivepenicilloicacidinquantitiesequivalenttoupto10to25%of

theinitialdose.Clavulanicacidisextensivelymetabolizedinmanandeliminatedinurineandfaecesandascarbon

dioxideinexpiredair.

Elimination

Themajorrouteofeliminationforamoxicillinisviathekidney,whereasforclavulanicaciditisbybothrenalandnon-

renalmechanisms.

Amoxicillin/clavulanicacidhasameaneliminationhalf-lifeofapproximatelyonehourandameantotalclearanceof

approximately25l/hinhealthysubjects.Approximately60to70%oftheamoxicillinandapproximately40to65%of

theclavulanicacidareexcretedunchangedinurineduringthefirst6hafteradministrationofsingleAugmentin

250mg/125mgor500mg/125mgtablets.Variousstudieshavefoundtheurinaryexcretiontobe50-85%for

amoxicillinandbetween27-60%forclavulanicacidovera24hourperiod.Inthecaseofclavulanicacid,thelargest

amountofdrugisexcretedduringthefirst2hoursafteradministration.

Concomitantuseofprobeneciddelaysamoxicillinexcretionbutdoesnotdelayrenalexcretionofclavulanicacid(see

Mean( ±

SD)pharmacokineticparameters

Activesubstance(s)

administered Dose C

(0-24h) T1/2

(mg) (µg/ml) (h) ((µg.h/ml) (h)

Amoxicillin

AMX/CA

875mg/125mg 875 11.64

2.78 1.50

(1.0-2.5) 53.52

12.31 1.19

0.21

Clavulanicacid

AMX/CA

875mg/125mg 125 2.18

0.99 1.25

(1.0-2.0) 10.16

3.04 0.96

0.12

AMX–amoxicillin,CA–clavulanicacid

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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,genotoxicityand

toxicitytoreproduction.

Repeatdosetoxicitystudiesperformedindogswithamoxicillin/clavulanicaciddemonstrategastricirritancyand

vomiting,anddiscolouredtongue.

CarcinogenicitystudieshavenotbeenconductedwithAugmentinoritscomponents.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Magnesiumstearate

SodiumstarchglycollatetypeA

Colloidalanhydroussilica

Microcrystallinecellulose

Filmcoat

Titaniumdioxide(E171)

Hypromellose

Macrogol

Dimeticone

6.2Incompatibilities

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6.3ShelfLife

2years

6.4Specialprecautionsforstorage

Donotstoreabove25ºC

Storeintheoriginalpackageinordertoprotectfrommoisture.Donotremovethedessicant.Keepblisterintheouter

cartoninordertoprotectfromlight.

6.5Natureandcontentsofcontainer

Aluminium/PVC/PvDCblisterinadesiccatedaluminiumpouchorAluminium/PVC/PVdCblisterenclosedinacold

formedlaminateoverwrapconsistingofAluminiumandpolyamidewithaPVClacquer

Packscontaining4or14tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

GlaxoSmithKlineConsumerHealthcare(Ireland)Limited

StonemasonsWay,

Rathfarnham,

Dublin16,

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA678/12/6

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:12November2004

Dateoflastrenewal:12November2009

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 09/12/2010 CRN 2074998 page number: 12