AUGMENTIN-DUO

Main information

  • Trade name:
  • AUGMENTIN-DUO Powder for Oral Suspension 400/57 MG/5ml
  • Dosage:
  • 400/57 MG/5ml
  • Pharmaceutical form:
  • Powder for Oral Suspension
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • AUGMENTIN-DUO Powder for Oral Suspension 400/57 MG/5ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1328/050/002
  • Authorization date:
  • 11-07-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Augmentin-Duo400mg/57mg/5mlPowderforOralSuspension

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each5mlofreconstitutedproductcontainsAmoxicillintrihydrateequivalenttoAmoxicillin400mgandpotassium

clavulanateequivalenttoclavulanicacid57mg.

Excipients:Aspartame(E951),Maltodextrin(dextrose)

Forafulllistofexcipientsseesection6.1.

3PHARMACEUTICALFORM

Powderfororalsuspension.

ProductimportedfromPortugalandItaly:

Drypowderforreconstitutionwithoff-whitegrainsandacharacteristicodour.

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)

Theseverityandthesiteoftheinfection

Theage,weightandrenalfunctionofthepatientasshownbelow.

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ratiosofamoxicillintoclavulanicacid)shouldbeconsideredasnecessary(seesections4.4and5.1).

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).

NoclinicaldataareavailableforAugmentin7:1formulationsregardingdoseshigherthan

45mg/6.4mgperkgperdayinchildrenunder2years

TherearenoclinicaldataforAugmentin7:1formulationsforpatientsunder2monthsofage.Dosingrecommendations

inthispopulationthereforecannotbemade.

Elderly

Nodoseadjustmentisconsiderednecessary.

Renalimpairment

Nodoseadjustmentisrequiredinpatientswithcreatinineclearance(CrCl)greaterthan30ml/min.

Inpatientswithcreatinineclearancelessthan30ml/min,theuseofAugmentinpresentationswithanamoxicillinto

clavulanicacidratioof7:1isnotrecommended,asnorecommendationsfordoseadjustmentsareavailable.

Hepaticimpairment

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Methodofadministration

Augmentinisfororaluse.

Administeratthestartofamealtominimisepotentialgastrointestinalintoleranceandoptimizeabsorptionof

amoxicillin/clavulanicacid.

TherapycanbestartedparenterallyaccordingtotheSmPCoftheIV-formulationandcontinuedwithanoral

preparation.

Shaketoloosenpowder,addwaterasdirected,invertandshake.

Shakethebottlebeforeeachdose(seesection6.6).

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.

Theoccurrenceatthetreatmentinitiationofafeverishgeneralisederythemaassociatedwithpustulemaybeasymptom

ofacutegeneralisedexanthemouspustulosis(AGEP)(seeSection4.8).ThisreactionrequiresAugmentin

discontinuationandcontra-indicatesanysubsequentadministrationofamoxicillin.

Amoxicillin/clavulanicacidshouldbeusedwithcautioninpatientswithevidenceofhepaticimpairment(seesections

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Hepaticeventshavebeenreportedpredominantlyinmalesandelderlypatientsandmaybeassociatedwithprolonged

treatment.Theseeventshavebeenveryrarelyreportedinchildren.Inallpopulations,signsandsymptomsusually

occurduringorshortlyaftertreatmentbutinsomecasesmaynotbecomeapparentuntilseveralweeksaftertreatment

hasceased.Theseareusuallyreversible.Hepaticeventsmaybesevereandinextremelyrarecircumstances,deaths

havebeenreported.Thesehavealmostalwaysoccurredinpatientswithseriousunderlyingdiseaseortaking

concomitantmedicationsknowntohavethepotentialforhepaticeffects(seesection4.8).

Antibiotic-associatedcolitishasbeenreportedwithnearlyallantibacterialagentsincludingamoxicillinandmayrange

inseverityfrommildtolifethreatening(seesection4.8).Therefore,itisimportanttoconsiderthisdiagnosisinpatients

whopresentwithdiarrhoeaduringorsubsequenttotheadministrationofanyantibiotics.Shouldantibiotic-associated

colitisoccur,Augmentinshouldimmediatelybediscontinued,aphysicianbeconsultedandanappropriatetherapy

initiated.Antiperistalticdrugsarecontra-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

presenceofglucoseinurinebecausefalsepositiveresultsmayoccurwithnonenzymaticmethods.

ThepresenceofclavulanicacidinAugmentinmaycauseanon-specificbindingofIgGandalbuminbyredcell

membranesleadingtoafalsepositiveCoombstest.

TherehavebeenreportsofpositivetestresultsusingtheBio-RadLaboratoriesPlateliaAspergillusEIAtestinpatients

receivingamoxicillin/clavulanicacidwhoweresubsequentlyfoundtobefreeofAspergillusinfection.Cross-reactions

withnon-AspergilluspolysaccharidesandpolyfuranoseswithBio-RadLaboratoriesPlateliaAspergillusEIAtesthave

beenreported.Therefore,positivetestresultsinpatientsreceivingamoxicillin/clavulanicacidshouldbeinterpreted

cautiouslyandconfirmedbyotherdiagnosticmethods.

Augmentin400mg/57mg/5mlpowderfororalsuspensioncontains3.32mgofaspartame(E951)perml,asourceof

phenylalanine.Thismedicineshouldbeusedwithcautioninpatientswithphenylketonuria.

Thismedicinalproductcontainsmaltodextrin(glucose).Patientswithrareglucose-galactosemalabsorptionshouldnot

takethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Oralanticoagulants

Oralanticoagulantsandpenicillinantibioticshavebeenwidelyusedinpracticewithoutreportsofinteraction.

However,intheliteraturetherearecasesofincreasedinternationalnormalisedratioinpatientsmaintainedon

acenocoumarolorwarfarinandprescribedacourseofamoxicillin.Ifcoadministrationisnecessary,theprothrombin

timeorinternationalnormalisedratioshouldbecarefullymonitoredwiththeadditionorwithdrawalofamoxicillin.

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Methotrexate

Penicillinsmayreducetheexcretionofmethotrexatecausingapotentialincreaseintoxicity.

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)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)

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Infectionsandinfestations

Mucocutaneouscandidosis Common

Overgrowthofnon-susceptibleorganisms Notknown

Bloodandlymphaticsystemdisorders

Reversibleleucopenia(includingneutropenia) Rare

Thrombocytopenia Rare

Reversibleagranulocytosis Notknown

Haemolyticanaemia Notknown

Prolongationofbleedingtimeandprothrombintime1 Notknown

Immunesystemdisorders10

Angioneuroticoedema Notknown

Anaphylaxis Notknown

Serumsickness-likesyndrome Notknown

Hypersensitivityvasculitis Notknown

Nervoussystemdisorders

Dizziness Uncommon

Headache Uncommon

Reversiblehyperactivity Notknown

Convulsions2 Notknown

Gastrointestinaldisorders

Diarrhoea Common

Nausea3 Common

Vomiting Common

Indigestion Uncommon

Antibiotic-associatedcolitis4 Notknown

Blackhairytongue Notknown

Toothdiscolouration11 Notknown

Hepatobiliarydisorders

RisesinASTand/orALT5 Uncommon

Hepatitis6 Notknown

Cholestaticjaundice6 Notknown

Skinandsubcutaneoustissuedisorders7

Skinrash Uncommon

Pruritus Uncommon

Urticaria Uncommon

Erythemamultiforme Rare

Stevens-Johnsonsyndrome Notknown

Toxicepidermalnecrolysis Notknown

Bullousexfoliative-dermatitis Notknown

Acutegeneralisedexanthemouspustulosis(AGEP)

Notknown

Renalandurinarydisorders

Interstitialnephritis Notknown

Crystalluria8 Notknown

1Seesection4.4

2Seesection4.4

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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)inthebiosyntheticpathwayofbacterial

peptidoglycan,whichisanintegralstructuralcomponentofthebacterialcellwall.Inhibitionof

peptidoglycansynthesisleadstoweakeningofthecellwall,whichisusuallyfollowedbycelllysisanddeath.

Amoxicillinissusceptibletodegradationbybeta-lactamasesproducedbyresistantbacteriaandthereforethespectrum

ofactivityofamoxicillinalonedoesnotincludeorganismswhichproducetheseenzymes.

Clavulanicacidisabeta-lactamstructurallyrelatedtopenicillins.Itinactivatessomebeta-lactamaseenzymesthereby

preventinginactivationofamoxicillin.Clavulanicacidalonedoesnotexertaclinicallyusefulantibacterialeffect.

PK/PDrelationship

Thetimeabovetheminimuminhibitoryconcentration(T>MIC)isconsideredtobethemajordeterminantofefficacy

evident,theymaybereducedbytakingAugmentinatthestartofameal.

4Includingpseudomembranouscolitisandhaemorrhagiccolitis(seesection4.4)

5AmoderateriseinASTand/orALThasbeennotedinpatientstreatedwithbeta-lactam

classantibiotics,butthesignificanceofthesefindingsisunknown.

6Theseeventshavebeennotedwithotherpenicillinsandcephalosporins(seesection4.4).

7Ifanyhypersensitivitydermatitisreactionoccurs,treatmentshouldbediscontinued(see

section4.4).

8Seesection4.9

9Seesection4.3

10Seesection4.4

11Superficialtoothdiscolourationhasbeenreportedveryrarelyinchildren.Goodoral

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Mechanismsofresistance

Thetwomainmechanismsofresistancetoamoxicillin/clavulanicacidare:

Inactivationbythosebacterialbeta-lactamasesthatarenotthemselvesinhibitedbyclavulanicacid,

includingclassB,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-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 >8

Gram-positiveAnaerobes 1 ≤4 8 >8

Non-speciesrelated

breakpoints 1 ≤2 4-8 >8

ThereportedvaluesareforAmoxicillinconcentrations.Forsusceptibilitytestingpurposes,the

concentrationofClavulanicacidisfixedat2mg/l.

ThereportedvaluesareOxacillinconcentrations.

BreakpointvaluesinthetablearebasedonAmpicillinbreakpoints.

TheresistantbreakpointofR>8mg/lensuresthatallisolateswithresistancemechanismsare

reportedresistant.

BreakpointvaluesinthetablearebasedonBenzylpenicillinbreakpoints.

Commonlysusceptiblespecies

AerobicGram-positivemicro-organisms

Enterococcusfaecalis

Gardnerellavaginalis

Staphylococcusaureus(methicillin-susceptible)£

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Streptococcuspneumoniae 1

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

Streptococcuspneumoniaethatareresistanttopenicillinshouldnotbetreatedwiththis

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

StrainswithdecreasedsusceptibilityhavebeenreportedinsomecountriesintheEUwitha

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5.2Pharmacokineticproperties

Absorption

Amoxicillinandclavulanicacid,arefullydissociatedinaqueoussolutionatphysiologicalpH.Bothcomponentsare

rapidlyandwellabsorbedbytheoralrouteofadministration.Absorptionofamoxicillin/clavulanicacidisoptimised

whentakenatthestartofameal.Followingoraladministration,amoxicillinandclavulanicacidareapproximately

70%bioavailable.Theplasmaprofilesofbothcomponentsaresimilarandthetimetopeakplasmaconcentration

(Tmax)ineachcaseisapproximatelyonehour.

Thepharmacokineticresultsforastudy,inwhichamoxicillin/clavulanicacid(875mg/125mgtabletsgiventwice

daily)wasadministeredinthefastingstatetogroupsofhealthyvolunteersarepresentedbelow.

Amoxicillinandclavulanicacidserumconcentrationsachievedwithamoxicillin/clavulanicacidaresimilartothose

producedbytheoraladministrationofequivalentdosesofamoxicillinorclavulanicacidalone.

Distribution

About25%oftotalplasmaclavulanicacidand18%oftotalplasmaamoxicillinisboundtoprotein.

Theapparentvolumeofdistributionisaround0.3-0.4l/kgforamoxicillinandaround0.2l/kgfor

clavulanicacid.

Followingintravenousadministration,bothamoxicillinandclavulanicacidhavebeenfoundingallbladder,abdominal

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

Amoxicillindoesnotadequatelydistributeintothecerebrospinalfluid.

Fromanimalstudiesthereisnoevidenceforsignificanttissueretentionofdrug-derivedmaterialforeithercomponent.

Amoxicillin,likemostpenicillins,canbedetectedinbreastmilk.Tracequantitiesofclavulanicacidcanalsobe

detectedinbreastmilk(seesection4.6).

Bothamoxicillinandclavulanicacidhavebeenshowntocrosstheplacentalbarrier(seesection4.6).

Biotransformation

Amoxicillinispartlyexcretedintheurineastheinactivepenicilloicacidinquantitiesequivalenttoupto10to25%of

theinitialdose.Clavulanicacidisextensivelymetabolizedinmanandeliminatedinurineandfaecesandascarbon

dioxideinexpiredair.

Elimination

Themajorrouteofeliminationforamoxicillinisviathekidney,whereasforclavulanicaciditisbybothrenalandnon-

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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Amoxicillin/clavulanicacidhasameaneliminationhalf-lifeofapproximatelyonehourandameantotalclearanceof

approximately25l/hinhealthysubjects.Approximately60to70%oftheamoxicillinandapproximately40to65%of

theclavulanicacidareexcretedunchangedinurineduringthefirst6hafteradministrationofsingleAugmentin250

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

andbetween27-60%forclavulanicacidovera24hourperiod.Inthecaseofclavulanicacid,thelargestamountof

drugisexcretedduringthefirst2hoursafteradministration.

Concomitantuseofprobeneciddelaysamoxicillinexcretionbutdoesnotdelayrenalexcretionof

clavulanicacid(seesection4.5).

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.

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Crospovidone

Carmellosesodium

Xanthangum

Colloidalanhydroussilica

Magnesiumstearate

Sodiumbenzoate(E211)

Aspartame(E951)

Strawberryflavour

Silicondioxide

6.2Incompatibilities

Notapplicable

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

Afterreconstitutionsuspensionshouldbestoredinarefrigeratorbetween2-8°C,andusedwithin7days.

6.4Specialprecautionsforstorage

Drypowder:Donotstoreabove25°C.Keepthecontainertightlyclosed.

Storeintheoriginalpackage

Reconstitutedsuspension:Storeinarefrigerator(2°C-8°C.)Donotfreeze.

6.5Natureandcontentsofcontainer

Clear,glassbottlescontainingsufficientpowdertoprovide70mlreconstitutedsuspension.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Checkcapsealisintactbeforeusing.Shakebottletoloosenpowder.Addvolumeofwater(asindicatedbelow)invert

andshakewell.Alternativelyfillthebottlewithwatertojustbelowthemarkonbottlelabel,invertandshakewell.

Thentopupwithwaterexactlytothemark,invertandagainshakewell.

Shakethebottlewellbeforeeachdose. Strength Volumeofwatertobeaddedat

reconstitution(ml) Finalvolumeofreconstitutedoral

suspension(ml)

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 23/02/2011 CRN 2096245 page number: 12

7PARALLELPRODUCTAUTHORISATIONHOLDER

B&SHealthcare,

Unit4,

BradfieldRoad,

Ruislip,

MiddlesexHA4ONU

UnitedKingdom

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1328/50/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:11thJuly2007

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 23/02/2011 CRN 2096245 page number: 13