CLAVAMEL PEDIATRIC

Main information

  • Trade name:
  • CLAVAMEL PEDIATRIC
  • Dosage:
  • 125/31.25 Milligram
  • Pharmaceutical form:
  • Powder for Oral Suspension
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CLAVAMEL PEDIATRIC
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0126/103/002
  • Authorization date:
  • 17-09-1999
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ClavamelPaediatric125mg/31.25mgper5mlPowderforOralSuspension

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each5mlofreconstitutedsuspensioncontainsAmoxicillinTrihydrateequivalentto125mgofamoxicillinand

potassiumclavulanateequivalentto31.25mgofclavulanicacid.

Excipients:Each5mlofreconsitutedoralsuspensioncontains

12.5mgofAspartame(E951)

0.0009mgofEthanol

<0.0002mgSulphites(includingSulphurDioxideE220)

1.63mgGumArabicE414(maycontainsmallamountsofGalactose)

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Powderfororalsuspension

Clear,glassbottles,containingawhitetooff-whitepowderforreconstitutionwithwater.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Clavamelisindicatedforthetreatmentofthefollowinginfectionsinadultsandchildren(seesections4.2,4.4and5.1):

Acutebacterialsinusitis(adequatelydiagnosed)

Acuteotitismedia

Acuteexacerbationsofchronicbronchitis(adequatelydiagnosed)

Communityacquiredpneumonia

Cystitis

Pyelonephritis

Skinandsofttissueinfectionsinparticularcellulitis,animalbites,severedentalabscesswithspreading

cellulitis.

Boneandjointinfections,inparticularosteomyelitis.

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantibacterialagents.

4.2Posologyandmethodofadministration

Dosesareexpressedthroughoutintermsofamoxicillin/clavulanicacidcontentexceptwhendosesarestatedinterms

ofanindividualcomponent.

ThedoseofClavamelthatisselectedtotreatanindividualinfectionshouldtakeintoaccount:

Theexpectedpathogensandtheirlikelysusceptibilitytoantibacterialagents(seesection4.4)

Theseverityandthesiteoftheinfection

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TheuseofalternativepresentationsofClavamel(e.g.thosethatprovidehigherdosesofamoxicillinand/ordifferent

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

Foradultsandchildren 40kg,thisformulationofClavamelprovidesatotaldailydoseof1500mg

amoxicillin/375mgclavulanicacid,whenadministeredasrecommendedbelow.Forchildren<40kg,thisformulation

ofClavamelprovidesamaximumdailydoseof2400mgamoxicillin/600mgclavulanicacid,whenadministeredas

recommendedbelow.Ifitisconsideredthatahigherdailydoseofamoxicillinisrequired,itisrecommendedthat

anotherpreparationofClavamelisselectedinordertoavoidadministrationofunnecessarilyhighdailydosesof

clavulanicacid(seesections4.4and5.1).

Thedurationoftherapyshouldbedeterminedbytheresponseofthepatient.Someinfections(e.g.osteomyelitis)

requirelongerperiodsoftreatment.Treatmentshouldnotbeextendedbeyond14dayswithoutreview(seesection4.4

regardingprolongedtherapy).

Adultsandchildren 40kg

One500mg/125mgdosetakenthreetimesaday.

Children<40kg

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

ChildrenmaybetreatedwithClavameltablets,suspensionsorpaediatricsachets.Childrenaged6yearsandbelow

shouldpreferablybetreatedwithClavamelsuspensionorpaediatricsachets.

NoclinicaldataareavailableondosesofClavamel4:1formulationshigherthan40mg/10mg/kgperdayinchildren

under2years.

Elderly

Nodoseadjustmentisconsiderednecessary.

Renalimpairment

Doseadjustmentsarebasedonthemaximumrecommendedlevelofamoxicillin.

Noadjustmentindoseisrequiredinpatientswithcreatinineclearance(CrCl)greaterthan30ml/min.

Adultsandchildren 40kg

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

CrCl<10ml/min 500mg/125mgoncedaily

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

toberepeatedattheendofdialysis(asserumconcentrationsofboth

amoxicillinandclavulanicacidaredecreased)

CrCl:10-30ml/min 15mg/3.75mg/kgtwicedaily(maximum500mg/125mgtwice

daily).

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

Haemodialysis 15mg/3.75mg/kgperdayoncedaily.

Priortohaemodialysis15mg/3.75mg/kg.Inordertorestore

circulatingdruglevels,15mg/3.75mgperkgshouldbeadministered

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Hepaticimpairment

Dosewithcautionandmonitorhepaticfunctionatregularintervals(seesections4.3and4.4).

Methodofadministration

Clavamelisfororaluse.

Administeratthestartofamealtominimisepotentialgastrointestinalintoleranceandoptimiseabsorptionof

amoxicillin/clavulanicacid.

TherapycanbestartedparenterallyaccordingtheSPCoftheIV-formulationandcontinuedwithanoralpreparation.

Shaketoloosenpowder,addwaterasdirected,invertandshake.

Shakethebottlebeforeeachdose(seesection6.6).

4.3Contraindications

Hypersensitivitytotheactivesubstances,toanyofthepenicillinsortoanyoftheexcipients.

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

cephalosporin,carbapenemor

monobactam).

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.

ThispresentationofClavamelisnotsuitableforusewhenthereisahighriskthatthepresumptivepathogenshave

reducedsusceptibilityorresistancetobeta-lactamagentsthatisnotmediatedbybeta-lactamasessusceptibleto

inhibitionbyclavulanicacid.Thispresentationshouldnotbeusedtotreatpenicillin-resistantS.pneumoniae.

Convulsionsmayoccurinpatientswithimpairedrenalfunctionorinthosereceivinghighdoses(seesection4.8).

Amoxicillin/clavulanicacidshouldbeavoidedifinfectiousmononucleosisissuspectedsincetheoccurrenceofa

morbilliformrashhasbeenassociatedwiththisconditionfollowingtheuseofamoxicillin.

Concomitantuseofallopurinolduringtreatmentwithamoxicillincanincreasethelikelihoodofallergicskinreactions.

Prolongedusemayoccasionallyresultinovergrowthofnon-susceptibleorganisms.

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ofacutegeneralisedexanthemouspustulosis(AGEP)(seeSection4.8).ThisreactionrequiresClavameldiscontinuation

andcontra-indicatesanysubsequentadministrationofamoxicillin.

Amoxicillin/clavulanicacidshouldbeusedwithcautioninpatientswithevidenceofhepaticimpairment(seesection

4.2).

Hepaticeventshavebeenreportedpredominantlyinmalesandelderlypatientsandmaybeassociatedwithprolonged

treatment.Theseeventshavebeenveryrarelyreportedinchildren.Inallpopulations,signsandsymptomsusually

occurduringorshortlyaftertreatmentbutinsomecasesmaynotbecomeapparentuntilseveralweeksaftertreatment

hasceased.Theseareusuallyreversible.Hepaticeventsmaybesevereand,inextremelyrarecircumstances,deaths

havebeenreported.Thesehavealmostalwaysoccurredinpatientswithseriousunderlyingdiseaseortaking

concomitantmedicationsknowntohavethepotentialforhepaticeffects(seesection4.8).

Antibiotic-associatedcolitishasbeenreportedwithnearlyallantibacterialagentsandmayrangeinseverityfrommild

tolifethreatening(seesection4.8).Therefore,itisimportanttoconsiderthisdiagnosisinpatientswhopresentwith

diarrhoeaduringorsubsequenttotheadministrationofanyantibiotics.Shouldantibiotic-associatedcolitisoccur,

amoxicillin/clavulanicacidshouldimmediatelybediscontinued,aphysicianbeconsultedandanappropriatetherapy

initiated.Anti-peristalticmedicinalproductsarecontra-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.

ThepresenceofClavulanicacidinClavamelmaycauseanon-specificbindingofIgGandalbuminbyredcell

membranesleadingtoafalsepositiveCoombstest.

TherehavebeenreportsofpositivetestresultsusingtheBio-RadLaboratoriesPlateliaAspergillusEIAtestinpatients

receivingamoxicillin/clavulanicacidwhoweresubsequentlyfoundtobefreeofAspergillusinfection.Cross-reactions

withnon-AspergilluspolysaccharidesandpolyfuranoseswithBio-RadLaboratoriesPlateliaAspergillusEIAtesthave

beenreported.Therefore,positivetestresultsinpatientsreceivingamoxicillin/clavulanicacidshouldbeinterpreted

cautiouslyandconfirmedbyotherdiagnosticmethods.

Thismedicinalproductcontains2.5mgofaspartame(E951)perml,asourceofphenylalanine.Thismedicineshould

beusedwithcautioninpatientswithphenylketonuria.

Thismedicinalproductcontainsmaltodextrin(glucose).Patientswithrareglucose-galactosemalabsorptionshouldnot

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Oralanticoagulants

Oralanticoagulantsandpenicillinantibioticshavebeenwidelyusedinpracticewithoutreportsofinteraction.

However,intheliteraturetherearecasesofincreasedinternationalnormalisedratioinpatientsmaintainedon

acenocoumarolorwarfarinandprescribedacourseofamoxicillin.Ifco-administrationisnecessary,theprothrombin

timeorinternationalnormalisedratioshouldbecarefullymonitoredwiththeadditionorwithdrawalofamoxicillin.

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

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,

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-marketingsurveillancewithClavamel,sortedbyMedDRASystem

OrganClassarelistedbelow.

Thefollowingterminologieshavebeenusedinordertoclassifytheoccurrenceofundesirableeffects.

Verycommon(1/10)

Common(1/100to<1/10)

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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

prothrombintime 1 Notknown

Immunesystemdisorders 10

Angioneuroticoedema Notknown

Anaphylaxis Notknown

Serumsickness-likesyndrome Notknown

Hypersensitivityvasculitis Notknown

Nervoussystemdisorders

Dizziness Uncommon

Headache Uncommon

Reversiblehyperactivity Notknown

Convulsions 2 Notknown

Gastrointestinaldisorders

Diarrhoea Common

Nausea 3 Common

Vomiting Common

Indigestion Uncommon

Antibiotic-associatedcolitis 4 Notknown

Blackhairytongue Notknown

Toothdiscolouration 11 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

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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

(AGEP) 9

Renalandurinarydisorders

Interstitialnephritis Notknown

Crystalluria 8 Notknown

Seesection4.4

Seesection4.4

Nauseaismoreoftenassociatedwithhigheroraldoses.Ifgastrointestinalreactions

areevident,theymaybereducedbytakingClavamelatthestartofameal.

Includingpseudomembranouscolitisandhaemorrhagiccolitis(seesection4.4)

AmoderateriseinASTand/orALThasbeennotedinpatientstreatedwithbeta-

lactamclassantibiotics,butthesignificanceofthesefindingsisunknown.

Theseeventshavebeennotedwithotherpenicillinsandcephalosporins(seesection

4.4).

Ifanyhypersensitivitydermatitisreactionoccurs,treatmentshouldbediscontinued

(seesection4.4).

Seesection4.9

Seesection4.4

Seesections4.3and4.4

Superficialtoothdiscolourationhasbeenreportedveryrarelyinchildren.Goodoral

hygienemayhelptopreventtoothdiscolourationasitcanusuallyberemovedby

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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

Gram-negativebacteria.

Breakpoints

MICbreakpointsforamoxicillin/clavulanicacidarethoseoftheEuropeanCommitteeonAntimicrobialSusceptibility

Testing(EUCAST)

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

Non-speciesrelated

breakpoints 1 ≤2 4-8 >8

ThereportedvaluesareforAmoxicillinconcentrations.Forsusceptibilitytestingpurposes,

theconcentrationofClavulanicacidisfixedat2mg/l.

ThereportedvaluesareOxacillinconcentrations.

BreakpointvaluesinthetablearebasedonAmpicillinbreakpoints.

TheresistantbreakpointofR>8mg/lensuresthatallisolateswithresistancemechanismsare

reportedresistant.

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Theprevalenceofresistancemayvarygeographicallyandwithtimeforselectedspecies,andlocalinformationon

resistanceisdesirable,particularlywhentreatingsevereinfections.Asnecessary,expertadviceshouldbesoughtwhen

thelocalprevalenceofresistanceissuchthattheutilityoftheagentinatleastsometypesofinfectionsisquestionable.

Commonlysusceptiblespecies

AerobicGram-positivemicro-organisms

Enterococcusfaecalis

Gardnerellavaginalis

Staphylococcusaureus(methicillin-susceptible)£

Coagulase-negativestaphylococci(methicillin-susceptible)

Streptococcusagalactiae

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

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5.2Pharmacokineticproperties

Absorption

Amoxicillinandclavulanicacid,arefullydissociatedinaqueoussolutionatphysiologicalpH.Bothcomponentsare

rapidlyandwellabsorbedbytheoralrouteofadministration.Absorptionofamoxicillin/clavulanicacidisoptimised

whentakenatthestartofameal.Followingoraladministration,amoxicillinandclavulanicacidareapproximately

70%bioavailable.Theplasmaprofilesofbothcomponentsaresimilarandthetimetopeakplasmaconcentration

)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. Amoxicillindoesnotadequately

distributeintothecerebrospinalfluid.

Fromanimalstudiesthereisnoevidenceforsignificanttissueretentionofdrug-derivedmaterialforeithercomponent.

Amoxicillin,likemostpenicillins,canbedetectedinbreastmilk.Tracequantitiesofclavulanicacidcanalsobe

detectedinbreastmilk(seesection4.6).

$Naturalintermediatesusceptibilityintheabsenceofacquiredmechanismof

resistance.

£Allmethicillin-resistantstaphylococciareresistanttoamoxicillin/clavulanicacid

Streptococcuspneumoniaethatareresistanttopenicillinshouldnotbetreatedwiththis

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

StrainswithdecreasedsusceptibilityhavebeenreportedinsomecountriesintheEU

withafrequencyhigherthan10%.

Mean( ±

SD)pharmacokineticparameters

Activesubstance(s)

administered Dose C

(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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Biotransformation

Amoxicillinispartlyexcretedintheurineastheinactivepenicilloicacidinquantitiesequivalenttoupto10to25%of

theinitialdose.Clavulanicacidisextensivelymetabolizedinmanandeliminatedinurineandfaecesandascarbon

dioxideinexpiredair.

Elimination

Themajorrouteofeliminationforamoxicillinisviathekidney,whereasforclavulanicaciditisbybothrenalandnon-

renalmechanisms.

Amoxicillin/clavulanicacidhasameaneliminationhalf-lifeofapproximatelyonehourandameantotalclearanceof

approximately25l/hinhealthysubjects.Approximately60to70%oftheamoxicillinandapproximately40to65%of

theclavulanicacidareexcretedunchangedinurineduringthefirst6hafteradministrationofsingleClavamel

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

amoxicillinandbetween27-60%forclavulanicacidovera24hourperiod.Inthecaseofclavulanicacid,thelargest

amountofdrugisexcretedduringthefirst2hoursafteradministration.

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,genotoxicityand

toxicitytoreproduction.

Repeatdosetoxicitystudiesperformedindogswithamoxicillin/clavulanicaciddemonstrategastricirritancyand

vomiting,anddiscolouredtongue.

Irish Medicines Board

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Xanthangum(E415)

Hypromellose(E464)

Aspartame(E951)

Colloidalhydratedsilica

Colloidalanhydroussilica

Succinicacid

Raspberrydryflavour

Orangedryflavour1

Orangedryflavour2

Goldensyrupdryflavour

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

DryPowder:2years.

ReconstitutedSuspension:7days.

6.4Specialprecautionsforstorage

Drypowder: Donotstoreabove25 o

Reconstitutedsuspensionsshouldbekeptinarefrigeratorat2 o

C-8 o

Cforuptosevendays.Donotfreeze.

6.5Natureandcontentsofcontainer

GlassbottleswithaluminiumscrewcapsoraROPP(rollonpilferproof),internallylacqueredexternallyenameled

closure,containingaflowed-inPVCliner.Containingpowderforreconstitutionto100ml.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Checkcapsealisintactbeforeusing.Shakebottletoloosenpowder.Addvolumeofwater(asindicatedbelow)invert

andshakewell.Alternativelyfillthebottlewithwatertojustbelowthemarkonbottlelabel,invertandshakewell.

Thentopupwithwaterexactlytothemark,invertandagainshakewell.

Shakethebottlewellbeforeeachdose. Strength Volumeofwatertobeadded

atreconsitution(ml) Finalvolumeof

reconsitutedoralsuspension

(ml)

Irish Medicines Board

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7MARKETINGAUTHORISATIONHOLDER

ClonmelHealthcareLtd

WaterfordRoad

Clonmel

CoTipperary

8MARKETINGAUTHORISATIONNUMBER

PA126/103/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:17September1999

Dateoflastrenewal:17September2009

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 02/11/2010 CRN 2090661 page number: 13