CLAVAMEL FORTE

Main information

  • Trade name:
  • CLAVAMEL FORTE
  • Dosage:
  • 500/ 125 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0126/103/006
  • Authorization date:
  • 10-09-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ClavamelForte500mg/125mgFilm-CoatedTablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

EachtabletcontainsAmoxicillinTrihydrateequivalentto500mgamoxicillinandPotassiumClavulanateequivalentto

125mgclavulanicacid.

Forfulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Whitetooffwhiteovalshaped,film-coatedtabletdebossedwith‘AC’andascorelineononesideandplainonthe

otherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

ClavamelForteisindicatedforthetreatmentofthefollowinginfectionsinadultsandchildren(seesections4.2,4.4and

5.1):

Acutebacterialsinusitis(adequatelydiagnosed)

Acuteotitismedia

Acuteexacerbationsofchronicbronchitis(adequatelydiagnosed)

Communityacquiredpneumonia

Cystitis

Pyelonephritis

Skinandsofttissueinfectionsinparticularcellulitis,animalbites,severedentalabscesswithspreadingcellulitis.

Boneandjointinfections,inparticularosteomyelitis.

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantibacterialagents.

4.2Posologyandmethodofadministration

Dosesareexpressedthroughoutintermsofamoxicillin/clavulanicacidcontentexceptwhendosesarestatedinterms

ofanindividualcomponent.

ThedoseofClavamelFortethatisselectedtotreatanindividualinfectionshouldtakeintoaccount:

Theexpectedpathogensandtheirlikelysusceptibilitytoantibacterialagents(seesection4.4)

Theseverityandthesiteoftheinfection

Theage,weightandrenalfunctionofthepatientasshownbelow.

TheuseofalternativepresentationsofClavamelForte(e.g.thosethatprovidehigherdosesofamoxicillinand/or

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

Foradultsandchildren 40kg,thisformulationofClavamelForteprovidesatotaldailydoseof1500mg

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ofClavamelForteprovidesamaximumdailydoseof2400mgamoxicillin/600mgclavulanicacid,whenadministered

asrecommendedbelow.Ifitisconsideredthatahigherdailydoseofamoxicillinisrequired,itisrecommendedthat

anotherpreparationofClavamelForteisselectedinordertoavoidadministrationofunnecessarilyhighdailydosesof

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.

ChildrenmaybetreatedwithClavamelFortetabletsorsuspensionsChildrenaged6yearsandbelowshouldpreferably

betreatedwithClavamelsuspension.

NoclinicaldataareavailableondosesofClavamelForte4:1formulationshigherthan40mg/10mg/kgperdayin

childrenunder2years.

Elderly

Nodoseadjustmentisconsiderednecessary.

Renalimpairment

Doseadjustmentsarebasedonthemaximumrecommendedlevelofamoxicillin.

Noadjustmentindoseisrequiredinpatientswithcreatinineclearance(CrCl)greaterthan30ml/min.

Adultsandchildren 40kg

Children<40kg

Hepaticimpairment

Dosewithcautionandmonitorhepaticfunctionatregularintervals(seesections4.3and4.4).

Methodofadministration

ClavamelForteisfororaluse.

Administeratthestartofamealtominimisepotentialgastrointestinalintoleranceandoptimiseabsorptionof

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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TherapycanbestartedparenterallyaccordingtheSPCoftheIV-formulationandcontinuedwithanoralpreparation.

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.

ThispresentationofClavamelForteisnotsuitableforusewhenthereisahighriskthatthepresumptivepathogens

havereducedsusceptibilityorresistancetobeta-lactamagentsthatisnotmediatedbybeta-lactamasessusceptibleto

inhibitionbyclavulanicacid.Thispresentationshouldnotbeusedtotreatpenicillin-resistantS.pneumoniae.

Convulsionsmayoccurinpatientswithimpairedrenalfunctionorinthosereceivinghighdoses(seesection4.8).

Amoxicillin/clavulanicacidshouldbeavoidedifinfectiousmononucleosisissuspectedsincetheoccurrenceofa

morbilliformrashhasbeenassociatedwiththisconditionfollowingtheuseofamoxicillin.

Concomitantuseofallopurinolduringtreatmentwithamoxicillincanincreasethelikelihoodofallergicskinreactions.

Prolongedusemayoccasionallyresultinovergrowthofnon-susceptibleorganisms.

Theoccurrenceatthetreatmentinitiationofafeverishgeneralisederythemaassociatedwithpustulamaybeasymptom

ofacutegeneralisedexanthemouspustulosis(AGEP)(seeSection4.8).ThisreactionrequiresClavamelForte

discontinuationandcontra-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

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Periodicassessmentoforgansystemfunctions,includingrenal,hepaticandhaematopoieticfunctionisadvisableduring

prolongedtherapy.

Prolongationofprothrombintimehasbeenreportedrarelyinpatientsreceivingamoxicillin/clavulanic

acid.Appropriatemonitoringshouldbeundertakenwhenanticoagulantsareprescribedconcomitantly.Adjustmentsin

thedoseoforalanticoagulantsmaybenecessarytomaintainthedesiredlevelofanticoagulation(seesection4.5and

4.8).

Inpatientswithrenalimpairment,thedoseshouldbeadjustedaccordingtothedegreeofimpairment(seesection4.2).

Inpatientswithreducedurineoutput,crystalluriahasbeenobservedveryrarely,predominantlywithparenteral

therapy.Duringtheadministrationofhighdosesofamoxicillin,itisadvisabletomaintainadequatefluidintakeand

urinaryoutputinordertoreducethepossibilityofamoxicillincrystalluria.Inpatientswithbladdercatheters,aregular

checkofpatencyshouldbemaintained(seesection4.9).

Duringtreatmentwithamoxicillin,enzymaticglucoseoxidasemethodsshouldbeusedwhenevertestingforthe

presenceofglucoseinurinebecausefalsepositiveresultsmayoccurwithnon-enzymaticmethods.

ThepresenceofClavulanicacidinClavamelFortemaycauseanon-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

acid.

4.6Fertility,pregnancyandlactation

Pregnancy

Animalstudiesdonotindicatedirectorindirectharmfuleffectswithrespecttopregnancy,embryonal/foetal

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

acidduringpregnancyinhumansdonotindicateanincreasedriskofcongenitalmalformations.Inasinglestudyin

womenwithpreterm,prematureruptureofthefoetalmembraneitwasreportedthatprophylactictreatmentwith

amoxicillin/clavulanicacidmaybeassociatedwithanincreasedriskofnecrotisingenterocolitisinneonates.Use

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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-marketingsurveillancewithClavamelForte,sortedbyMedDRA

SystemOrganClassarelistedbelow.

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

prothrombintime 1 Notknown

Immunesystemdisorders 10

Angioneuroticoedema Notknown

Anaphylaxis Notknown

Serumsickness-likesyndrome Notknown

Hypersensitivityvasculitis Notknown

Nervoussystemdisorders

Dizziness Uncommon

Headache Uncommon

Reversiblehyperactivity Notknown

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4.9Overdose

Symptomsandsignsofoverdose

Gastrointestinalsymptomsanddisturbanceofthefluidandelectrolytebalancesmaybeevident.Amoxicillin

crystalluria,insomecasesleadingtorenalfailure,hasbeenobserved(seesection4.4).

Convulsionsmayoccurinpatientswithimpairedrenalfunctionorinthosereceivinghighdoses.

Amoxicillinhasbeenreportedtoprecipitateinbladdercatheters,predominantlyafterintravenousadministrationof

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,theymaybereducedbytakingClavamelForteatthestartofameal.

Includingpseudomembranouscolitisandhaemorrhagiccolitis(seesection4.4)

AmoderateriseinASTand/orALThasbeennotedinpatientstreatedwithbeta-

lactamclassantibiotics,butthesignificanceofthesefindingsisunknown.

Theseeventshavebeennotedwithotherpenicillinsandcephalosporins(seesection

4.4).

Ifanyhypersensitivitydermatitisreactionoccurs,treatmentshouldbediscontinued

(seesection4.4).

Seesection4.9

Seesection4.4

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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,whichisanintegralstructural

componentofthebacterialcellwall.Inhibitionofpeptidoglycansynthesisleadstoweakeningofthecellwall,whichis

usuallyfollowedbycelllysisanddeath.

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( µ

g/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

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Theprevalenceofresistancemayvarygeographicallyandwithtimeforselectedspecies,andlocalinformationon

resistanceisdesirable,particularlywhentreatingsevereinfections.Asnecessary,expertadviceshouldbesoughtwhen

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,

theconcentrationofClavulanicacidisfixedat2mg/l.

ThereportedvaluesareOxacillinconcentrations.

BreakpointvaluesinthetablearebasedonAmpicillinbreakpoints.

TheresistantbreakpointofR>8mg/lensuresthatallisolateswithresistancemechanismsare

reportedresistant.

BreakpointvaluesinthetablearebasedonBenzylpenicillinbreakpoints.

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$

AcrobicGram-negativemicro-organism

Escherichiacoli

Klebsiellaoxytoca

Klebsiellapneumoniae

Proteusmirabilis

Proteusvulgaris

Inherentlyresistantorganisms

AerobicGram-negativemicro-organisms

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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

Citrobacterfreundii

Enterobactersp.

Legionellapneumophila

Morganellamorganii

Providenciaspp.

Pseudomonassp.

Serratiasp.

Stenotrophomonasmaltophilia

Othermicro-organisms

Chlamydophilapneumoniae

Chlamydophilapsittaci

Coxiellaburnetti

Mycoplasmapneumoniae

$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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Distribution

About25%oftotalplasmaclavulanicacidand18%oftotalplasmaamoxicillinisboundtoprotein.Theapparent

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

Followingintravenousadministration,bothamoxicillinandclavulanicacidhavebeenfoundingallbladder,abdominal

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

intothecerebrospinalfluid.

Fromanimalstudiesthereisnoevidenceforsignificanttissueretentionofdrug-derivedmaterialforeither

component.Amoxicillin,likemostpenicillins,canbedetectedinbreastmilk.Tracequantitiesofclavulanicacidcan

alsobedetectedinbreastmilk(seesection4.6).

Bothamoxicillinandclavulanicacidhavebeenshowntocrosstheplacentalbarrier(seesection4.6).

Biotransformation

Amoxicillinispartlyexcretedintheurineastheinactivepenicilloicacidinquantitiesequivalenttoupto10to25%of

theinitialdose.Clavulanicacidisextensivelymetabolizedinmanandeliminatedinurineandfaecesandascarbon

dioxideinexpiredair.

Elimination

Themajorrouteofeliminationforamoxicillinisviathekidney,whereasforclavulanicaciditisbybothrenalandnon-

renalmechanisms.

Amoxicillin/clavulanicacidhasameaneliminationhalf-lifeofapproximatelyonehourandameantotalclearanceof

approximately25l/hinhealthysubjects.Approximately60to70%oftheamoxicillinandapproximately40to65%of

theclavulanicacidareexcretedunchangedinurineduringthefirst6hafteradministrationofsingleCo-Amoxiclav

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

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5.3Preclinicalsafetydata

Nonclinicaldatarevealnospecialhazardforhumansbasedonstudiesofsafetypharmacology,genotoxicityand

toxicitytoreproduction.

Repeatdosetoxicitystudiesperformedindogswithamoxicillin/clavulanicaciddemonstrategastricirritancyand

vomiting,anddiscolouredtongue.

CarcinogenicitystudieshavenotbeenconductedwithCo-Amoxiclavoritscomponents.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Eachtabletcontains:

MagnesiumstearateE572

Sodiumstarchglycollate

Colloidalsilica

MicrocrystallinecelluloseE460

TitaniumdioxidesuspensionE171

Hypromellose(MethocelE5andE15)E464

Macrogol6000

Macrogol4000

Dimeticone

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Blisterpack2years,Glassbottles3years.

6.4Specialprecautionsforstorage

Donotstoreabove25 o

C.Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

AluminiumPVC/PVdCblisterenclosedwithinanaluminiumlaminatepouchcontainingadesiccantsachet,referredto

asadesiccatedpouchpack(DPP).Packsof21tablets.

Amberglassbottlescontaining6,30,50,100and500tablets,closedwithanROPPcapwithpre-insertedwad2.5gof

molecularsieveper30tabletsasdesiccantwillbeincluded.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Irish Medicines Board

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Date Printed 12/10/2011 CRN 2092868 page number: 11

7MARKETINGAUTHORISATIONHOLDER

ClonmelHealthcareLimited

WaterfordRoad

Clonmel

Co.Tipperary

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA0126/103/006

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation: 12January2001

Dateoflastrenewal: 12January2006

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 12/10/2011 CRN 2092868 page number: 12