AMOXICILLIN/CLAVULANIC ACID 500/125 Milligram Film Coated Tablet

Ireland - English - HPRA (Health Products Regulatory Authority)

Buy It Now

Active ingredient:
AMOXICILLIN TRIHYDRATE CLAVULANATE POTASSIUM
Available from:
Rowex Ltd
INN (International Name):
AMOXICILLIN TRIHYDRATE CLAVULANATE POTASSIUM
Dosage:
500/125 Milligram
Pharmaceutical form:
Film Coated Tablet
Prescription type:
Product subject to prescription which may not be renewed (A)
Authorization status:
Withdrawn
Authorization number:
PA0711/187/001
Authorization date:
2014-05-28

PACKAGELEAFLET:INFORMATIONFORTHEUSER

Amoxicillin/clavulanicacid500mg/125mgFilm-coatedtablets

Amoxicillin/clavulanicacid

Readallofthisleafletcarefullybeforeyoustarttakingthismedicine.

- Keepthisleaflet.Youmayneedtoreaditagain.

- Ifyouhaveanyfurtherquestions,askyourdoctororpharmacist.

- Thismedicinehasbeenprescribedforyou(orforyourchild).Donotpassitonto

others.Itmayharmthem,eveniftheirsymptomsarethesameasyours.

- Ifanyofthesideeffectsgetsserious,orifyounoticeanysideeffectsnotlistedinthis

leaflet,pleasetellyourdoctororpharmacist.

Inthisleaflet :

1. WhatAmoxicillin/clavulanicacidisandwhatitisusedfor

2. BeforeyoutakeAmoxicillin/clavulanicacid

3. HowtotakeAmoxicillin/clavulanicacid

4. Possiblesideeffects

5. HowtostoreAmoxicillin/clavulanicacid

6. Furtherinformation

1.WHATAMOXICILLIN/CLAVULANICACIDISANDWHATITISUSEDFOR

Amoxicillin/clavulanicacidisanantibioticandworksbykillingbacteriathatcause

infections.Itcontainstwodifferentmedicinescalledamoxicillinandclavulanicacid.

Amoxicillinbelongstoagroupofmedicinescalled“penicillins”thatcansometimesbe

stoppedfromworking(madeinactive).Theotheractivecomponent(clavulanicacid)stops

thisfromhappening.

Amoxicillin/clavulanicacidisusedinadultsandchildrentotreatthefollowinginfections:

middleearandsinusinfections

respiratorytractinfections

urinarytractinfections

skinandsofttissueinfectionsincludingdentalinfections

boneandjointinfections.

2. BEFOREYOUTAKEAMOXICILLIN/CLAVULANICACID

DonottakeAmoxicillin/clavulanicacid :

ifyouareallergic(hypersensitive)toamoxicillin,clavulanicacid,penicillinoranyof

theotheringredientsofAmoxicillin/clavulanicacid(listedinsection6)

ifyouhaveeverhadasevereallergic(hypersensitive)reactiontoanyotherantibiotic.

Thiscanincludeaskinrashorswellingofthefaceorneck

ifyouhaveeverhadliverproblemsorjaundice(yellowingoftheskin)whentakingan

antibiotic.

DonottakeAmoxicillin/clavulanicacidifanyoftheaboveapplytoyou

Ifyouarenotsure,talktoyourdoctororpharmacistbeforetaking

Amoxicillin/clavulanicacid

TakespecialcarewithAmoxicillin/clavulanicacid

Talktoyourdoctororpharmacistbeforetakingthismedicineifyou:

haveglandularfever

arebeingtreatedforliverorkidneyproblems

arenotpassingwaterregularly.

Ifyouarenotsureifanyoftheaboveapplytoyou,talktoyourdoctororpharmacistbefore

takingAmoxicillin/clavulanicacid.

Insomecases,yourdoctormayinvestigatethetypeofbacteriathatiscausingyourinfection.

Dependingontheresults,youmaybegivenadifferentstrengthofAmoxicillin/clavulanic

acidoradifferentmedicine.

Conditionsyouneedtolookoutfor

Amoxicillin/clavulanicacidcanmakesomeexistingconditionsworse,orcauseseriousside

effects.Theseincludeallergicreactions,convulsions(fits)andinflammationofthelarge

intestine.Youmustlookoutforcertainsymptomswhileyouaretaking

Amoxicillin/clavulanicacid,toreducetheriskofanyproblems.See‘Conditionsyouneedto

lookoutfor’inSection4.

Bloodandurinetests

Ifyouarehavingbloodtests(suchasredbloodcellstatustestsorliverfunctiontests)orurine

tests(forglucose),letthedoctorornurseknowthatyouaretakingAmoxicillin/clavulanic

acid.ThisisbecauseAmoxicillin/clavulanicacidcanaffecttheresultsofthesetypesof

tests.

Usingothermedicines

Pleasetellyourdoctororpharmacistifyouareusingorhaverecentlyusedanyother

medicines.Thisincludesmedicinesthatcanbeboughtwithoutaprescriptionandherbal

medicines.

Ifyouaretakingallopurinol(usedforgout)withAmoxicillin/clavulanicacid,itmaybemore

likelythatyou’llhaveanallergicskinreaction.

Ifyouaretakingprobenecid(usedforgout),yourdoctormaydecidetoadjustyourdoseof

Amoxicillin/clavulanicacid.

Ifmedicinestohelpstopbloodclots(suchaswarfarin)aretakenwithAmoxicillin/clavulanic

acidthenextrabloodtestsmaybeneeded.

Amoxicillin/clavulanicacidcanaffecthowmethotrexate(amedicineusedtotreatcanceror

rheumaticdiseases)works.

Amoxicillin/clavulanicacidmayaffecthowmycophenolatemofetil(amedicineusedto

preventtherejectionofneworgansintransplantpatients)works.

Pregnancyandbreast-feeding

Ifyouarepregnant,youthinkyoumightbepregnantorifyouarebreast-feeding,pleasetell

yourdoctororpharmacist.

Askyourdoctororpharmacistforadvicebeforetakinganymedicine.

Drivingandusingmachines

Amoxicillin/clavulanicacidcanhavesideeffectsandthesymptomsmaymakeyouunfitto

drive.

Don’tdriveoroperatemachineryunlessyouarefeelingwell.

3. HOWTOTAKEAMOXICILLIN/CLAVULANICACID

AlwaystakeAmoxicillin/clavulanicacidexactlyasyourdoctorhastoldyou.Youshould

checkwithyourdoctororpharmacistifyouarenotsure.

Adultsandchildrenweighing40kgandover

Theusualdoseis:

1tabletthreetimesaday

Childrenweighinglessthan40kg

Childrenaged6yearsorlessshouldpreferablybetreatedwithAmoxicillin/clavulanicacid

oralsuspension.

AskyourdoctororpharmacistforadvicewhengivingAmoxicillin/clavulanicacidtabletsto

childrenweighinglessthan40kg.Thetabletsarenotsuitableforchildrenweighinglessthan

25kg.

Patientswithkidneyandliverproblems

Ifyouhavekidneyproblemsthedosemightbechanged.Adifferentstrengthora

differentmedicinemaybechosenbyyourdoctor.

Ifyouhaveliverproblemsyoumayhavemorefrequentbloodteststocheckhowyour

liverisworking.

HowtotakeAmoxicillin/clavulanicacid

Swallowthetabletswholewithaglassofwateratthestartofamealorslightlybefore.

Tabletscanbebrokenalongthescorelinetomakethemeasiertoswallow.Youmust

takebothpiecesofthetabletatthesametime.

Spacethedosesevenlyduringtheday,atleast4hoursapart.Donottake2dosesin1

hour.

DonottakeAmoxicillin/clavulanicacidformorethan2weeks.Ifyoustill

feelunwellyoushouldgobacktoseethedoctor.

IfyoutakemoreAmoxicillin/clavulanicacid thanyoushould

IfyoutaketoomuchAmoxicillin/clavulanicacid,signsmightincludeanupsetstomach

(feelingsick,beingsickordiarrhoea)orconvulsions.Talktoyourdoctorassoonaspossible.

Takethemedicinecartonorbottletoshowthedoctor.

IfyouforgettotakeAmoxicillin/clavulanicacid

Ifyouforgettotakeadose,takeitassoonasyouremember.Youshouldnottakethenext

dosetoosoon,butwaitabout4hoursbeforetakingthenextdose.

IfyoustoptakingAmoxicillin/clavulanicacid

KeeptakingAmoxicillin/clavulanicaciduntilthetreatmentisfinished,evenifyoufeel

better.Youneedeverydosetohelpfighttheinfection.Ifsomebacteriasurvivetheycan

causetheinfectiontocomeback.

Ifyouhaveanyfurtherquestionsontheuseofthisproduct,askyourdoctororpharmacist.

4. POSSIBLESIDEEFFECTS

Likeallmedicines,Amoxicillin/clavulanicacidcancausesideeffects,althoughnot

everybodygetsthem.

Conditionsyouneedtolookoutfor

Allergicreactions:

skinrash

inflammationofbloodvessels(vasculitis)whichmaybevisibleasredorpurpleraised

spotsontheskin,butcanaffectotherpartsofthebody

fever,jointpain,swollenglandsintheneck,armpitorgroin

swelling,sometimesofthefaceormouth(angioedema),causingdifficultyinbreathing

collapse.

Contactadoctorimmediatelyifyougetanyofthesesymptoms.Stoptaking

Amoxicillin/clavulanicacid.

Inflammationoflargeintestine

Inflammationofthelargeintestine,causingwaterydiarrhoeausuallywithbloodandmucus,

stomachpainand/orfever.

Contactyourdoctorassoonaspossibleforadviceifyougetthesesymptoms.

Verycommonsideeffects

Thesemayaffectmorethan1in10people

diarrhoea(inadults).

Commonsideeffects

Thesemayaffectupto1in10people

thrush(candida-ayeastinfectionofthevagina,mouthorskinfolds)

feelingsick(nausea),especiallywhentakinghighdoses

→ ifaffectedtakeAmoxicillin/clavulanicacidbeforefood

vomiting

diarrhoea(inchildren).

Uncommon sideeffects

Thesemayaffectupto1in100people

skinrash,itching

raiseditchyrash(hives)

indigestion

dizziness

headache.

Uncommonsideeffectsthatmayshowupinyourbloodtests:

increaseinsomesubstances(enzymes)producedbytheliver.

Raresideeffects

Thesemayaffectupto1in1000people

skinrash,whichmayblister,andlookslikesmalltargets(centraldarkspotssurrounded

byapalerarea,withadarkringaroundtheedge–erythemamultiforme)

ifyounoticeanyofthesesymptomscontactadoctorurgently.

Raresideeffectsthatmayshowupinyourbloodtests:

lownumberofcellsinvolvedinbloodclotting

lownumberofwhitebloodcells.

Othersideeffects

Othersideeffectshaveoccurredinaverysmallnumberofpeoplebuttheirexactfrequencyis

unknown.

Allergicreactions(seeabove)

Inflammationofthelargeintestine(seeabove)

Seriousskinreactions:

- awidespreadrashwithblistersandpeelingskin,particularlyaroundthemouth,nose,

eyesandgenitals(Stevens-Johnsonsyndrome),andamoresevereform,causing

extensivepeelingoftheskin(morethan30%ofthebodysurface–toxicepidermal

necrolysis)

- widespreadredskinrashwithsmallpus-containingblisters(bullousexfoliative

dermatitis)

- ared,scalyrashwithbumpsundertheskinandblisters(exanthemouspustulosis).

Contactadoctorimmediatelyifyougetanyofthesesymptoms.

inflammationoftheliver(hepatitis)

jaundice,causedbyincreasesinthebloodofbilirubin(asubstanceproducedinthe

liver)whichmaymakeyourskinandwhitesoftheeyesappearyellow

inflammationoftubesinthekidney

bloodtakeslongertoclot

hyperactivity

convulsions(inpeopletakinghighdosesofAmoxicillin/clavulanicacidor

whohavekidneyproblems)

blacktonguewhichlookshairy

stainedteeth(inchildren),usuallyremovedbybrushing.

Sideeffectsthatmayshowupinyourbloodorurinetests:

severereductioninthenumberofwhitebloodcells

lownumberofredbloodcells(haemolyticanaemia)

crystalsinurine.

Ifyougetsideeffects

Tellyourdoctororpharmacistifanyofthesideeffectsbecomesevereor

troublesome ,orifyounoticeanysideeffectsnotlistedinthisleaflet.

5. HOWTOSTOREAMOXICILLIN/CLAVULANICACID

Keepoutofthereachandsightofchildren.

DonotuseAmoxicillin/clavulanicacidtabletsaftertheexpirydatewhichisstatedonthe

carton.Theexpirydatereferstothelastdayofthatmonth.

Tabletssuppliedinpouchesshouldbeusedwithin30daysofopeningthepouch.

Storeintheoriginalpackageinordertoprotectfrommoisture.

Donotuseifthetabletsarechippedordamaged.

Medicinesshouldnotbedisposedofviawastewaterorhouseholdwaste.Askyourpharmacist

howtodisposeofmedicinesnolongerrequired.Thesemeasureswillhelptoprotectthe

environment.

6. FURTHERINFORMATION

WhatAmoxicillin/clavulanicacid contains

Theactivesubstancesareamoxicillinandclavulanicacid.Eachtabletcontainsamoxicillin

trihydrateequivalentto500mgofamoxicillinandpotassiumclavulanateequivalentto125mg

ofclavulanicacid.

Theotheringredientsare:Tabletcore:magnesiumstearate(E572),sodiumstarchglycollate

typeA,colloidalanhydroussilica,microcrystallinecellulose.

Film-coat-titaniumdioxide(E171),hypromellose,macrogol(4000,6000)

andsiliconeoil(dimeticone).

WhatAmoxicillin/clavulanicacid lookslikeandcontentsofthepack

Amoxicillin/clavulanicacid500mg/125mgFilm-coatedtabletsarewhitetooff-whiteoval

shapedtabletdebossedwith‘AC’andascorelineononeside.

Theyarepackagedin:

 blisterpacks,enclosedinacarton.Eachpackcontains4,10,12,14,16,20,24,30,100or

500tablets;

 blister

packs

insideapouch,enclosedinacarton.Eachpackcontains14,20or21tablets.

Notallpacksizesmaybemarketed.

MarketingAuthorisationHolderandManufacturer

ProductAuthorisationHolder:

RowexLtd.,Bantry,Co.Cork.Ireland.

Manufacturer:

SmithKlineBeechamPharmaceuticals,Worthing,WestSussex,UnitedKingdom.

RowaPharmaceuticalsLtd.,Bantry,Co.Cork.

Thisleafletwaslastapprovedin01.2014 .

Advice/medicaleducation

Antibioticsareusedtotreatinfectionscausedbybacteria.Theyhavenoeffectagainstinfections

causedbyviruses.

Sometimesaninfectioncausedbybacteriadoesnotrespondtoacourseofanantibiotic.Oneofthe

commonestreasonsforthistooccurisbecausethebacteriacausingtheinfectionareresistanttothe

antibioticthatisbeingtaken.Thismeansthattheycansurviveandevenmultiplydespitethe

antibiotic.

Bacteriacanbecomeresistanttoantibioticsformanyreasons.Usingantibioticscarefullycanhelp

toreducethechanceofbacteriabecomingresistanttothem.

Whenyourdoctorprescribesacourseofanantibioticitisintendedtotreatonlyyourcurrent

illness.Payingattentiontothefollowingadvicewillhelppreventtheemergenceofresistant

bacteriathatcouldstoptheantibioticworking.

1.Itisveryimportantthatyoutaketheantibioticattherightdose,attherighttimesandforthe

rightnumberofdays.Readtheinstructionsonthelabelandifyoudonotunderstand

anythingaskyourdoctororpharmacisttoexplain.

2.Youshouldnottakeanantibioticunlessithasbeenprescribedspecificallyforyouandyou

shoulduseitonlytotreattheinfectionforwhichitwasprescribed.

3.Youshouldnottakeantibioticsthathavebeenprescribedforotherpeopleeveniftheyhad

aninfectionthatwassimilartoyours.

4. Youshouldnotgiveantibioticsthatwereprescribedforyoutootherpeople.

5.Ifyouhaveanyantibioticleftoverwhenyouhavetakenthecourseasdirectedbyyour

doctoryoushouldtaketheremaindertoapharmacyforappropriatedisposal.

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Amoxicillin/Clavulanicacid500mg/125mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

EachtabletcontainsAmoxicillinTrihydrateequivalentto500mgAmoxicillinandPotassiumClavulanateequivalentto

125mgclavulanicacid.

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Film-coatedtablet.

Whitetooffwhiteovalshaped,film-coatedtabletdebossedwith"AC"andascorelineononesideandplainonthe

otherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Amoxicillin/Clavulanicacidisindicatedforthetreatmentofthefollowinginfectionsinadultsandchildren(see

sections4.2,4.4and5.1):

Acutebacterialsinusitis(adequatelydiagnosed)

Acuteotitismedia

Acuteexacerbationsofchronicbronchitis(adequatelydiagnosed)

Communityacquiredpneumonia

Cystitis

Pyelonephritis

Skinandsofttissueinfectionsinparticularcellulitis,animalbites,severedentalabscesswithspreadingcellulitis.

Boneandjointinfections,inparticularosteomyelitis.

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantibacterialagents.

4.2Posologyandmethodofadministration

Dosesareexpressedthroughoutintermsofamoxicillin/clavulanicacidcontentexceptwhendosesarestatedinterms

ofanindividualcomponent.

ThedoseofAmoxicillin/Clavulanicacidthatisselectedtotreatanindividualinfectionshouldtakeintoaccount:

Theexpectedpathogensandtheirlikelysusceptibilitytoantibacterialagents(seesection4.4)

Theseverityandthesiteoftheinfection

Theage,weightandrenalfunctionofthepatientasshownbelow.

TheuseofalternativepresentationsofAmoxicillin/Clavulanicacid(e.g.thosethatprovidehigherdosesofamoxicillin

and/ordifferentratiosofamoxicillintoclavulanicacid)shouldbeconsideredasnecessary(seesections4.4and5.1).

Foradultsandchildren 40kg,thisformulationofAmoxicillin/Clavulanicacidprovidesatotaldailydoseof1500mg

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Forchildren<40kg,thisformulationofAmoxicillin/Clavulanicacidprovidesamaximumdailydoseof2400mg

amoxicillin/600mgclavulanicacid,whenadministeredasrecommendedbelow.Ifitisconsideredthatahigherdaily

doseofamoxicillinisrequired,itisrecommendedthatanotherpreparationofamoxicillin/clavulanicisselectedinorder

toavoidadministrationofunnecessarilyhighdailydosesofclavulanicacid(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.

ChildrenmaybetreatedwithAmoxicillin/Clavulanicacidtabletsorsuspension.Childrenaged6yearsandbelow

shouldpreferablybetreatedwithAmoxicillin/Clavulanicacidsuspension.

Noclinicaldataareavailableondosesofamoxicillin/clavulanicacid4:1formulationshigherthan40mg/10mg/kgper

dayinchildrenunder2years.

Elderly

Nodoseadjustmentisconsiderednecessary.

Renalimpairment

Doseadjustmentsarebasedonthemaximumrecommendedlevelofamoxicillin.

Noadjustmentindoseisrequiredinpatientswithcreatinineclearance(CrCl)greaterthan30ml/min.

Adultsandchildren 40kg

Children<40kg

Hepaticimpairment

CrCl:10-30ml/min 500mg/125mgtwicedaily

CrCl<10ml/min 500mg/125mgoncedaily

Haemodialysis 500mg/125mgevery24hours,plus500mg/125mgduring

dialysis,toberepeatedattheendofdialysis(asserum

concentrationsofbothamoxicillinandclavulanicacidare

decreased)

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

daily).

CrCl<10ml/min 15mg/3.75mg/kgasasingledailydose(maximum

500mg/125mg).

Haemodialysis 15mg/3.75mg/kgperdayoncedaily.

Priortohaemodialysis15mg/3.75mg/kg.Inordertorestore

circulatingdruglevels,15mg/3.75mgperkgshouldbe

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Methodofadministration

Amoxicillin/Clavulanicacidisfororaluse.

Administeratthestartofamealtominimisepotentialgastrointestinalintoleranceandoptimiseabsorptionof

amoxicillin/clavulanicacid.

TherapycanbestartedparenterallyaccordingtheSPCoftheIV-formulationandcontinuedwithanoralpreparation.

4.3Contraindications

Hypersensitivitytotheactivesubstances,toanyofthepenicillinsortoanyoftheexcipients.

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

cephalosporin,carbapenemormonolactam).

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.

ThispresentationofAmoxicillin/Clavulanicacidisnotsuitableforusewhenthereisahighriskthatthepresumptive

pathogenshavereducedsusceptibilityorresistancetobeta-lactamagentsthatisnotmediatedbybeta-lactamases

susceptibletoinhibitionbyclavulanicacid.Thispresentationshouldnotbeusedtotreatpenicillin-resistantS.

pneumoniae.

Convulsionsmayoccurinpatientswithimpairedrenalfunctionorinthosereceivinghighdoses(seesection4.8).

Amoxicillin/clavulanicacidshouldbeavoidedifinfectiousmononucleosisissuspectedsincetheoccurrenceofa

morbilliformrashhasbeenassociatedwiththisconditionfollowingtheuseofamoxicillin.

Concomitantuseofallopurinolduringtreatmentwithamoxicillincanincreasethelikelihoodofallergicskinreactions.

Prolongedusemayoccasionallyresultinovergrowthofnon-susceptibleorganisms.

Theoccurrenceatthetreatmentinitiationofafeverishgeneralisederythemaassociatedwithpustulamaybeasymptom

ofacutegeneralisedexanthemouspustulosis(AGEP)(seeSection4.8).ThisreactionrequiresAmoxicillin/Clavulanic

aciddiscontinuationandcontra-indicatesanysubsequentadministrationofamoxicillin.

Amoxicillin/clavulanicacidshouldbeusedwithcautioninpatientswithevidenceofhepaticimpairment(seesection

4.2).

Hepaticeventshavebeenreportedpredominantlyinmalesandelderlypatientsandmaybeassociatedwithprolonged

treatment.Theseeventshavebeenveryrarelyreportedinchildren.Inallpopulations,signsandsymptomsusually

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hasceased.Theseareusuallyreversible.Hepaticeventsmaybesevereand,inextremelyrarecircumstances,deaths

havebeenreported.

Thesehavealmostalwaysoccurredinpatientswithseriousunderlyingdiseaseortakingconcomitantmedications

knowntohavethepotentialforhepaticeffects(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.

ThepresenceofclavulanicacidinAmoxicillin/Clavulanicacidmaycauseanon-specificbindingofIgGandalbumin

byredcellmembranesleadingtoafalsepositiveCoombstest.

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,theymaybereducedbytakingAmoxicillin/Clavulanicacidatthestartofa

meal.

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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,whichisanintegralstructural

componentofthebacterialcellwall.Inhibitionofpeptidoglycansynthesisleadstoweakeningofthecellwall,whichis

usuallyfollowedbycelllysisanddeath.

Amoxicillinissusceptibletodegradationbybeta-lactamasesproducedbyresistantbacteriaandthereforethespectrum

ofactivityofamoxicillinalonedoesnotincludeorganismswhichproducetheseenzymes.

Clavulanicacidisabeta-lactamstructurallyrelatedtopenicillins.Itinactivatessomebeta-lactamaseenzymesthereby

preventinginactivationofamoxicillin.Clavulanicacidalonedoesnotexertaclinicallyusefulantibacterialeffect.

PK/PDrelationship

AmoderateriseinASTand/orALThasbeennotedinpatientstreatedwithbeta-

lactamclassantibiotics,butthesignificanceofthesefindingsisunknown.

Theseeventshavebeennotedwithotherpenicillinsandcephalosporins(seesection

4.4).

Ifanyhypersensitivitydermatitisreactionoccurs,treatmentshouldbediscontinued

(seesection4.4).

Seesection4.9

Seesection4.4

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foramoxicillin.

Mechanismsofresistance

Thetwomainmechanismsofresistancetoamoxicillin/clavulanicacidare:

Inactivationbythosebacterialbeta-lactamasesthatarenotthemselvesinhibitedbyclavulanicacid,includingclass

B,CandD.

AlterationofPBPs,whichreducetheaffinityoftheantibacterialagentforthetarget.

Impermeabilityofbacteriaoreffluxpumpmechanismsmaycauseorcontributetobacterialresistance,particularlyin

Gram-negativebacteria.

Breakpoints

MICbreakpointsforamoxicillin/clavulanicacidarethoseoftheEuropeanCommitteeonAntimicrobialSusceptibility

Testing(EUCAST)

Theprevalenceofresistancemayvarygeographicallyandwithtimeforselectedspecies,andlocalinformationon

resistanceisdesirable,particularlywhentreatingsevereinfections.Asnecessary,expertadviceshouldbesoughtwhen

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

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,

theconcentrationofClavulanicacidisfixedat2mg/l.

ThereportedvaluesareOxacillinconcentrations.

BreakpointvaluesinthetablearebasedonAmpicillinbreakpoints.

TheresistantbreakpointofR>8mg/lensuresthatallisolateswithresistancemechanismsare

reportedresistant.

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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)

wasadministeredinthefastingstatetogroupsofhealthyvolunteers,arepresentedbelow.

Amoxicillinandclavulanicacidserumconcentrationsachievedwithamoxicillin/clavulanicacidaresimilartothose

producedbytheoraladministrationofequivalentdosesofamoxicillinorclavulanicacidalone.

Distribution

About25%oftotalplasmaclavulanicacidand18%oftotalplasmaamoxicillinisboundtoprotein.Theapparent

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

Followingintravenousadministration,bothamoxicillinandclavulanicacidhavebeenfoundingallbladder,abdominal

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

intothecerebrospinalfluid.

Fromanimalstudiesthereisnoevidenceforsignificanttissueretentionofdrug-derivedmaterialforeithercomponent.

Amoxicillin,likemostpenicillins,canbedetectedinbreastmilk.Tracequantitiesofclavulanicacidcanalsobe

detectedinbreastmilk(seesection4.6).

$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) ( µ

g/ml) (h) (( µ

g.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

theclavulanicacidareexcretedunchangedinurineduringthefirst6hafteradministrationofsingle

Amoxicillin/Clavulanicacid250mg/125mgor500mg/125mgtablets.Variousstudieshavefoundtheurinary

excretiontobe50-85%foramoxicillinandbetween27-60%forclavulanicacidovera24hourperiod.Inthecaseof

clavulanicacid,thelargestamountofdrugisexcretedduringthefirst2hoursafteradministration.

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.

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore

Magnesiumstearate

Sodiumstarchglycollate

Colloidalanhydroussilica

Microcrystallinecellulose

Tabletcoat

Titaniumdioxide(E171)

Hypromellose(MethocelE5andE15)

Macrogol4000

Macrogol6000

Dimeticone

6.2Incompatibilities

Notapplicable

6.3Shelflife

Blisterpack–2years

Glassbottles–3years

6.4Specialprecautionsforstorage

Donotstoreabove25˚C.

Storeintheoriginalpackageinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

PVC/Aluminium/polyamidelaminatewithaluminiumliddingfoilreferredtoasacoldformedaluminiumblister

(CFB).

Packsof4,10,12,16,20,24,30,100or500tablets

AluminiumPVC/PVdCblisterenclosedwithinanaluminiumlaminatepouchcontainingadesiccantsachet,referredto

asadesiccatedpouchpack(DPP)

Packsof14,20or21tabletsandsamplepacksof6.

Amberglassbottles

Packsof30,50,100and500tablets

Notallpacksizesmaybemarketed

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

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7MARKETINGAUTHORISATIONHOLDER

RowexLtd

Bantry

Co.Cork.

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA0711/187/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:1 st

October2010

10DATEOFREVISIONOFTHETEXT

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