AUGMENTIN 1000/62.5 MG PROLONGED RELEASE FILM-COAT

Main information

  • Trade name:
  • AUGMENTIN 1000/62.5 MG PROLONGED RELEASE FILM-COAT
  • Dosage:
  • 562.5/437. Milligram
  • Pharmaceutical form:
  • Tablet Prolonged Release
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • AUGMENTIN 1000/62.5 MG PROLONGED RELEASE FILM-COAT
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0678/012/008
  • Authorization date:
  • 25-02-2005
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Augmentin1000/62.5mgfilmcoatedprolongedreleasetablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Tabletcontaining1000mgamoxicillin,562.5mgasamoxicillintrihydrate,and437.5mgasamoxicillinsodiumand

62.5mgclavulanicacidaspotassiumclavulanate(16:1).

Forexcipients,see6.1

3PHARMACEUTICALFORM

Film-coatedtablet

Awhitecapsuleshapedfilmcoatedtabletdebossedwith1000/62.5ononesideandabisectbreaklineontheother.

4CLINICALPARTICULARS

Generaldescription

Amoxicillin-clavulanateSR(thebeta-lactamantibacterialamoxicillincoformulatedwiththebeta-lactamaseinhibitor

clavulanate)isanantibioticagentwithanotablybroadspectrumofactivityagainstthecommonly-occurringbacterial

pathogensingeneralandhospitalpractice.Thebeta-lactamaseinhibitoryactionofclavulanateextendsthespectrumof

amoxicillintoembraceawiderrangeoforganisms,includingmanyresistanttootherbeta-lactamantibiotics.

Amoxicillin-clavulanateSRisasustainedreleasetabletthatprovidesanextendedamoxicillinpharmacokineticprofile.

TheAmoxicillin-clavulanateSRformulationextendsthespectrumofAmoxicillin-clavulanatetoincludethemajority

ofS.pneumoniaewhereresistanceismediatedbypenicillin-bindingproteins(penicillin-resistantS.pneumoniae,or

PRSP).

4.1TherapeuticIndications

Amoxicillin-clavulanateSRisindicatedforshort-termtreatmentofbacterialinfectionsatthefollowingsiteswhen

causedbyamoxicillin-clavulanateSR-susceptibleorganisms:

RespiratoryTractInfections,e.g.community-acquiredpneumonia,acuteexacerbationsofchronicbronchitisandacute

bacterialsinusitis,typicallycausedbyStreptococcuspneumoniae(includingpenicillin-resistantS.pneumoniae-

PRSP),Haemophilusinfluenzae #

,Moraxellacatarrhalis #

andStreptococcuspyogenes.

Somemembersofthesespeciesofbacteriaproducebeta-lactamase,renderingthemnon-susceptibletoamoxicillin

alone).

AcomprehensivelistofsusceptibleorganismsisprovidedinClinicalPharmacology,Pharmacodynamics.

Infectionscausedbyamoxicillin-susceptibleorganismsareamenabletoamoxicillin-clavulanateSRtreatmentduetoits

amoxicillincontent.

Mixedinfectionscausedbyamoxicillin-susceptibleorganismsinconjunctionwithamoxicillin-clavulanate-susceptible

beta-lactamase-producingorganismsmaythereforebytreatedbyamoxicillin-clavulanateSR.Amoxicillin-clavulanate

SRhasbeenshowntobeeffectiveagainststrainsofS.pneumoniaeresistanttopenicillin(penicillinMICgreaterthan

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4.2Posologyandmethodofadministration

Administeramoxicillin-clavulanateSRatthestartofamealtooptimiseabsorption.

Treatmentshouldnotbeextendedbeyond14dayswithoutreview.

Populations

Adults(greaterthanorequalto16years)

Respiratorytractinfections:twotabletstwicedailyforseventotendays,Including:

Children

Amoxicillin-clavulanateSRisindicatedforuseinadultsgreaterthan16yearsonly.

Elderly

Noadjustmentneeded.

RenalImpairment

Noadjustmentindosageisrequiredinpatientswithcreatinineclearancegreaterthanorequalto30ml/min.

Amoxicillin-clavulanateSRisnotrecommendedinpatientswithcreatinineclearancelessthan30ml/min.

Haemodialysis

Amoxicillin-clavulanateSRisnotrecommendedinhaemodialysispatients

HepaticImpairment

Dosewithcaution;monitorhepaticfunctionatregularintervals.

Thereareinsufficientdataonwhichtobaseadosagerecommendation.

4.3Contraindications

Amoxicillin-clavulanateSRiscontraindicated:

Inpatientswithahistoryofhypersensitivitytobeta-lactams,e.g.penicillinsandcephalosporins.

Inpatientswithaprevioushistoryofamoxicillin-clavulanate-associatedjaundice/hepaticdysfunction.

4.4Specialwarningsandprecautionsforuse

Beforeinitiatingtherapywithamoxicillin-clavulanateSR,carefulenquiryshouldbemadeconcerningprevious

hypersensitivityreactionstopenicillinsorcephalosporins.

Seriousandoccasionallyfatalhypersensitivity(anaphylactoid)reactionshavebeenreportedinpatientsonpenicillin

therapy.Thesereactionsaremorelikelytooccurinindividualswithahistoryofpenicillinhypersensitivity.Ifan

allergicreactionoccurs,amoxicillin-clavulanateSRtherapymustbediscontinuedandappropriatealternativetherapy

instituted.Seriousanaphylactoidreactionsrequireimmediateemergencytreatmentwithadrenaline.Oxygen,i.v.

steroidsandairwaymanagement(includingintubation)mayalsoberequired.

Amoxicillin-clavulanateSRshouldbeavoidedifinfectiousmononucleosisissuspected,sincetheoccurrenceofa

morbilliformrashhasbeenassociatedwiththisconditionfollowingtheuseofamoxicillin.

Prolongedusemayalsooccasionallyresultinovergrowthofnon-susceptibleorganisms.

Prolongationofprothrombintimehasbeenreportedrarelyinpatientsreceivingamoxicillin-clavulanate.Appropriate

Communityacquiredpneumonia Twotabletstwicedailyforseventoten

days

Acuteexacerbationsofchronic

bronchitis Twotabletstwicedailyforsevendays

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Noadjustmentinamoxicillin-clavulanateSRdosageisrequiredinpatientswithcreatinineclearancegreaterthanor

equalto30ml/min.Amoxicillin-clavulanateSRisnotrecommendedinpatientswithcreatinineclearancelessthan30

ml/min.

Inpatientswithreducedurineoutput,crystalluriahasbeenobservedveryrarely,predominantlywithparenteral

therapy.Duringtheadministrationofhighdosesofamoxicillin,itisadvisabletomaintainadequatefluidintakeand

urinaryoutputinordertoreducethepossibilityofamoxicillincrystalluria.

Amoxicillin-clavulanateSRshouldbeusedwithcautioninpatientswithevidenceofhepaticdysfunction.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Concomitantuseofprobenecidisnotrecommended.Probeneciddecreasestherenaltubularsecretionofamoxicillin.

Concomitantusewithamoxicillin-clavulanatemayresultinincreasedandprolongedbloodlevelsofamoxicillin,butno

ofclavulanateacid.

Concomitantuseofallopurinolduringtreatmentwithamoxicillincanincreasethelikelihoodofallergicskinreactions.

Therearenodataontheconcomitantuseofamoxicillin-clavulanateandallopurinol.

Incommonwithotherantibiotics,amoxicillin-clavulanatemayaffectthegutflora,leadingtoloweroestrogen

reabsorptionandreducedefficacyofcombinedoralcontraceptives.

4.6Pregnancyandlactation

Pregnancy

Reproductionstudiesinanimals(miceandratsatdosesupto10timesthehumandose)withorallyandparenterally

administeredamoxicillin-clavulanatehaveshownnoteratogeniceffects.Inasinglestudyinwomenwithpreterm,

prematureruptureofthefoetalmembrane(pPROM),itwasreportedthatprophylactictreatmentwithamoxicillin-

clavulanatemaybeassociatedwithanincreasedriskofnecrotisingenterocolitisinneonates.Aswithallmedicines,use

shouldbeavoidedinpregnancy,unlessconsideredessentialbythephysician.

Lactation

Amoxicillin-clavulanatemaybeadministeredduringtheperiodoflactation.Withtheexceptionoftheriskof

sensitisation,associatedwiththeexcretionoftracequantitiesinbreastmilk,therearenoknowndetrimentaleffectsfor

thebreast-fedinfant.

4.7Effectsonabilitytodriveandusemachines

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4.8Undesirableeffects

Datafromlargeclinicaltrialswasusedtodeterminethefrequencyofverycommontorareundesirableeffects.The

frequenciesassignedtoallotherundesirableeffects(i.e.,thoseoccurringat<1/10,000)weremainlydeterminedusing

post-marketingdataandrefertoareportingrateratherthanatruefrequency.

Thefollowingconventionhasbeenusedfortheclassificationoffrequency:

verycommon>1/10

common>1/100and<1/10

uncommon>1/1000and<1/100

rare>1/10,000and<1/1000

veryrare<1/10,000.

Infectionsandinfestations

Common Genitalmonialiasis,mucocutaneouscandidiasis

Bloodandlymphaticsystemdisorders

Rare Reversibleleucopenia(includingneutropenia)andthrombocytopenia

Veryrare Reversibleagranulocytosisandhaemolyticanaemia.Prolongationofbleedingtimeandprothrombin

time(seesection4.4SpecialwarningsandPrecautionsforuse)

Immunesystemdisorders

Veryrare Angioneuroticoedema,anaphylaxis,serumsickness-likesyndrome,hypersensitivityvasculitis

Nervoussystemdisorders

Uncommon Dizziness,headache

Veryrare Reversiblehyperactivity,convulsions

Gastrointestinaldisorders

VerycommonDiarrhoea

Common Nausea,abdominalpain

Uncommon Vomiting,indigestion

Veryrare Antibiotic-associatedcolitis(includingpseudomembranouscolitisandhaemorrhagiccolitis).

Blackhairytongue

Hepatobiliarydisorders

Uncommon AmoderateriseinASTand/orALThasbeennotedinpatientstreatedwithbeta-lactamclass

antibiotics,butthesignificanceofthesefindingsisunknown.

Veryrare Hepatitisandcholestaticjaundice.Theseeventshavebeennotedwithotherpenicillinsand

cephalosporins.

Hepaticeventshavebeenreportedpredominantlyinmalesandelderlypatientsandmaybeassociatedwithprolonged

treatment.

Signsandsymptomsusuallyoccurduringorshortlyaftertreatmentbutinsomecasesmaynotbecomeapparentuntil

severalweeksaftertreatmenthasceased.Theseareusuallyreversible.Hepaticeventsmaybesevereandinextremely

rarecircumstances,deathshavebeenreported.Thesehavealmostalwaysoccurredinpatientswithseriousunderlying

diseaseortakingconcomitantmedicationsknowntohavethepotentialforhepaticeffects.

Skinandsubcutaneoustissuedisorders

Uncommon Skinrash,pruritus,urticaria

Rare Erythemamultiforme

Veryrare Stevens-Johnsonsyndrome,toxicepidermalnecrolysis,bullousexfoliative-dermatitis,acutegeneralised

exanthemouspustulosis(AGEP)

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Renalandurinarydisorders

Veryrare Interstitialnephritis,crystalluria

4.9Overdose

SymptomsandSigns

Gastrointestinalsymptomsanddisturbanceofthefluidandelectrolytebalancesmaybeevident.

Amoxicillincrystalluria,insomecasesleadingtorenalfailure,hasbeenobserved(seesection4.4Specialwarnings

andPrecautionsforuse).

Treatment

GIsymptomsmaybetreatedsymptomatically,withattentiontothewater/electrolytebalance.

Amoxicillin-clavulanatecanberemovedfromthecirculationbyhaemodialysis.

Drugabuseanddependence

Drugdependence,addictionandrecreationalabusehavenotbeenreportedasaproblemwiththiscompound.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

MechanismofAction:

Amoxicillinisasemisyntheticantibioticwithabroadspectrumofantibacterialactivityagainstmanygram-positiveand

gram-negativemicroorganisms.Amoxicillinis,however,susceptibletodegradationbybeta-lactamases,andtherefore

thespectrumofactivityofamoxicillinalonedoesnotincludeorganismswhichproducetheseenzymes.

Clavulanateisabeta-lactam,structurallyrelatedtothepenicillins,whichpossessestheabilitytoinactivateawide

rangeofbeta-lactamaseenzymescommonlyfoundinmicro-organismsresistanttopenicillinsandcephalosporins.In

particular,ithasgoodactivityagainsttheclinicallyimportantplasmidmediatedbeta-lactamasesfrequentlyresponsible

fortransferreddrugresistance.Itisgenerallylesseffectiveagainstchromosomally-mediatedtype1beta-lactamases.

ThepresenceofclavulanateinAUGMENTINSRformulationsprotectsamoxicillinfromdegradationbybeta-

lactamaseenzymes,andeffectivelyextendstheantibacterialspectrumofamoxicillintoincludemanybacterianormally

resistanttoamoxicillinandotherpenicillinsandcephalosporins.

ThusAUGMENTINSRpossessesthedistinctivepropertiesofabroad-spectrumantibioticandabeta-lactamase

inhibitor.AUGMENTINSRisasustainedreleasetabletthatprovidesanextendedamoxicillinpharmacokinetic

profile.Theamox-clav-SRformulationextendsthespectrumofamox-clavtoincludethemajorityofS.pneumoniae

whereresistanceismediatedbypenicillinbindingproteins(penicillin-resistantS.pneumoniaeorPRSP).

Microbiology:AUGMENTINSRisbactericidaltoawiderangeoforganisms(seesusceptibilitytablebelow).

Breakpoints Susceptible Intermediate Resistant

Streptococcus

pneumoniae 4mg/l 8mg/l 16mg/l

Haemophilus

influenzae 4/2mg/l - 8/4mg/l

Moraxella

catarrhalis 4/2mg/l - 8/4mg/l

Staphylococcus

aureus(MSSA) # 4/2mg/l - 8/4mg/l

Klebsiella

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OtherInformation

Cross-resistance:Amoxicillinonitsownshowscross-resistancetootherbeta-lactams,beta-lactam/beta-lactamase

inhibitorcombinations,andcephalosporins.

ResistanceMechanisms:Clavulanateprotectsagainstresistancemediatedbycertainbeta-lactamaseenzymes.The

sustained-releaseformulationofAUGMENTINSRimprovesefficacyagainstorganismswithresistancemediatedby

modifiedpencillin-bindingproteins(PBPs).

5.2Pharmacokineticproperties

Absorption

Thetwocomponentsofamoxicillin-clavulanateSR(amoxicillinandclavulanate)arefullydissociatedinaqueous

solutionatphysiologicalpH.Bothcomponentsarerapidlyandwellabsorbedbytheoralrouteofadministration.

Susceptibility

Susceptibleaerobesgram-positive

Staphylococcusaureus(MSSA) #

*

StaphylococcusepidermidisMSSE) #

Streptococcuspneumoniae(includingPRSP&

macrolide-resistant)*

Streptococcuspyogenes*

ViridansGroupStreptococcus*

Susceptibleanaerobesgram-positive

Peptostreptococcusanaerobius

Peptostreptococcusmagnus

Peptostreptococcusmicros

Susceptibleaerobesgram-negative

Haemophilusinfluenzae #

*

Haemophilusparainfluenzae #

*

Klebsiellapneumoniae #

*

Moraxellacatarrhalis #

*

Susceptibleanaerobesgram-negative

Bacteroidesfragilis #

Eikenellacorrodens #

Fusobacteriumnucleatum #

Porphyromonassp.

Prevotellasp.

#Somemembersofthesespeciesofbacteriaproduce-lactamase,rendering

themnon-susceptibletoamoxicillinalone.

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Thepharmacokineticresultsthathavebeenobtainedforamoxicillinandclavulanatefollowingtheadministrationof

amoxicillin-clavulanateSR2x1000/62.5mgtohealthyadultsatthestartofamealarepresentedbelow:

Theamoxicillin-clavulanateSRsustainedreleaseformulationhasanuniquePK/PDprofile.TheT>MICobtainedwith

amoxicillin-clavulanateSRcannotbeachievedwiththesamedoseformulatedasanimmediatereleasetablet.

Distribution

Followingi.v.administrationofamoxicillin/clavulanate,therapeuticconcentrationsofbothamoxicillinandclavulanate

maybedetectedinthetissuesandinterstitialfluid.Therapeuticconcentrationsofbothdrugshavebeenfoundingall

bladder,abdominaltissue,skin,fat,andmuscletissues;fluidsfoundtohavetherapeuticlevelsincludesynovialand

peritonealfluids,bileandpus.

Neitheramoxicillinnorclavulanateishighlyprotein-bound,studiesshowthatabout25%forclavulanateand18%for

amoxicillinoftotalplasmadrugcontentisboundtoprotein.

Fromanimalstudiesthereisnoevidencetosuggestthateithercomponentaccumulatesinanyorgan.

Amoxicillin,likemostpenicillins,canbedetectedinbreastmilk.Tracequantitiesofclavulanatecanalsobedetectedin

breastmilk.Withtheexceptionoftheriskofsensitisationassociatedwiththisexcretion,therearenoknown

detrimentaleffectsforthebreast-fedinfant.

Reproductionstudiesinanimalshaveshownthatbothamoxicillinandclavulanatepenetratetheplacentalbarrier.

However,noevidenceofimpairedfertilityorharmtothefoetuswasdetected.

Metabolism

Amoxicillinispartlyexcretedintheurineastheinactivepenicilloicacidinquantitiesequivalenttoupto10to25%of

theinitialdose.Clavulanateisextensivelymetabolizedinmanto2,5-dihydro-4-(2-hydroxyethyl)-5-oxo-1H-pyrrole-3-

carboxylicacidand1-amino-4-hydroxy-butan-2-one,andeliminatedinurineandfaeces,andascarbondioxidein

expiredair.

Elimination

Aswithotherpenicillins,themajorrouteofeliminationforamoxicillinisviathekidney,whereasforclavulanateitis

bybothrenalandnon-renalmechanisms.

Previousstudieshaveshownthat,onaverage,uptoapproximately60to70%oftheamoxicillinandapproximatelyup

to40to65%oftheclavulanateareexcretedunchangedintheurine.

Concomitantuseofprobeneciddelaysamoxicillinexcretionbutdoesnotdelayrenalexcretionofclavulanate(see

section4.5Interactionwithothermedicinalproductsandotherformsofinterction).

5.3Preclinicalsafetydata

Meanpharmacokineticparameters

Drug

administered Dose(mg) T>MIC ^

h(%) Cmax

(mg/l) Tmax(h) AUC

(ug.h/ml) T1/2(h)

Amoxicillin

Amoxicillin-

clavulanateSR

1000/62.5mgx2 2000 5.9(49.4) 17.0 1.50 71.6 1.27

Clavulanate

Amoxicillin-

clavulanateSR

1000/62.5mgx2 125 ND 2.05 1.03 5.29 1.03

ND–Notdetermined

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Microcrystallinecellulose

Sodiumstarchglycollate

Colloidalanhydroussilica

Magnesiumstearate

Xanthamgum

Citricacid

Filmcoat(opadryYS17700):

Hypromellose6cp

Hypromellose15cp

Titaniumdioxide(E171)

Macrogol3350

Macrogol8000

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

2years.

6.4Specialprecautionsforstorage

Donotstoreabove25 °

Storeinoriginalpackage.

6.5Natureandcontentsofcontainer

PVC/aluminiumoraluminium/aluminiumblisterstripswithonefilm-coatedtabletperblisterpocketand2x2tablets

perblister.Packsof28tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

GlaxoSmithKline(Ireland)Limited,

Stonemasonsway,

Rathfarnham,

Dublin16.

8MARKETINGAUTHORISATIONNUMBER

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:25February2005

10DATEOFREVISIONOFTHETEXT

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