CLONOCID

Main information

  • Trade name:
  • CLONOCID Granules for Oral Suspension 25 Mg/ Ml
  • Dosage:
  • 25 Mg/ Ml
  • Pharmaceutical form:
  • Granules for Oral Suspension
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CLONOCID Granules for Oral Suspension 25 Mg/Ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0126/136/003
  • Authorization date:
  • 15-04-2005
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Clonocid125mg/5mlgranulesfororalsuspension.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

1mlreconstitutedoralsuspensioncontains25mgclarithromycin.

5mlreconstitutedoralsuspensioncontains125mgclarithromycin.

Forexcipients,see6.1.

3PHARMACEUTICALFORM

Granulesfororalsuspension.

Whitetooff-whitegranules.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Streptococcaltonsillitis,otitismedia,skinandsofttissueinfectionsofmildtomoderateseverityinpenicillin

hypersensitivepatientsorincaseswherepenicillinisinappropriateforotherreasons.Availabledataon

epidemiologicalresistancetomacrolideantibioticsshouldbeconsidered.

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantibacterialagents.

4.2Posologyandmethodofadministration

General:

ThedosageofClarithromycindependsontheclinicalconditionofthepatientandhastobedefinedinanycasebythe

physician.

Theusualdoseinchildrenaged6monthsorolderis7.5mg/kgtwicedaily.

Recommendationsfordosage:

“Children<8kgshouldbedosedonaperkgbasis(approx.7.5mg/kgtwicedaily)whichisequalto0.3mlofreadyto

usesuspensionperkgbodyweight.”

Dosageinrenalfunctionalimpairment:

Dosageadjustmentisnotusuallyrequiredexceptinpatientswithsevererenalimpairment(creatinineclearance<30

ml/min).Ifadjustmentisnecessary,thetotaldailystandarddosageshouldbereducedbyhalf.Treatmentsshouldnotbe

Weight Age Dosage

8-11kg 1-2years 2.5mltwicedaily

12-19kg 2-4years 5.0mltwicedaily

20-29kg 4-8years 7.5mltwicedaily

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Durationoftherapy:

ThedurationoftherapywithClarithromycindependsontheclinicalconditionofthepatient.Thedurationoftherapy

hasinanycasetobedeterminedbythephysician.

Theusualdurationoftreatmentis6to14days.

Therapyshouldbecontinuedatleastfortwodaysaftersymptomshavesubsided.

InStreptococcuspyogenesinfectionsthedurationoftherapyshouldbeatleast10daysinordertoprevent

complicationssuchasrheumaticfeverandglomerulonephritis.

Methodofadministration:

Clarithromycinmaybegivenirrespectiveoffoodintake(seesection5.2).

Preparationforuse:

Beforeadministrationthegranulesmustbereconstitutedwithwater,seesection6.6.Foradministrationafter

reconstitutionanoralsyringeorameasuringspoonareused.

4.3Contraindications

Clarithromycinshouldnotbeusedinpatientswithhypersensitivitytoclarithromycin,toothermacrolidesortoany

oftheexcipients.

Clarithromycinandergotderivativesshouldnotbeco-administered.

Concomitantadministrationofclarithromycinandanyofthefollowingactivesubstancesiscontraindicated:

cisapride,pimozideandterfenadine.Elevatedcisapride,pimozideandterfenadinelevelshavebeenreportedin

patientsreceivingeitheroftheseactivesubstancesandclarithromycinconcomitantly.ThismayresultinQT

prolongationandcardiacarrhythmiasincludingventriculartachycardia,ventricularfibrillationandTorsadede

Pointes.Similareffectshavebeenobservedwithconcomitantadministrationofastemizoleandothermacrolides

(seesection4.5).

Clarithromycinshouldnotbeadministeredtohypokalemicpatients(prolongationofQT-time).

Clarithromycinshouldnotbeusedconcomitantlywithsimvastatinoratorvastatin.Treatmentwithanyofthese

agentsshouldbeinterruptedduringclarithromycintreatment(seesection4.5).

4.4Specialwarningsandprecautionsforuse

Clarithromycinismainlyexcretedbytheliver.Therefore,cautionshouldbetakeninadministeringclarithromycin

topatientswithimpairedhepaticfunction.

Whenrenalfunctionispoor,dosageofClarithromycinshouldbesuitablyreduceddependingonthedegreeofthe

impairment(seesection4.2).Inelderlypatients,thepossibilityofrenalimpairmentshouldbeconsidered.

Patientswhoarehypersensitivetoothermacrolides,clindamycinandlincomycinmayalsobehypersensitiveto

Clarithromycin.Thereforecautionisrequiredwhenprescribingclarithromycinforsuchpatients.

Pseudomembranouscolitishasbeenreportedwiththeuseofbroad-spectrumantibiotics.Therefore,itisimportant

toconsideritsdiagnosisinpatientswhodevelopseverediarrhoeaduringoraftertherapywithclarithromycin.

Clarithromycintreatmentshouldbestoppedandanadequatetherapyshouldbestarted.Anti-peristalticsare

contraindicated.

Prolongedorrepeateduseofclarithromycinmayresultinsuperinfectionswithinsusceptibleorganisms.Incaseof

superinfection,clarithromycintherapyshouldbestopped.

DuetoariskofincreasedQT-interval,clarithromycinshouldbeusedwithcautioninpatientswithacoronary

vesseldisease,ahistoryofventriculararrhythmia,severecardiacinsufficiency,non-compensatedhypokalemia

and/orhypomagnesaemia,bradycardia(<50bpm),orwhenco-administeredwithothermedicinalproductswitha

QT-prolongingeffect.ClarithromycinshouldnotbeusedinpatientswithcongenitalordocumentedacquiredQT

prolongation(seesection4.5).

Clarithromycinshouldbeusedwithcautionwheneverindicatedforuseinpatientsreceivingtreatmentwithan

inducerofCYP3A4duetothepossibilityofsubtherapeuticlevelsofclarithromycin(seesection4.5).

ClarithromycinisaninhibitorofCYP3A4,andconcomitantusewithothermedicinalproductsthataremetabolised

toalargeextentbythisenzymeshouldberestrictedtosituationswhereitisclearlyindicated(seesection4.5).

ClarithromycininhibitsthemetabolismofsomeHMG-CoAreductaseinhibitors,whichresultsinincreasedplasma

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AsknownforothermacrolidesclarithromycinmaycauseexacerbationoraggravationofMyastheniagravisand

shouldthereforebeusedwithcautioninpatientswithMyastheniagravis.

Thismedicinalproductcontainsasourceofphenylalanine.Maybeharmfulforpeoplewithphenylketonuria.

Patientswithrarehereditaryproblemsoffructoseintolerance,glucose-galactosemalabsorptionorsucrase-

isomaltaseinsufficiencyshouldnottakethismedicine.

Thismedicinalproductcontains2.93gsucroseper5ml.Thisshouldbetakenintoaccountinpatientswithdiabetes

mellitus.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

TheeffectofClarithromycingranulesfororalsuspensiononothermedicinalproducts

ClarithromycinisaninhibitorofthemetabolisingenzymeCYP3A4andthetransportproteinP-glycoprotein.The

degreeofinhibitionwithdifferentCYP3A4substratesisdifficulttopredict.Hence,clarithromycinshouldnotbeused

duringtreatmentwithothermedicinalproductsthataresubstratesforCYP3A4,unlessplasmalevels,therapeuticeffect

oradverseeventsoftheCYP3A4substratecanbecloselymonitored.Adosereductionmaybenecessaryformedicinal

productsthataresubstratesforCYP3A4ifco-administeredwithclarithromycin.Alternatively,treatmentwiththese

productsmaybeinterruptedduringclarithromycintreatment.

MedicinalproductswithapotentialtoprolongQT-interval

Clarithromycinhasbeenreportedtoinhibitthemetabolismofcisaprideandterfenadine,witha2to3-foldincreasein

plasmalevelsreportedforterfenadine.ThishasbeenassociatedwithQT-prolongationandcardiacarrhythmias

includingventriculartachycardia,ventricularfibrilationandtorsadesdepointes.Similarsymptomshavebeen

describedforpatientstreatedwithpimozidewhencombinedwithclarithromycin.Concomitantadministrationof

clarithromycinandterfenadine,cisaprideorpimozideiscontraindicated(seesection4.3)

Caseswithtorsadesdepointeshasbeenreportedinpatientswhereclarithromycinhasbeenco-administeredwith

quinidineordisopyramide.Thesecombinationsshouldthereforebeavoided,orplasmalevelsofquinidineor

disopyramidecloselymonitoredtoallowdoseadjustment.

Cautioniswarrantedwhenclarithromycinisadministeredtopatientstreatedtakingothermedicinalproductswiththe

potentialtoprolongQT(seesection4.4).

HMG-CoAreductaseinhibitors

ClarithromycininhibitsthemetabolismofsomeHMG-CoAreductaseinhibitors,whichresultsinincreasedplasma

concentrationsofthesemedicinalproducts.Rhabdomyolysisinassociationwithincreasedplasmaconcentrationshave

inrarecasesbeenreportedinpatientstreatedwithclarithromycinandsimvastatin.Clarithromycinmayproducea

similarinteractionwithatorvastatinandalesserinteractionwithcerivastatin.

Clarithromycinshouldnotbeusedconcomitantlywithsimvastatinandatorvastatin.Treatmentwithanyoftheseagents

shouldbeinterruptedduringclarithromycintreatment(seesection4.3).Whentreatmentwithclarithromycinis

indicatedinpatientsreceivingtreatmentwithcerivastatinpatientsshouldbemonitoredforsignsandsymptomsof

myopathy.

Ergotvasoconstrictors(e.g.dihydroergotamine,ergotamine)

Casesofergotismduetoincreasedplasmalevelsofergotalkaloidshavebeenreportedwhentheseproductshavebeen

co-administeredwithmacrolides.Thecombinationiscontraindicated(seesection4.3).

Benzodiazepines

Whenmidazolamwasco-administeredwithclarithromycintablets(250mgtwicedaily),midazolamAUC(areaunder

theplasmacurve)wasincreased2.7-foldafterintravenousadministrationofmidazolamand7-foldafteroral

administration.Concomitantadministrationoforalmidazolamandclarithromycinshouldbeavoided.Ifintravenous

midazolamisco-administeredwithclarithromycin,thepatientmustbecloselymonitoredtoallowdoseadjustment.

ThesameprecautionsshouldalsoapplytootherbenzodiazepinesthataremetabolisedbyCYP3A4,especially

triazolambutalsoalprazolam.ForbenzodiazepineswhicharenotmetabolisedbyCYP3A4(temazepam,nitrazepam,

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Ciclosporin,tacrolimusandsirolimus

Concomitantuseoforalclarithromycinandciclosporinortacrolimushaveresultedinmorethana2-foldincreaseof

theCmin(minimalplasmaconcentration)-levelsofbothciclosporinandtacrolimus.Similareffectsarealsoexpected

forsirolimus.Wheninitiatingtreatmentwithclarithromycininpatientsalreadyreceivinganyofthese

immunosuppressiveagents,ciclosporin,tacrolimusorsirolimusplasmalevelsmustbecloselymonitoredandtheir

dosesdecreasedasnecessary.Whenclarithromycinisdiscontinuedinthesepatients,closemonitoringofplasmalevels

ofciclosporin,tacrolimusorsirolimus,isagainnecessarytoguidedoseadjustment.

Digoxin

Theconcentrationofdigoxinmaybeincreasedwhenco-administeredwithclarithromycin.Monitoringofplasmalevels

ofdigoxinshouldbeconsideredwhenco-treatmentwithclarithromycinisinitiatedorterminatedsinceadose

adjustmentmaybewarranted.

Theophylline

Theadministrationofclarithromycintopatientswhoarereceivingtheophyllinehasbeenassociatedwithanincreasein

serumtheophyllinelevelsandpotentialtheophyllinetoxicity.

Zidovudine

SimultaneousoraladministrationofclarithromycintabletsandzidovudinetoHIV(HumanImmunodeficiencyVirus)

infectedadultpatientsmayresultindecreasedsteady-statezidovudinelevels.Thiscanbelargelyavoidedbystaggering

thedosesofclarithromycinandzidovudineby1-2hours.Nosuchreactionhasbeenreportedinchildren.

TheeffectofothermedicinalproductsonClarithromycingranulesfororalsuspension

ClarithromycinismetabolisedbytheenzymeCYP3A4.Hence,stronginhibitorsofthisenzymemayinhibitthe

metabolismofclarithromycin,resultinginincreasedplasmaconcentrationsofclarithromycin.

Althoughtheplasmaconcentrationsofclarithromycinandomeprazolemaybeincreasedwhentheyareadministered

concurrently,noadjustmenttothedosageisnecessary.Increasedplasmaconcentrationsofclarithromycinmayalso

occurwhenitisco-administeredwithantacidsorranitidine.Noadjustmenttothedosageisnecessary.

Ritonavir(200mgthreetimesdaily)havebeenshowntoinhibitthemetabolismofclarithromycin(500mgtwice

daily),withanincreaseinCmax(maximalplasmaconcentration),CminandAUCof31,182and77%,respectively,

whenco-administeredwithritonavir.Formationoftheactive14-hydroxymetabolitewasalmostcompletelyinhibited.

Ageneraldosereductionisprobablynotrequiredinpatientswithnormalrenalfunction,butthedailydoseof

clarithromycinshouldnotexceed1g.Dosereductionshouldbeconsideredinpatientswithrenalimpairment.For

patientswithacreatinineclearanceof30to60ml/min,theclarithromycindoseshouldbereducedwith50%,andata

creatinineclearanceof<30ml/minthedoseshouldbereducedwith75%.

ProductsthatareinducersofCYP3A4(e.g.rifampicin,phenytoin,carabamazepine,phenobarbital,St.Johnswort)may

inducethemetabolismofclarithromycin.Thismayresultinsub-therapeuticlevelsofclarithromycinleadingtoa

reducedefficacy.Whenclarithromycinisclearlyindicateditmightbenecessarytoincreasethedoseofclarithromycin

andmonitortheefficacyandsafetyofclarithromycincarefully.Furthermoremonitoringtheplasmalevelsofthe

CYP3A4inducermightbenecessarybecausethelattercouldbeincreasedowingtotheinhibitionofCYP3A4by

clarithromycin(seealsotherelevantproductinformationfortheCYP3A4induceradministered).

Concomitantadministrationofrifabutinandclarithromycinresultedinanincreaseanddecrease,respectively,inserum

levels,followedbyanincreasedriskofuveitis.

A39%reductioninAUCforclarithromycinanda34%increaseinAUCfortheactive14-hydroxymetabolitehave

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4.6Pregnancyandlactation

Pregnancy

Dataontheuseofclarithromycinduringthefirsttrimesterofmorethan200pregnanciesshownoclearevidenceof

teratogeniceffects,orofadverseeffectsonthehealthoftheneonate.Datafromalimitednumberofpregnantwomen

exposedinthefirsttrimesterindicateapossibleincreasedriskofabortions.Todatenootherrelevantepidemiological

dataareavailable.

Datafromanimalstudieshaveshownreproductivetoxicity(seesection5.3).Theriskforhumansisunknown.

Clarithromycinshouldonlybegiventopregnantwomenafteracarefulbenefit/riskassessment.

Lactation

Clarithromycinanditsactivemetaboliteareexcretedinbreastmilk.Therefore,diarrhoeaandfungusinfectionofthe

mucousmembranescouldoccurinthebreast-fedinfant,sothatnursingmighthavetobediscontinued.Thepossibility

ofsensitisationshouldbeborninmind.Thebenefitoftreatmentofthemothershouldbeweighedagainstthepotential

riskfortheinfant.

4.7Effectsonabilitytodriveandusemachines

Therearenodataavailableontheeffectofclarithromycinontheabilitytodriveorusemachines.Whenperforming

theseactivitiesthepossibleoccurrenceoftheadversereactionsdizziness,vertigo,confusionanddisorientationshould

betakenintoaccount.

4.8Undesirableeffects

Themostfrequentlyreportedeventsinadultstakingclarithromycingranulesfororalsuspensionwerediarrhoea(3%),

nausea(3%),abnormaltaste(3%),dyspepsia(2%),abdominalpain/discomfort(2%),andheadache(2%).

Inthissectionundesirableeffectsaredefinedasfollows:

verycommon(>1/10);common(>1/100,<1/10);uncommon(>1/1000,<1/100);rare(>1/10000,<1/1000);veryrare(<

1/10000),includingisolatedreports.

Infectionsandinfestations

Common:Oralmonilia

Prolongedusemayresultintheovergrowthofnon-susceptibleorganisms.

Bloodandthelymphaticsystemdisorders

Uncommon:Decreasedleucocytelevels

Veryrare:Thrombocytopenia

Immunesystemdisorders

Uncommon:Allergicreactionsrangingfromurticariaandmildskineruptionstoanaphylaxis.

Psychiatricdisorders

Veryrare:Anxiety,insomnia,hallucinations,psychosis,disorientation,depersonalisation,baddreamsandconfusion.

Nervoussystemdisorders

Common:Headache,smellalteration.

Veryrare:Dizziness,vertigo,paraesthesia,convulsions.

Earandlabyrinthdisorders

Rare:Tinnitus

Veryrare:Reversiblehearingloss

Cardiacdisorders

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Gastrointestinaldisorders

Common:Nausea,diarrhoea,vomiting,abdominalpain,dyspepsia,stomatitis,glossitis,reversibletoothandtongue

discoloration,andtasteperversion,i.e.metallicorbittertaste.

Veryrare:Pancreatitis.Pseudomembranouscolitishasbeenreportedveryrarelywithclarithromycin,andmayrangein

severityfrommildtolifethreatening.

Hepato-biliarydisorders

Uncommon:Hepaticdysfunction,whichisusuallytransientandreversible,hepatitisandcholestasiswithorwithout

jaundice.

Veryrare:Fatalhepaticfailurehasbeenreportedparticularlyinpatientswithpre-existingliverdiseaseortakingother

hepatotoxicmedicinalproducts.

Skinandsubcutaneoustissuedisorders

Veryrare:Stevens-Johnsonsyndromeandtoxicepidermalnecrolysis

Musculoskeletal,connectivetissueandbonedisorders

Uncommon:Arthralgia,myalgia.

Renalandurinarydisorders

Veryrare:Interstitialnephritis,renalfailure.

Investigations

Common:ElevatedBUN(bloodureanitrogen)

Uncommon:Prolongationofprothrombintime,elevatedserumcreatinine,alteredliverfunctiontests(increased

transaminaselevels).

Veryrare:Hypoglycaemiahasbeenobservedespeciallyafterconcomitantadministrationwithantidiabeticmedicinal

productsandinsulin

4.9Overdose

Symptomsofintoxication:

Reportsindicatethattheingestionoflargeamountsofclarithromycincanbeexpectedtoproducegastrointestinal

symptoms.Symptomsofoverdosemaylargelycorrespondtotheprofileofadversereactions.Onepatientwhohada

historyofbipolardisorderingested8gramsofclarithromycinandshowedalteredmentalstatus,paranoidbehaviour,

hypokalaemiaandhypoxaemia.

Therapyofintoxication:

Thereisnospecificantidoteonoverdose.Serumlevelsofclarithromycincannotbereducedbyhaemodialysisor

peritonealdialysis.

Adversereactionsaccompanyingoverdoseshouldbetreatedbygastriclavageandsupportivemeasures.Severeacute

allergicreactionsmaybeseenveryrarely,e.g.anaphylacticshock.Atfirstsignsofhypersensitivityreactionstherapy

withclarithromycinmustbediscontinuedandtherequiredmeasuresshouldbeinitiatedimmediately.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Macrolides

ATCcode:J01FA09.

Mechanismofaction:

Clarithromycinexertsitsantibacterialactionbybindingtothe50sribosomalsub-unitofsusceptiblebacteriaand

suppressesproteinsynthesis.Itishighlypotentagainstawidevarietyofaerobicandanaerobicgram-positiveand

gram-negativeorganisms.Theminimuminhibitoryconcentrations(MICs)ofclarithromycinaregenerallytwo-fold

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The14-hydroxymetaboliteofclarithromycinalsohasantimicrobialactivity.TheMICsofthismetaboliteareequalor

two-foldhigherthantheMICsoftheparentcompound,exceptforHaemophilusinfluenzaewherethe14-hydroxy

metaboliteistwo-foldmoreactivethantheparentcompound.

Breakpoints:

AccordingtotheNCCLS(USNationalCommitteeonClinicalLaboratoryStandards)inJanuary2004thefollowing

breakpointshavebeendefinedforclarithromycin:

NCCLS: Staphylococcusspp.:S ≤2µg/ml,R≥8µg/ml

Haemophilusspp.:S ≤8µg/ml,R≥32µg/ml

Streptococcuspneumoniae:S ≤0.25µg/ml,R≥1µg/ml

Streptococcusspp.otherthanS.pneumoniae:S ≤0.25µg/ml,R≥1µg/ml

Helicobacterpylori:S ≤0.25µg/ml,R≥1µg/ml

SRGA(SwedishReferenceGroupofAntibiotics):otherrelevantmicro-organisms(i.e.Moraxella,Enterococci,

Bordetella,Chlamydia,Mycoplasma,LegionellaandMycobacterium):

0.5µg/ml,R ≥8.0µg/ml

Susceptibility:

Theprevalenceofresistancemayvarygeographicallyandwithtimeforselectedspeciesandlocalinformationon

resistanceisdesirable,particularlywhentreatingsevereinfections.Thisinformationgivesonlyanappropriate

guidanceontheprobabilitieswhethermicro-organismswillbesusceptibletoclarithromycinornot.Asfarasapplicable

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+commentsregardingresistanceseebelow

Otherinformation:

SusceptibilityandresistanceofStreptococcuspneumoniaeandStreptococcusspp.toclarithromycincanbepredicted

Species FrequencyofresistancerangesinEU(if

>10%)(extremevalues)

Commonlysusceptiblespecies

Gram-positiveaerobes

GroupC,F,GStreptococci

Corynebacteriumdiptheriae

Gram-negativeaerobes

Legionellaspp.

Moraxellacatarrhalis*

Pasteurellamultocida

Anaerobes

Bacteroidesspp.

Clostridiumspp.otherthanC.difficile

Fusobacteriumspp.

Peptococcus/Peptostreptococcusspp.

Others

Chlamydiatrachomatis

Chlamydiapneumoniae*

Mycoplasmapneumoniae*

Speciesforwhichacquiredresistance

maybeaproblem

Gram-positiveaerobes

Staphylococcusaureus

methicillin-susceptible (18.1%)

GroupA,BStreptococci(beta-

haemolytic) (21.4%)

Streptococcuspneumoniae+ (37.8%)

Gram-negativeaerobes

Haemophilusinfluenzae

Inherentlyresistantorganisms

Gram-positiveaerobes

Enterococcusspp.

Staphylococcusaureus

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Themechanismsofacquiredresistanceinmacrolidesare:effluxofactivesubstancebyanactivepumpmechanism,

inducibleorconstitutiveproductionofamethylaseenzymethatmodifiestheribosomaltarget,hydrolysisofmacrolides

byesterases,chromosomalmutationsthataltera50sribosomalprotein.Cross-resistancebetweenclarithromycinand

othermacrolidesandclindamycinandlincomycinmaythereforeoccur.Methicillin-resistantstaphylococcusaureus

(MRSA)andpenicillin-resistantpneumococciareresistanttoallcurrentlyavailablebeta-lactamantibioticsand

macrolidessuchasclarithromycin.

5.2Pharmacokineticproperties

Absorption:

Clarithromycinhasasignificantfirst-passmetabolism.Itsabsolutebioavailabilityisabout55%,andconcurrentfood

intakedoesnotaffectit.Plasmapeakconcentrationsoccurinabout2hoursafteradministration.Theelimination

kineticsaredose-dependent(non-linear).Atadosageof7.5mg/kg/bodyweightinthemorningandtheevening,plasma

peakconcentrationsinsteadystateafter5daysoftreatmentareabout4.6mg/l.Proteinbindingis70%.

Distribution:

Clarithromycinishighlylipophilic,anditsdistributionvolumeis200-400l.Clarithromycineasilypenetratestonsillar

tissueandmiddleearsecretions,wheretwofoldconcentrationscomparedtoplasmahavebeenfound.

Biotransformationandelimination:

Clarithromycinismetabolisedintheliverbyhydroxylationanddemethylation.Thehalf-lifeoftheactive14-hydroxy

metabolite(about75%ofclarithromycinactivity)isabout5h,andplasmapeakconcentration0.6mg/l.About20%of

thedoseisexcretedrenallyasunchangedclarithromycin;theproportionincreaseswithincreasingdose.Thehydroxy

metaboliteismetabolisedandexcretedinthefeces.Thecalculatedplasmaclearanceisabout700ml/minandrenal

clearanceabout170ml/min.Inrenalfailure,clarithromycinlevelsareelevatedinplasma.

Severehepaticfailurelowershydroxymetaboliteconcentrationsbecauseofanimpairedcapacityformetabolisation.

Specialpopulations:

Renalimpairment:Reducedrenalinsufficiencyfunctionresultsinincreasedplasmalevelsofclarithromycinandthe

activemetabolitelevelsinplasma.

5.3Preclinicalsafetydata

In4-week-studiesinanimals,toxicityofclarithromycinwasfoundtoberelatedtothedoseandtothedurationofthe

treatment.Inallspecies,thefirstsignsoftoxicitywereobservedintheliver,inwhichlesionswereseenwithin14

daysindogsandmonkeys.Thesystemiclevelsofexposure,relatedtothistoxicity,arenotknownindetail,buttoxic

doses(300mg/kg/day)wereclearlyhigherthanthetherapeuticdosesrecommendedforhumans.Cardiovascular

malformationswereobservedinratstreatedwithdosesof150mg/kg/d.

Nomutageniceffectswerefoundininvitro-andinvivo-studieswithclarithromycin.Studiesonreproductiontoxicity

showedthatadministrationofclarithromycinatdoses2xtheclinicaldoseinrabbit(intravenous)andx10theclinical

doseinmonkey(peros)resultedinanincreasedincidenceofspontaneousabortions.Thesedoseswererelatedto

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Coatedgranules:

Hypromellose

Microcrystallinecellulose

Hydroxypropylcellulose

Croscarmellosesodium

Alginicacid

Metacrylicacid-ethylene-acrylatecopolymer(1:1)dispersion30percent

Macrogol1500

Talc

Carbomer

Otheringredients:

Sucrose

Aspartame(E951)

Xanthangum

Silicacolloidalanhydrous

Monosodiumcitrate

Sodiumbenzoate(E211)

Titaniumdioxide(E171)

Sodiumchloride

Flavouringtuttifrutti

Flavouringpeppermint

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

2years

Ready-to-usesuspension:14days.

6.4Specialprecautionsforstorage

Donotrefrigerateorfreeze.

Keepthebottletightlyclosed.

6.5Natureandcontentsofcontainer

Package:HDPEbottlewithchildresistantPPcaphavinginductionsealliner.

Packagesizes:50,60,70,100,140ml.

Thepackageincludesanoralsyringewitha10mlscalegraduatedinstepsof0.25mlononesideofthescaleand

markedat2.5/5/7.5/10mlwiththecorrespondingbodyweight-rangeinkgontheothersideofthescaleand/ora

measuringspoonfor2.5mland5mldoses.

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6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Preparationforuse:

Thebottlehastobeknockedgently,untilallgranulesmovefreely.Forpreparationoftheready-to-usesuspensionthe

waterhastobeaddeduntilthemarkofthebottle(ifapplicable)orbyadditionofthementionedvolumeofwaterintwo

lots.Aftereachadditionthesuspensionshouldbeshakedvigorously.Afterreconstitutionwithwaterthemedicinal

productresultsinanoff-whitesuspension.

Preparationoftheready-to-usesuspensionifthereisnomark:

50mlbottle:28mlofpurifiedwatershouldbeaddedtothegranulesinthebottleintwolotstoyield50mlof

reconstitutedsuspension.Aftereachadditionthesuspensionshouldbeshakedvigorously.

60mlbottle:34mlofpurifiedwatershouldbeaddedtothegranulesinthebottleintwolotstoyield60mlof

reconstitutedsuspension.Aftereachadditionthesuspensionshouldbeshakedvigorously.

70mlbottle:40mlofpurifiedwatershouldbeaddedtothegranulesinthebottleintwolotstoyield70mlof

reconstitutedsuspension.Aftereachadditionthesuspensionshouldbeshakedvigorously.

100mlbottle:55mlofpurifiedwatershouldbeaddedtothegranulesinthebottleintwolotstoyield100mlof

reconstitutedsuspension.Aftereachadditionthesuspensionshouldbeshakedvigorously.

140mlbottle:77mlofpurifiedwatershouldbeaddedtothegranulesinthebottleintwolotstoyield140mlof

reconstitutedsuspension.Aftereachadditionthesuspensionshouldbeshakedvigorously.

7MARKETINGAUTHORISATIONHOLDER

ClonmelHealthcareLtd

WaterfordRoad

Clonmel

Co.Tipperary

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA0126/136/003

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:15April2005

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 17/11/2009 CRN 2074341 page number: 11