CLARITHROMYCIN

Main information

  • Trade name:
  • CLARITHROMYCIN Oral Suspension 250/5 MG/5ml
  • Dosage:
  • 250/5 MG/5ml
  • Pharmaceutical form:
  • Oral Suspension
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CLARITHROMYCIN Oral Suspension 250/5 MG/5ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0408/063/004
  • Authorization date:
  • 02-06-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0408/063/004

CaseNo:2043628

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

RanbaxyIrelandLimited

Spafield,CorkRoad,Cashel,Co.Tipperary,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Clarithromycin250mg/5mlOralSuspension

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom13/12/2007until31/05/2011.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Clarithromycin250mg/5mlOralSuspension

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each5mlofthesuspensioncontainsclarithromycin250mg.

1mlofthesuspensioncontainsclarithromycin50mg.

Forfulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Granulesfororalsuspension.

Whitetooff-whitegranulesformingwhitetooff-whitesuspensiononreconstitutionwithwater.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofthefollowinginfectionsinchildrenwhencausedbyclarithromycin-susceptibleorganisms:

-Lowerrespiratorytractinfectionssuchascommunityacquiredpneumonia.

-Upperrespiratorytractinfectionssuchaspharyngitisorsinusitis.

-Skinandsofttissueinfectionsofmildtomoderateseverity.

-Acuteotitismedia.

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantibacterialagents.

4.2Posologyandmethodofadministration

TherecommendeddailydoseofClarithromycin250mg/5mlOralSuspensioninchildrenisgiveninthefollowingtable

andisbasedonanapproximate7.5mg/kgtwicedailydosingregimen.Dosesupto500mgtwicedailyhavebeenused

inthetreatmentofsevereinfections.

Forsomechildren,dependingonbodyweight,itmaybemoreappropriatetoadministerthe125mg/5mloral

suspension.

Theusualdurationoftreatmentisfor5to10daysdependingonthepathogeninvolvedandtheseverityofthe

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Clarithromycin250mg/5mlOralSuspensiondosageinchildrenbasedonbodyweight(kg)

children<8kgshouldbedosedbasedonaperkgbasis(approx.7.5mg/kgtwicedaily)

inordertoavoidtheneedtoestimatequarterteaspoonfuls,itisrecommendedthatthe125mg/5mloral

suspensionisusedforchildrenintheseweightbands(pleaseconsulttheprescribinginformationforthe125mg/5ml

oralsuspensionfordetails).

Agraduatedsyringeisprovidedwiththebottleforuseasapipette(seesections6.5and6.6).Thisenablesmore

accuratedosingthanthe5mlspoon(alsoprovidedwiththebottle)whenfractionsofaspoonfulareneededtoachieve

therightdose.

Renalandhepaticinsufficiency

Clarithromycinshouldnotbeadministeredtopaediatricpatientswithseverehepaticorrenalinsufficiency.Cautionis

requiredwhenadministeringclarithromycintochildrenwithlesserdegreesofrenalorhepaticinsufficiency.

MethodofAdministration

ClarithromycinOralSuspensionmaybegivenwithoutregardtomeals,asfooddoesnotaffecttheextentof

bioavailability.

ClarithromycinOralSuspensionshouldbeadministeredtwicedailyasrecommendedinthetableabove.Thedoses

shouldbegivenat12-hourintervals.

4.3Contraindications

Hypersensitivitytotheactivesubstanceclarithromycin,toothermacrolidesortoanazalideantibacterialagentorto

anyoftheexcipients.

Patientstakingergotderivatives.

Patientstakinganyofcisapride,pimozide,astemizoleorterfenadine.Elevatedplasmalevelsofcisapride,

pimozideandterfenadinehavebeenreportedinpatientsreceivingconcomitantclarithromycin.Thismayresultin

QTprolongationandcardiacarrhythmiasincludingventriculartachycardia,ventricularfibrillationandTorsade

dePointes.Similareffectshavebeenobservedwithconcomitantadministrationofastemizoleandother

macrolides.

PatientswithcongenitalordocumentedacquiredQTprolongationorwithhypokalaemia(duetotheriskof

prolongationofQT-time).

4.4Specialwarningsandprecautionsforuse

Clarithromycinisprincipallyexcretedbytheliverandkidney.Thisantibioticshouldnotbeadministeredto

paediatricpatientswithhepaticorrenalfailure.Cautionisrequiredwhenadministeringclarithromycinto

childrenwithlesserdegreesofrenalorhepaticinsufficiency.

Patientswhoarehypersensitivetolincosamideantibacterialagents(e.g.lincomycinorclindamycin)mayalsobe

hypersensitivetoclarithromycin.Therefore,cautionisrequiredwhenprescribingclarithromycinforsuch

Weight(kg)* Approximate

ageinyears Doseinmgof

clarithromycinto

begiventwice

daily Doseinmlof

250mg/5ml

oralsuspension

tobegiven

twicedailyby

pipette*** Numberof5ml

spoonfulstobe

giventwice

daily

8-11 1-2 62.5 1.25** ¼**

12-19 3-6 125 2.5 ½

20-29 7-9 187.5 3.75** ¾**

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Prolongedorrepeateduseofclarithromycinmayresultinsuperinfectionswithinsusceptibleorganisms.Incase

ofsuperinfection,clarithromycintherapyshouldbestopped.

Pseudomembranouscolitishasbeenreportedwiththeuseofbroad-spectrumantibiotics.Therefore,itis

importanttoconsideritsdiagnosisinpatientswhodevelopseverediarrhoeaduringoraftertherapywith

clarithromycin.

DuetoariskofincreasedQT-interval,clarithromyciniscontraindicatedinpersonswithhypokalaemia,those

withcongenitalordocumentedacquiredQTprolongationandthosetakinganyofthemedicationslistedin

section4.3.Cautionisneededwhenadministeringclarithromycintopatientswithcoronaryvesseldisease,a

historyofventriculararrhythmia,severecardiacinsufficiency,hypomagnesaemia,bradycardia(<50bpm),or

whenco-administeredwithothermedicinalproducts(otherthanlistedinsection4.3)withaQT-prolonging

effect.(seesection4.5).

ClarithromycinshouldbeusedwithcautioninpatientsreceivingtreatmentwithaninducerofCYP3A4(see

section4.5).

ClarithromycinisaninhibitorofCYP3A4.Concomitantusewithmedicinalproductsthataremetabolisedtoa

largeextentbythisenzymeshouldberestrictedtosituationswhereitisclearlyindicated(seesection4.5).

ClarithromycininhibitsthemetabolismofsomeHMG-CoAreductaseinhibitors,whichresultsinincreased

plasmaconcentrationsofthesemedicinalproducts(seesection4.5).

Aswithothermacrolides,clarithromycinmaycauseexacerbationoraggravationofmyastheniagravis.

Each5mlofClarithromycinOralSuspensioncontainsapproximately3gofsucrose.Patientswithrarehereditary

problemsoffructoseintolerance,glucose-galactosemalabsorptionorsucrase-isomaltaseinsufficiencyshouldnottake

thismedicine.

Each5mlofClarithromycinOralSuspensionalsocontainsapproximately20mgofaspartame,whichissourceof

phenylalanine.Thesuspensionshouldnotbeadministeredtochildrenwithphenylketonuria.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

TheeffectofothermedicinalproductsonClarithromycinsuspension

ClarithromycinismetabolisedbytheenzymeCYP3A4.Hence,stronginhibitorsofthisenzymemayinhibitthe

metabolismofclarithromycin,resultinginincreasedplasmaconcentrations.

Ritonavir(200mgthreetimesdaily)hasbeenshowntoinhibitthemetabolismofclarithromycin(500mgtwicedaily),

withanincreaseinC

,C

andAUCof31,182and77%,respectively.Formationoftheactive14-OH-hydroxy

metabolitewasalmostcompletelyinhibited.Ageneraldosereductionisprobablynotrequiredinpatientswithnormal

renalfunction,butthedailydoseofclarithromycinshouldnotexceed1g.Dosereductionshouldbeconsideredin

patientswithrenalimpairment.Forpatientswithacreatinineclearanceof30to60ml/min,theclarithromycindose

shouldbereducedby50%,andatacreatinineclearanceof<30ml/minthedoseshouldbereducedby75%.

ProductsthatareinducersofCYP3A4(e.g.rifampicin,rifabutinphenytoin,carabamazepine,phenobarbital,St.John’s

wort)mayinducethemetabolismofclarithromycin.Thismayresultinsub-therapeuticlevelsofclarithromycinleading

toareducedefficacy.

Itmightbenecessarytoincreasethedoseofclarithromycinandmonitortheefficacyandsafetyofclarithromycin

carefully.FurthermoremonitoringtheplasmalevelsoftheCYP3A4inducermightbenecessarybecausethelatter

couldbeincreasedowingtotheinhibitionofCYP3A4byclarithromycin(seealsotherelevantproductinformationfor

theCYP3A4induceradministered).

Concomitantadministrationofrifabutinandclarithromycinresultedinanincreaseanddecrease,respectively,inserum

level,followedbyanincreasedriskofuveitis.

A39%reductioninAUCforclarithromycinanda34%increaseinAUCfortheactive14-OH-hydroxymetabolitehave

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Omeprazoleandranitidine

Althoughtheplasmaconcentrationsofclarithromycinandomeprazolemaybeincreasedwhentheyareadministered

concurrently,noadjustmenttothedosageisnecessary.Atthedosagesrecommended,thereisnoclinicallysignificant

interactionbetweenclarithromycinandlansoprazole.Increasedplasmaconcentrationsofclarithromycinmayalso

occurwhenitisco-administeredwithantacidsorranitidine.Noadjustmenttothedosageisnecessary.

TheeffectofClarithromycinsuspensiononothermedicinalproducts

ClarithromycinisaninhibitorofthemetabolisingenzymeCYP3A4andthetransportproteinP-glycoprotein.The

degreeofinhibitionwithdifferentCYP3A4substratesisdifficulttopredict.Hence,clarithromycinshouldnotbeused

duringtreatmentwithothermedicinalproductsthataresubstratesforCYP3A4,unlessplasmalevels,therapeuticeffect

oradverseeventsoftheCYP3A4substratecanbecloselymonitored.Duringtherapywithclarithromycin,dose

reductionorinterruptionoftherapywithmedicinalproductsthataresubstratesforCYP3A4maybenecessary.

Ergotvasoconstrictors(e.g.dihydroergotamine,ergotamine)

Casesofergotismduetoincreasedplasmalevelsofergotalkaloidshavebeenreportedwhentheseproductshavebeen

co-administeredwithmacrolides.Thecombinationiscontraindicated(seesection4.3).

MedicinalproductswithapotentialtoprolongQT-interval

Clarithromycinhasbeenreportedtoinhibitthemetabolismofcisaprideandterfenadine,witha2to3-foldincreasein

plasmalevelsreportedforterfenadine.ThishasbeenassociatedwithQT-prolongationandcardiacarrhythmias

includingventriculartachycardia,ventricularfibrillationandtorsadesdepointes.Similarsymptomshavebeen

describedforpatientstreatedwithpimozidewhencombinedwithclarithromycin.Concomitantadministrationof

clarithromycinandterfenadine,cisaprideorpimozideiscontraindicated(seesection4.3)

Caseswithtorsadesdepointeshavebeenreportedinpatientswhereclarithromycinhasbeenco-administeredwith

quinidineordisopyramide.Thesecombinationsshouldthereforebeavoidedorplasmalevelsofquinidineor

disopyramideshouldbecloselymonitoredtoallowdoseadjustment.

Cautioniswarrantedwhenclarithromyinisadministeredtopatientswhoaretakingothermedicinalproductswiththe

potentialtoprolongQTinterval(seesection4.4).

HMG-CoAreductaseinhibitors

ClarithromycininhibitsthemetabolismofsomeHMG-CoAreductaseinhibitors,whichresultsinincreasedplasma

concentrationsofthesemedicinalproducts.Rhabdomyolysisinassociationwithincreasedplasmaconcentrationsof

HMG-CoAreductaseinhibitorshasbeenreportedrarelyinpatientstreatedwithclarithromycinandsimvastatinor

lovastatin.Clarithromycinmayproduceasimilarinteractionwithatorvastatin.Patientsshouldbemonitoredforsigns

andsymptomsofmyopathyduringco-administrationofclarithromycinwiththeseHMGCo-Areductaseinhibitors.

Benzodiazepines

Whenmidazolamwasco-administeredwithclarithromycintablets(250mgtwicedaily),midazolamAUCwas

increased2.7-foldafterintravenousadministrationofmidazolamand7-foldafteroraladministration.Concomitant

administrationoforalmidazolamandclarithromycinshouldbeavoided.Ifintravenousmidazolamisco-administered

withclarithromycin,thepatientmustbecloselymonitoredtoallowdoseadjustment.Thesameprecautionsshouldalso

applytootherbenzodiazepinesthataremetabolisedbyCYP3A4,especiallytriazolamandalprazolam.For

benzodiazepinesthatarenotmetabolisedbyCYP3A4(temazepam,nitrazepam,lorazepam)aninteractionwith

clarithromycinisunlikely.

Ciclosporin,tacrolimusandsirolimus

Concomitantuseoforalclarithromycinandciclosporinortacrolimushaveresultedinmorethana2-foldincreaseof

theC

-levelsofbothciclosporinandtacrolimus.Similareffectsarealsoexpectedforsirolimus.Wheninitiating

treatmentwithclarithromycininpatientsalreadyreceivinganyoftheseimmunosuppressiveagents,plasmalevelsof

ciclosporin,tacrolimusorsirolimusmustbecloselymonitoredandthedosedecreasedasnecessary.When

clarithromycinisdiscontinuedinthesepatients,closemonitoringofplasmalevelsofciclosporin,tacrolimusor

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DigoxinandotheractivesubstancestransportedbyP-glycoprotein

ClarithromycinisapotentinhibitorofthetransportproteinP-glycoprotein(Pgp).Thiscouldgiverisetoincreased

plasmaconcentrationsofactivesubstancesthataretransportedbythismechanismandmayalsoincreasetheir

distributiontoorganshavingPgpasadistributionbarriere.g.CNS.Theplasmaconcentrationofdigoxinmaybe

increasedwhenco-administeredwithclarithromycinandmonitoringofplasmalevelsshouldbeconsideredwhenco-

treatmentwithclarithromycinisinitiatedorterminatedsinceadoseadjustmentmaybewarranted.

Warfarin

Theuseofclarithromycininpatientsreceivingwarfarinmayresultinpotentiationoftheeffectsofwarfarin.

Prothrombintimeshouldbefrequentlymonitoredinthesepatients.

Theophylline

Theadministrationofclarithromycintopatientswhoarereceivingtheophyllinehasbeenassociatedwithanincreasein

serumtheophyllinelevelsandpotentialtheophyllinetoxicity.

Zidovudine

SimultaneousoraladministrationofclarithromycintabletsandzidovudinetoHIVinfectedadultpatientsmayresultin

decreasedsteady-statezidovudinelevels.Thiscanbelargelyavoidedbystaggeringthedosesofclarithromycinand

zidovudineby1-2hours.Nosuchreactionhasbeenreportedinchildren.

4.6Pregnancyandlactation

Pregnancy

Dataontheuseofclarithromycinduringthefirsttrimesterofmorethan200pregnanciesshownoclearevidenceof

teratogeniceffects,orofadverseeffectsonthehealthoftheneonate.Datafromalimitednumberofpregnantwomen

exposedinthefirsttrimesterindicateapossibleincreasedriskofabortions.Todatenootherrelevantepidemiological

dataareavailable.

Datafromanimalstudieshaveshownreproductivetoxicity(seesection5.3).Theriskforhumansisunknown.

Clarithromycinshouldnotbegiventopregnantwomenunlessitisclearlyneeded.

Lactation

Clarithromycinanditsactivemetaboliteareexcretedinbreastmilk.Therefore,diarrhoeaandfungusinfectionofthe

mucousmembranescouldoccurinthebreast-fedinfant,sothatnursingmighthavetobediscontinued.Thepossibility

ofsensitisationshouldbeborninmind.Thebenefitoftreatmentofthemothershouldbeweighedagainstthepotential

riskfortheinfant.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.Whenperformingthese

activitiesthepossibleoccurrenceofdizziness,vertigo,confusionanddisorientation(seesection4.8)shouldbetaken

intoaccount.

4.8Undesirableeffects

Themostfrequentlyreportedeventsinadultstakingclarithromycintabletswerediarrhoea(3%),nausea(3%),

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

Inthissectionundesirableeffectsaredefinedasfollows:

Verycommon(>1/10);common(>1/100,<1/10);uncommon(>1/1,000,<1/100);rare(>1/10,000,<1/1,000);veryrare

(<1/10,000),includingisolatedreports.

Infectionsandinfestations

Common:Oralmonilia

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Bloodandthelymphaticsystemdisorders

Uncommon:Decreasedleukocytelevels

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

Veryrare:QTprolongation,ventriculartachycardiaandTorsadedePointes.

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:Elevatedbloodureanitrogen

Uncommon:Prolongationofprothrombintime,elevatedserumcreatinine,alteredliverfunctiontests(increased

transaminaselevels).

Veryrare:Hypoglycaemiahasbeenobservedespeciallyafterconcomitantadministrationwithantidiabeticmedicinal

productsandinsulin

4.9Overdose

Reportsindicatethattheingestionoflargeamountsofclarithromycincanbeexpectedtoproducegastro-intestinal

symptoms.Onepatientwhohadahistoryofbipolardisorderingested8gramsofclarithromycinandshowedaltered

mentalstatus,paranoidbehaviour,hypokalemiaandhypoxemia.Adversereactionsaccompanyingoverdosageshould

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Aswithothermacrolides,clarithromycinserumlevelsarenotexpectedtobeappreciablyaffectedbyhaemodialysisor

peritonealdialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharamacotherapeuticgroup:macrolides

ATCCode:J01FA09

Generalproperties

Modeofaction

Clarithromycinisasemi-syntheticderivativeoferythromycinA.Itexertsitsantibacterialactionbybindingtothe50s

ribosomalsub-unitofsusceptiblebacteriaandsuppressingproteinsynthesis.The14-hydroxymetaboliteof

clarithromycin,formedinmanbyfirstpassmetabolism,alsohasantimicrobialactivity.TheMICsofthismetabolite

areequalortwo-foldhigherthantheMICsoftheparentcompoundexceptforH.influenzaewherethe14-hydroxy

metaboliteistwo-foldmoreactivethantheparentcompound.

Mechanismsofresistance

Resistanceofgram-positiveorganismstothemacrolidesusuallyinvolvesanalterationoftheantimicrobialbinding

site.TheMLS

typeofresistance,whichmaybeconstitutiveorinducedbyexposuretocertainmacrolidesin

staphylococciandwhichisinducibleinstreptococci,ismediatedbyavarietyofacquiredgenes(ermfamily)encoding

methylasestargetedatthepeptidyltransferasecentreof23SribosomalRNA.Methylationimpedesbindingof

antibacterialstotheribosomeandgivesrisetocross-resistancetomacrolides(allmacrolideswhenconstitutive),

lincosamidesandtypeBstreptograminsbutnottotypeAstreptogramins.Lessfrequentmechanismsofresistance

includeantimicrobialdegradationbyinactivatingenzymessuchasesteraseandactiveeffluxoftheantimicrobialfrom

thebacteria.

Gramnegativeorganismsmaybeintrinsicallyresistanttothemacrolidesbecauseoftheinabilityofthemacrolideto

effectivelypenetratetheoutercellmembrane;macrolideshavingabetterpenetrationmayhaveactivityagainstsome

gram-negativeorganisms.

Gram-negativeorganismsmayalsoproduceribosomalmethylaseormacrolideinactivatingenzymes.

Breakpoints

ThefollowingMICbreakpoints,separatingsusceptible(S)fromresistant(R)organismsaresuggested:

BSACrecommendations:

Forstaphylococci,streptococciandM.catarrhalis:S: 0.5mg/L,R: 1.0mg/L

ForH.influenzae:S:0.5mg/L,R: 32.0mg/L

NCCLSrecommendations:

Forstaphylococci:S: 2.0mg/L,R: 8.0mg/L

Forstreptococci:S: 0.25mg/L,R: 1.0mg/L

ForH.influenzae:S:8.0mg/L,R: 32.0mg/L

Susceptibility

Theprevalenceofacquiredresistancemayvarygeographicallyandwithtimeforselectedspeciesandlocalinformation

onresistanceisdesirable,particularlywhentreatingsevereinfections.Asnecessary,expertadviceshouldbesought

whenthelocalprevalenceofresistanceissuchthattheutilityoftheagentinatleastsometypesofinfectionsis

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Thesusceptibilitypatternofvariousmicro-organismstoclarithromycinispresentedbelow:

*ResistancetomacrolidesamongMRSAiscommonlymorethan50%intheEUandaffectsnearlyallstrainsinsome

areas.

5.2Pharmacokineticproperties

Absorption:

Clarithromycinisrapidlyandwellabsorbedfromthegastrointestinaltract–primarilyinthejejunum-butundergoes

extensivefirst-passmetabolismafteroraladministration.Theabsolutebioavailabilityofa250-mgclarithromycintablet

isapproximately50%.Thebioavailabilityofthesuspensionisidenticaltoorslightlyhigherthanthebioavailabilityof

thetablets.Foodslightlydelaystheabsorptionbutdoesnotaffecttheextentofbioavailability.Therefore,

clarithromycinmaybegivenwithoutregardtofood.Duetoitschemicalstructure(6-O-Methylerythromycin)

clarithromycinisquiteresistanttodegradationbystomachacid.

Peakplasmalevelsof1–2µg/mlclarithromycinwereobservedinadultsafteroraladministrationof250mgtwice

daily.Afteradministrationof500mgclarithromycintwicedailythepeakplasmalevelwas2.8µg/ml.The

pharmacokineticprofileofthesuspensioninchildrencorrespondstothepharmacokineticprofileofthesuspensionin

adults.Inchildrenthefollowingsteady-stateparameterswereobservedaftertheninthdoseinadoseregimenof7,5

mg/kgtwicedailyonaverageforclarithromycin:C

4,60µg/ml,AUC15,7µg.hour/mlandT

2,8hours.The

correspondingaveragevaluesforthe14-OHmetabolitewererespectively:1.64µg/ml,6,69µg.hour/mland2,7hours.

Afteradministrationof250mgclarithromycintwicedailythemicrobiologicallyactive14-hydroxymetaboliteattains

peakplasmaconcentrationsof0.6µg/ml.Steadystateisattainedwithin2daysofdosing.

Distribution:

Clarithromycinpenetrateswellintodifferentcompartments,withanestimatedvolumeofdistributionof200-400L

Clarithromycinprovidesconcentrationsinsometissuesthatareseveraltimeshigherthanthecirculatinglevelofthe

activesubstance.Increasedlevelshavebeenfoundinbothtonsilsandlungtissue.Clarithromycinalsopenetratesthe

Commonlysusceptiblespecies

AerobicGram-negativemicroorganisms

Moraxellacatarrhalis

Anaerobicmicroorganisms

Peptococcusspecies

Peptostreptococcusspecies

Propionibacteriumacnes

Clostridiumperfringens

Othermicroorganisms

Chlamydiapneumoniae

Legionellapneumophila

Mycoplasmapneumoniae

Speciesforwhichacquiredresistancemaybeaproblem

AerobicGram-positivemicroorganisms

Staphylococcusaureus

Staphylococcusaureus(methicillin-resistant)*

Streptococcusagalactiae

Streptococcuspneumoniae

Streptococcuspyogenes

AerobicGram-negativemicroorganisms

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Biotransformationandelimination:

Clarithromycinisrapidlyandextensivelymetabolisedintheliver.MetabolisminvolvesmainlyN-dealkylation,

oxidationandstereospecifichydroxylationatpositionC14.

Thepharmacokineticsofclarithromycinisnon-linearduetosaturationofhepaticmetabolismathighdoses.

Eliminationhalf-lifeincreasedfrom2-4hoursfollowingadministrationof250mgclarithromycintwicedailyto5

hoursfollowingadministrationof500mgclarithromycintwicedaily.Witha250mgevery12hoursdosing,thehalf-

lifeoftheactive14-hydroxymetaboliterangesbetween5to6hours.

Afteroraladministrationofradioactiveclarithromycin70-80%oftheradioactivitywasfoundinthefaeces.

Approximately20-30%ofclarithromycinappearsastheunchangedactivesubstanceintheurine.Thisproportionis

increasedwhenthedoseisincreased.Renalinsufficiencyincreasesclarithromycinlevelsinplasma,ifthedoseisnot

decreased.

Totalplasmaclearancehasbeenestimatedtoapproximately700ml/min,witharenalclearanceofapproximately170

ml/min.

Renalimpairment:Reducedrenalinsufficiencyfunctionresultsinincreasedplasmalevelsofclarithromycinandthe

activemetabolitelevelsinplasma.

5.3Preclinicalsafetydata

TheacuteoralLD50valuesforaclarithromycinsuspensionadministeredto3-dayoldmicewere1290mg/kgformales

and1230mg/kgforfemales.TheLD50valuesin3-dayoldratswere1330mg/kgformalesand1270mg/kgfor

females.Forcomparison,theLD50oforally-administeredclarithromycinisabout2700mg/kgforadultmiceand

about3000mg/kgforadultrats.Theseresultsareconsistentwithotherantibioticsofthepenicillingroup,

cephalosporingroupandmacrolidegroupinthattheLD50isgenerallylowerinjuvenileanimalsthaninadults.

Inbothmiceandrats,bodyweightwasreducedoritsincreasesuppressedandsucklingbehaviourandspontaneous

movementsweredepressedforthefirstfewdaysfollowingdrugadministration.Necropsyofanimalsthatdied

discloseddark-reddishlungsinmiceandabout25%oftherats;ratstreatedwith2197mg/kgormoreofa

clarithromycinsuspensionwerealsonotedtohaveareddish-blacksubstanceintheintestines,probablybecauseof

bleeding.Deathsoftheseanimalswereconsideredduetodebilitationresultingfromdepressedsucklingbehaviouror

bleedingfromtheintestines.

Pre-weaningrats(5daysold)wereadministeredaclarithromycinsuspensionformulationfortwoweeksatdosesof0,

15,55and200mg/kg/day.Animalsfromthe200mg/kg/daygrouphaddecreasedbody-weightgains,decreasedmean

haemoglobinandhaematocritvalues,andincreasedmeanrelativekidneyweightscomparedtoanimalsfromthecontrol

group.Treatment-relatedminimaltomildmultifocalvacuolardegenerationoftheintrahepaticbileductepitheliumand

anincreasedincidenceofnephriticlesionswerealsoobservedinanimalsfromthistreatmentgroup.The"no-toxic

effect"dosageforthisstudywas55mg/kg/day.

Anoraltoxicitystudywasconductedinwhichimmatureratswereadministeredaclarithromycinsuspension(granules

forsuspension)for6weeksatdailydosagesof0,15,50and150mgbase/kg/day.Nodeathsoccurredandtheonly

clinicalsignobservedwasexcessivesalivationforsomeoftheanimalsatthehighestdosagefrom1to2hoursafter

administrationduringthelast3weeksoftreatment.Ratsfromthe150mg/kgdosegrouphadlowermeanbodyweights

duringthefirstthreeweeks,andwereobservedtohavedecreasedmeanserumalbuminvaluesandincreasedmean

relativeliverweightcomparedtothecontrols.

Notreatment-relatedgrossormicroscopichistopathologicalchangeswerefound.Adosageof150mg/kg/dayproduced

slighttoxicityinthetreatedratsandthe"noeffectdosage"wasconsideredtobe50mg/kg/day.

Juvenilebeagledogs,3weeksofage,weretreatedorallydailyforfourweekswith0,30,100,or300mg/kgof

clarithromycin,followedbya4-weekrecoveryperiod.Nodeathsoccurredandnochangesinthegeneralconditionof

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Uponhistologicalexamination,fattydepositionofcentrilobularhepatocytesandcellinfiltrationofportalareaswere

observedbylightmicroscopyandanincreaseinhepatocellularfatdropletswasnotedbyelectronmicroscopyinthe

300mg/kgdosegroup.Thetoxicdoseinjuvenilebeagledogswasconsideredtobegreaterthan300mg/kgandthe

"noeffectdose"100mg/kg.

Fertility,ReproductionandTeratogenicity

Fertilityandreproductionstudieshaveshowndailydosagesof150-160mg/kg/daytomaleandfemaleratscausedno

adverseeffectsontheoestruscycle,fertility,parturitionandnumberandviabilityofoffspring.Twoteratogenicity

studiesinbothWistar(p.o.)andSprague-Dawley(p.o.andi.v.)rats,onestudyinNewZealandwhiterabbitsandone

studyincynomolgusmonkeysfailedtodemonstrateanyteratogenicityfromclarithromycin.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Microcrystallinecellulose

Hypromellose

Hydroxypropylcellulose

Croscarmellosesodium

Alginicacid

Methacrylicacid–ethylacrylatecopolymer(1:1)dispersion30%

Macrogol1500

Talc

Carbomer(Carbopol974P)

Colloidalanhydroussilica

Sucrose

Aspartame(E951)

Xanthangum

Monosodiumcitrate

Sodiumbenzoate(E211)

Titaniumdioxide(E171)

Peppermintflavour

Tuttifruttiflavour

Sodiumchloride

6.2Incompatibilities

Notapplicable

6.3ShelfLife

2years(granules),

14days(reconstitutedsuspension)

6.4Specialprecautionsforstorage

Granules:Nospecialrequirementsforstorage.

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6.5Natureandcontentsofcontainer

NaturaltranslucentHDPEbottlewhite,opaque,childresistantcaphavinginductionsealliner.

NaturaltranslucentHDPEbottlewithcontinuousringmarkforfillingvolumeandwhite,opaque,childresistantcap

havinginductionsealliner.

NaturaltranslucentPP/HDPEdosingpipettehavingfillingmarksforweightandvolumeandLDPEcapadapter.

Transparentpolystyrenemeasuringspoonwithfillmarksat2.5mland5.0ml

PackSize–50,60,70,100or140ml.Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Preparationforuse:

Requiredquantityofwatershouldbeaddedtothegranulesinthebottleandshakenwell.Theconcentrationof

clarithromycininthereconstitutedsuspensionis250mgper5ml.

Thequantityofwaterrequiredforeachpackistabulatedbelow:

Afterreconstitutionwithwater,theproductresultsinawhitetooff-whitesuspension.

7MARKETINGAUTHORISATIONHOLDER

RanbaxyIrelandLtd

Spafield,

CorkRoad,

Cashel,

Co.Tipperary

Ireland

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

2ndJune2006

Pack Volumeofwatertobe

added

50mlBottle 28ml

60mlBottle 34ml

70mlBottle 40ml

100mlBottle 55ml

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