CLARITHROMYCIN

Main information

  • Trade name:
  • CLARITHROMYCIN Film Coated Tablet 250 Milligram
  • Dosage:
  • 250 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CLARITHROMYCIN Film Coated Tablet 250 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0822/103/001
  • Authorization date:
  • 29-06-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ClarithromycinPfizer250mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains250mgclarithromycin.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Lightyellowcoloured,ovalshaped,biconvexfilm-coatedtablets,with‘D’debossedononesideand‘62’ontheother

side.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Clarithromycinisindicatedforthetreatmentofthefollowinginfectionscausedbyclarithromycinsusceptibleorganisms

(seesections4.4and5.1).

Bacterialpharyngitis

Mildtomoderatecommunity-acquiredpneumonia

Acutebacterialsinusitis(adequatelydiagnosed)

Acuteexacerbationofchronicbronchitis

Skinandsofttissueinfectionsofmildtomoderateseverity.

Inappropriatecombinationwithantibacterialtherapeuticregimensandanappropriateulcerhealingmedicinalproduct

fortheeradicationofHelicobacterpyloriinadultpatientswithHelicobacterpylori-associatedulcers(seesection4.2).

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantibacterialagents.

4.2Posologyandmethodofadministration

Posology:

ThedosageofClarithromycinfilm-coatedtabletsdependsonthetypeandseverityoftheinfectionandhastobe

definedinanycasebythephysician.

Adultsandadolescents:

Standarddosage:Theusualdoseis250mgtwicedaily(inthemorningandintheevening)

Highdosagetreatment(severeinfections):Theusualdosemaybeincreasedto500mgtwicedailyinsevere

infections.

EradicationofHelicobacterpyloriinadults:

Inpatientswithgastro-duodenalulcersduetoHelicobacterpyloriinfectionclarithromycinisgiveninadosageof500

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Childrenupto12yearsofage:

Therecommendeddoseis7.5mg/kgtwiceaday(inthemorningandintheevening).

Weight Dosage

30–40kg 250mgtwicedaily

Clarithromycinintheformoftabletisnotsuitableforchildrenupto12yearsofageorhavinglessthan30kgbody

weight.Otherpharmaceuticalformsareavailableforthesepatients.

Durationoftherapy:

Thedurationoftherapywithclarithromycindependsonthetypeandseverityoftheinfection.

Theusualdurationoftreatmentis7to14days.

Dosageinrenalfunctionalimpairment:

Dosageadjustmentsarenotusuallyrequiredexceptinpatientswithsevererenalimpairment(creatinineclearance<30

ml/min(<0.5ml/s)).Ifadjustmentofdoseisnecessary,thetotaldailydosageshouldbereducedbyhalf.

Thedurationoftreatmentshouldnotexceed14daysinthesepatients.

Patientswithhepaticimpairment:

Cautionshouldbeexercisedwhenadministratingclarithromycininpatientswithhepaticimpairment(seesection4.3.

and4.4).

Methodofadministration:

Thetabletshouldbeswallowedwithasufficientamountoffluid(e.g.oneglassofwater).

Clarithromycinmaybegivenirrespectiveoffoodintake.

4.3Contraindications

Clarithromyciniscontra-indicatedinpatientswithknownhypersensitivitytoclarithromycin,toanyothermacrolide

antibiotics,ortoanyoftheexcipients.

Clarithromyciniscontraindicatedinpatientswithserioushepaticfailure.

Clarithromycinandergotderivativesshouldnotbeco-administered(seesection4.5).

Concomitantadministrationofclarithromycinandanyofthefollowingactivesubstancesiscontraindicated:

cisapride,pimozideandterfenadine.Elevatedcisapride,pimozideandterfenadinelevelshavebeenreportedinpatients

receivingeitheroftheseactivesubstancesandclarithromycinconcomitantly.ThismayresultinQTprolongationand

cardiacarrhythmiasincludingventriculartachycardia,ventricularfibrillationandTorsadedePointes.Similareffects

havebeenobservedwithconcomitantadministrationofastemizoleandothermacrolides(seesection4.5).

Concomitantadministrationwithsimvastatineiscontraindicated.

Clarithromycinshouldnotbeadministeredtohypokalaemicpatients(prolongationofQT-time,seesection4.4).

4.4Specialwarningsandprecautionsforuse

ClarithromycinshouldbereservedfordocumentedGroupAbeta-hemolyticstreptococcalpharyngitiswhen

treatmentwithbeta-lactamscannotbeused.

Clarithromycinismainlyexcretedbytheliver.Therefore,clarithromycinshouldbeadministeredwithcautionin

patientswithimpairedhepaticfunction,especiallyinpatientswithimpairedrenalfunction.

Whenrenalfunctionispoor,dosageofclarithromycinshouldbesuitablyreduceddependingonthedegreeofthe

impairment(seesection4.2).Inelderlypatients,thepossibilityofrenalimpairmentshouldbeconsidered.

ClarithromycintherapyforH.pylorimayselectfordrug-resistantorganisms.

Patientswhoarehypersensitivetolincomycinorclindamycinmayalsobehypersensitivetoclarithromycin.

Therefore,cautionisrequiredwhenprescribingclarithromycinforsuchpatients.

Prolongedorrepeateduseofclarithromycinmayresultinanovergrowthofnon-susceptiblebacteriaorfungi.If

super-infectionoccurs,clarithromycinshouldbediscontinuedandappropriatetherapyinstituted.

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wellaslincomycinandclindamycin.

Pseudomembranouscolitishasbeenreportedwiththeuseofbroad-spectrumantibiotics.Therefore,itisimportantto

consideritsdiagnosisinpatientswhodevelopseverediarrhoeaduringoraftertherapywithclarithromycin.

Asknownforothermacrolides,clarithromycinmaycauseexacerbationoraggravationofmyastheniagravisand

shouldthereforebeusedwithcautioninpatientswithmyastheniagravis.

DuetoariskofprolongedQT-interval,clarithromycinshouldbeusedwithcautioninpatientswithacoronaryvessel

disease,ahistoryofventriculararrhythmia,severecardiacinsufficiency,non-compensatedhypokalemiaand/or

hypomagnesemia,bradycardia(<50bpm),orwhenco-administeredwithothermedicinalproductswithaQT-

prolongingeffect.ClarithromycinshouldnotbeusedinpatientswithcongenitalordocumentedacquiredQT

prolongation(seesections4.3&4.5).

Theuseofclarithromycinshouldbeconsideredwithparticularcautionwheneverapatientisreceivingtreatmentwith

anothermedicinalproductknowntobesubstrateofCYP3A4,especiallywhenpatientistreatedwithaCYP3A4

substratehavingnarrowtherapeuticindex(likecarbamazepin)and/orismetabolisedtoalargeextentbythisenzyme

clarithromycinshouldnotbeusedunlessclearlyindicated(seesection4.5).

ClarithromycininhibitsthemetabolismofsomeHMG-CoAreductaseinhibitors,whichresultsinincreasedplasma

concentrationsofthesemedicinalproducts(seesection4.5).`

Therehavebeenpost-marketingreportsofcolchicinetoxicitywithconcomitantuseofclarithromycinandcolchicine,

especiallyintheelderly,someofwhichoccurredinpatientswithrenalinsufficiency.Deathshavebeenreportedin

somesuchpatients(seesection4.5).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Theuseofthefollowingdrugsisstrictlycontraindicatedduetothepotentialforseveredruginteractioneffects:

Cisapride,pimozide,terfenadineandastemizole

Clarithromycinhasbeenreportedtoelevateplasmalevelsofcisapride,pimozide,astemizole,andterfenadine.

Increasedlevelsofthesedrugsmayresultinincreasedriskofventricularrhythmdisorders,especiallyTorsadesde

Pointes.

Concomitantadministrationofclarithromycinandanyofthesemedicinalproductsiscontraindicated(seesection4.3).

Ergotamine/dihydroergotamine

Post-marketingreportsindicatethatcoadministrationofclarithromycinwithergotamineordihydroergotaminehasbeen

associatedwithacuteergottoxicitycharacterizedbyvasospasm,andischemiaoftheextremitiesandothertissues

includingthecentralnervoussystem.

Concomitantadministrationofclarithromycinandthesemedicinalproductsiscontraindicated(seesection4.3).

Theeffectofothermedicinalproductsonclarithromycin:

ClarithromycinismetabolisedbytheenzymeCYP3A4.Hence,stronginhibitorsofthisenzymemayinhibitthe

metabolismofclarithromycin,resultinginincreasedplasmaconcentrationsofclarithromycin.

Concomitantadministrationofclarithromycinandantimycoticsoftheazoleclass(fluconazol,itraconazol,ketoconazol)

increasestheriskofcardialtoxicity(prolongedQT-interval,TorsadesdesPointes,cardiacarrest).

Fluconazole:

Concomitantadministrationoffluconazole200mgdailyandclarithromycin500mgtwicedailyto21healthy

volunteersledtoincreasesinthemeansteady-stateminimumclarithromycinconcentration(C

)andareaunderthe

curve(AUC)of33%and18%respectively.Steadystateconcentrationsoftheactivemetabolite14(R)-hydroxy-

clarithromycinwerenotsignificantlyaffectedbyconcomitantadministrationoffluconazole.

Ritonavir:

Ritonavir(200mgthreetimesdaily)havebeenshowntoinhibitthemetabolismofclarithromycin(500mgtwice

daily.),withanincreaseinC

,C

andAUCof31,182and77%,respectively,whenco-administeredwith

ritonavir.Formationoftheactive14-OH-hydroxymetabolitewasalmostcompletelyinhibited.Ageneraldose

reductionisprobablynotrequiredinpatientswithnormalrenalfunction,butthedailydoseofclarithromycinshould

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Forpatientswithacreatinineclearanceof30to60ml/min(0.5-1ml/s),theclarithromycindoseshouldbereduced

with50%,andatacreatinineclearanceof<30ml/min(<0.5ml/s)thedoseshouldbereducedwith75%.

MedicinalProductsthatareinducersofCYP3A4(e.g.efavirenz,nevirapine,rifampicin,phenytoin,carbamazepine,

phenobarbital,St.Johnswort)mayinducethemetabolismofclarithromycin.Thismayresultinsub-therapeuticlevels

ofclarithromycinleadingtoareducedefficacy.

Concomitantadministrationofrifabutinandclarithromycinresultedinanincreaseanddecrease,respectively,inserum

levels,followedbyanincreasedriskofuveitis.

A39%reductioninAUCforclarithromycinanda34%increaseinAUCfortheactive14-OH-hydroxymetabolitehave

beenseenwhenclarithromycinwasusedconcomitantlywiththeCYP3A4inducerefavirenz.

Theeffectofclarithromycinonothermedicinalproducts

ClarithromycinisaninhibitorofthemetabolizingenzymeCYP3A4andthetransportproteinP-glycoprotein.The

degreeofinhibitionwithdifferentCYP3A4substratesisdifficulttopredict.Hence,clarithromycinshouldnotbeused

duringtreatmentwithothermedicinalproductsthataresubstratesforCYP3A4,unlessplasmalevels,therapeuticeffect

oradverseeventsoftheCYP3A4substratecanbecloselymonitored.Adosereductionmaybenecessary.

Sildenafil,tadalafil,andvardenafil

Eachofthesephosphodiesteraseinhibitorsismetabolized,atleastinpart,byCYP3A,andCYP3Amaybeinhibitedby

concomitantlyadministeredclarithromycin.Coadministrationofclarithromycinwithsildenafil,tadalafilorvardenafil

mayresultinincreasedphosphodiesteraseinhibitorexposure.

Reductionofsildenafil,tadalafilandvardenafildosagesshouldbeconsideredwhencoadministeredwith

clarithromycin.

Co-administrationwithmedicinalproductswithapotentialtoprolongQT-interval:

Casesoftorsadesdepointeshasbeenreportedinpatientswhereclarithromycinhasbeenco-administeredwith

quinidineordisopyramide.Thesecombinationsshouldthereforebeavoided,orplasmalevelsofquinidineor

disopyramidecloselymonitoredtoallowdoseadjustment.

HMG-CoAreductaseinhibitors:

ClarithromycininhibitsthemetabolismofsomeHMG-CoAreductaseinhibitors,whichresultsinincreasedplasma

concentrationsofthesemedicinalproducts.Rhabdomyolysisinassociationwithincreasedplasmaconcentrationshave

inrarecasesbeenreportedinpatientstreatedwithclarithromycinandsimvastatinorlovastatin.Clarithromycinmay

produceasimilarinteractionwithatorvastatinandalesserinteractionwithcerivastatin.Whentreatmentwith

clarithromycinisindicatedinpatientsreceivingstatintreatment,therapywithstatinsshouldbesuspendedduringthe

courseoftreatment.

Tolterodine

Theprimaryrouteofmetabolismfortolterodineisviathe2D6isoformofcytochromeP450(CYP2D6).However,ina

subsetofthepopulationdevoidofCYP2D6,theidentifiedpathwayofmetabolismisviaCYP3A.

Inthispopulationsubset,inhibitionofCYP3Aresultsinsignificantlyhigherserumconcentrationsoftolterodine.A

reductionintolterodinedosagemaybenecessaryinthepresenceofCYP3Ainhibitors,suchasclarithromycininthe

CYP2D6poormetabolizerpopulation.

Benzodiazepines

Whenmidazolamwasco-administeredwithclarithromycintablets(250mgtwicedaily),midazolamAUCwas

increased2.7-foldafterintravenousadministrationofmidazolamand7-foldafteroraladministration.Concomitant

administrationoforalmidazolamandclarithromycinshouldbeavoided.Ifintravenousmidazolamisco-administered

withclarithromycin,thepatientmustbecloselymonitoredtoallowdoseadjustment.Thesameprecautionsshouldalso

applytootherbenzodiazepinesthataremetabolisedbyCYP3A4,especiallytriazolambutalsoalprazolam.For

benzodiazepineswhicharenotmetabolisedbyCYP3A4(temazepam,nitrazepam,lorazepam)aninteractionwith

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Omeprazole

TheAUCofomeprazoleisincreasedby89%whenadministeredconcomitantlywithclarithromycinforH.pylori

eradication;howeverthechangeinthemean24-hourgastricpHvaluefrom5.2(omeprazolealone)to5.7(omeprazole

+clarithromycin)isnotconsideredclinicallysignificant.

Therearenoin-vivohumandataavailabledescribinganinteractionbetweenclarithromycinandthefollowingdrugs:

aprepitant,eletriptan,halofantrine,andziprasidone.However,becauseinvitrodatasuggestthesedrugsareCYP3A

substrates,cautionshouldbeusedwhentheyareco-administeredwithclarithromycin.

Eletriptanshouldnotbeco-administeredwithCYP3Ainhibitorssuchasclarithromycin.

TherehavebeenspontaneousorpublishedreportsofdruginteractionsofCYP3Ainhibitors,includingclarithromycin,

withcyclosporine,tacrolimus,methylprednisolone,vinblastine,andcilostazol.

Cyclosporin,tacrolimusandsirolimus:

Concomitantuseoforalclarithromycinhasresultedinmorethana2-foldincreaseoftheC

levelsofboth

cyclosporinandtacrolimus.Similareffectsarealsoexpectedforsirolimus.Wheninitiatingtreatmentwith

clarithromycininpatientsalreadyreceivinganyoftheseimmunosuppressiveagents,cyclosporin,tacrolimusor

sirolimusplasmalevelsmustbecloselymonitoredandtheirdosesdecreasedasnecessary.Whenclarithromycinis

discontinuedinthesepatients,closemonitoringofplasmalevelsofcyclosporine,tacrolimusorsirolimus,isagain

necessarytoguidedoseadjustment.

DigoxinandotheractivesubstancestransportedbyP-glycoprotein

TheconcentrationofthePgpsubstratedigoxinmaybeincreasedwhenco-administeredwithclarithromycin.

Monitoringofplasmalevelsofdigoxinshouldbeconsideredwhenco-treatmentwithclarithromycinisinitiatedor

terminatedsinceadoseadjustmentmaybewarranted.

Anti-diabeticproducts

AfterconcomitantadministrationofClarithromycinwithinsulinandotheranti-diabeticmedicinalproducts

Hypoglycaemiahasbeenobserved.

Themechanismforthisphenomenonisnotfullyunderstood,thoughitmayberelatedtopharmacokineticinteraction

betweenclarithromycinandsomeoralantidiabetics.Inhealthysubjects,theuseofclarithromycin250mgtwicedaily

fortwodaysincreasedglibenclamideplasmalevels(0.875mgsingledose)with1.3fold,possiblybyinhibitingP-

glycoproteinintheintestinalwall.Inastudyinhealthyvolunteers,clarithromycinuse(250mgtwicedailyfor5days)

increasestheplasmalevelsofrepaglinide(0.25mgsingledose)with40%,possiblybyinhibitingCYP3A4enzymesby

clarithromycin.

Warfarin:

Theuseofclarithromycininpatientsreceivingwarfarinmayresultinpotentiationoftheeffectsofwarfarin.

Prothrombintimeshouldbefrequentlymonitoredinthesepatients.

Theophylline:

Theadministrationofclarithromycintopatientswhoarereceivingtheophyllinehasbeenassociatedwithanincreasein

serumtheophyllinelevelsandpotentialtheophyllinetoxicity.

Zidovudine:

SimultaneousoraladministrationofclarithromycinandzidovudinetoHIVinfectedadultpatientsmayresultin

decreasedsteady-statezidovudinelevels.Thiscanbelargelyavoidedbystaggeringthedosesofclarithromycinand

zidovudineby1-2hours.Nosuchreactionhasbeenreportedinchildren.

Colchicine

ColchicineisasubstrateforbothCYP3Aandtheeffluxtransporter,P-glycoprotein(Pgp).Clarithromycinandother

macrolidesareknowntoinhibitCYP3AandPgp.Whenclarithromycinandcolchicineareadministeredtogether,

inhibitionofPgpand/orCYP3Abyclarithromycinmayleadtoincreasedexposuretocolchicine.Patientsshouldbe

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Phenytoinandvalproate

TherehavebeenspontaneousorpublishedreportsofinteractionswithCYP3Ainhibitors,includingclarithromycin,and

drugsnotthoughttobemetabolisedbyCYP3A,includingphenytoinandvalproate.

Serumleveldeterminationsarerecommendedforthesedrugswhenadministeredconcomitantlywithclarithromycin.

Increasedconcentrationshavebeenreported.

Bidirectionalpharmacokineticinteractions

Atazanavir

BothclarithromycinandatazanaviraresubstratesandinhibitorsofCYP3A,andthereisevidenceofabi-directional

druginteraction.Co-administrationofclarithromycin(500mgtwicedaily)withatazanavir(400mgoncedaily)

resultedina2-foldincreaseinexposuretoclarithromycinanda70%decreaseinexposureto14(R)-

hydroxyclarithromycin,witha28%increaseintheAUCofatazanavir.

Becauseofthelargetherapeuticwindowforclarithromycin,nodosagereductionshouldbenecessaryinpatientswith

normalrenalfunction.

Forpatientswithmoderaterenalfunction(creatinineclearance30to60ml/min),thedoseofclarithromycinshouldbe

decreasedby50%.

Forpatientswithcreatinineclearance<30ml/min,thedoseofclarithromycinshouldbedecreasedby75%usingan

appropriateclarithromycinformulation,suchasimmediate-releasetablets,sachet,orpaediatricsuspensions(notall

presentationsmaybemarketed).

Dosesofclarithromycingreaterthan1000mgperdayshouldnotbeco-administeredwithproteaseinhibitors.

Itraconazole

BothclarithromycinanditraconazolearesubstratesandinhibitorsofCYP3A,leadingtoabidirectionaldrug

interaction:Clarithromycinmayincreasetheplasmalevelsofitraconazole,whileitraconazolemayincreasetheplasma

levelsofclarithromycin.

Patientstakingitraconazoleandclarithromycinconcomitantlyshouldbemonitoredcloselyforsignsorsymptomsof

increasedorprolongedpharmacologiceffect.

Saquinavir

BothclarithromycinandsaquinaviraresubstratesandinhibitorsofCYP3A,andthereisevidenceofabidirectional

druginteraction.

Concomitantadministrationofclarithromycin(500mgbid)andsaquinavir(softgelatinecapsules,1200mgtid)to12

healthyvolunteersresultedinsteady-stateareaunderthecurve(AUC)andmaximumconcentration(Cmax)valuesof

saquinavir,whichwere177%and187%higherthanthoseseenwithsaquinaviralone.

ClarithromycinAUCandCmaxvalueswereapproximately40%higherthanthoseseenwithclarithromycinalone.

Nodoseadjustmentisrequiredwhenthetwodrugsareco-administeredforalimitedtimeatthedoses/formulations

studied.

Observationsfromdruginteractionstudiesusingthesoftgelatincapsuleformulationmaynotberepresentativeofthe

effectsseenusingthesaquinavirhardgelatincapsule.

Observationsfromdruginteractionstudiesdonewithunboostedsaquinavirmaynotberepresentativeoftheeffects

seenwithsaquinavir/ritonavirtherapy.Whensaquinavirisco-administeredwithritonavir,considerationshouldbe

giventothepotentialeffectsof

ritonavironclarithromycin(seesectionabove,effectofothermedicinalproductsonclarithromycin).

4.6Fertility,pregnancyandlactation

Pregnancy:

Dataontheuseofclarithromycinduringthefirsttrimesterofmorethan200pregnanciesshownoclearevidenceof

teratogeniceffectsoradverseeffectsonthehealthoftheneonate.Datafromalimitednumberofpregnantwomen

exposedinthefirsttrimesterindicateapossibleincreasedriskofabortions.Todatenootherrelevantepidemiological

dataareavailable.

Datafromanimalstudieshaveshownreproductivetoxicity(seesection5.3).Theriskforhumansisunknown.

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Lactation:

Clarithromycinanditsactivemetaboliteareexcretedinbreastmilk.Therefore,diarrhoeaandfungusinfectionofthe

mucousmembranescouldoccurinthebreast-fedinfant,sothatnursingmighthavetobediscontinued.Thepossibility

ofsensitisationshouldbeborneinmind.Thebenefitoftreatmentofthemothershouldbeweighedagainstthepotential

riskfortheinfant.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.Whenperformingthese

activitiesthepossibleoccurrenceoftheadversereactionsdizziness,vertigo,confusionanddisorientationshouldbe

takenintoaccount.

4.8Undesirableeffects

Themostfrequentlyreportedeventsinadultstakingclarithromycinwerediarrhoea(3%),nausea(3%),abnormaltaste

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

Inthissectionundesirableeffectsaredefinedasfollows:

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).

Investigations:

Common: Elevatedbloodureanitrogen(BUN)

Uncommon:Prolongationofprothrombintime,elevatedserumcreatinine,alteredliverfunctiontests(increased

transaminaselevels).

Veryrare:Hypoglycaemiahasbeenobservedespeciallyafterconcomitantadministrationwithantidiabeticmedicinal

productsandinsulin.

Cardiacdisorders:

Veryrare:QTprolongation,ventriculartachycardiaandtorsadedepointes.

Bloodandthelymphaticsystemdisorders:

Uncommon:Decreasedleukocytelevels.

Veryrare:Thrombocytopenia.

Nervoussystemdisorders:

Common:Headache,smellalteration.

Veryrare:Dizziness,vertigo,paraesthesia,convulsions.

Earandlabyrinthdisorders:

Rare: Tinnitus.

Veryrare:Reversiblehearingloss.

Gastrointestinaldisorders:

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

discoloration,andtasteperversion,i.e.metallicorbittertaste.

Veryrare:Pancreatitis.Pseudomembranouscolitishasbeenreportedveryrarelywithclarithromycin,andmayrangein

severityfrommildtolifethreatening.

Renalandurinarydisorders:

Veryrare:Interstitialnephritis,renalfailure.

Skinandsubcutaneoustissuedisorders:

Veryrare: Stevens-Johnsonsyndromeandtoxicepidermalnecrolysis.

Musculoskeletalandconnectivetissuedisorders:

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Infectionsandinfestations:

Common:Oralmonilia

Aswithotherantibiotics,prolongedusemayresultintheovergrowthofnon-susceptibleorganisms.

Immunesystemdisorders:

Uncommon:Allergicreactionsrangingfromurticariaandmildskineruptionstoanaphylaxis.

Hepato-biliarydisorders:

Uncommon:Hepaticdysfunction,whichisusuallytransientandreversible,hepatitisandcholestasiswithorwithout

jaundice.

Veryrare: Fatalhepaticfailurehasbeenreportedparticularlyinpatientswithpre-existingliverdiseaseortaking

otherhepatotoxicmedicinalproducts.

Psychiatricdisorders:

Uncommon:Depression

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

Therehavebeenpost-marketingreportsofcolchicinetoxicitywithconcomitantuseofclarithromycinandcolchicine,

especiallyintheelderly,someofwhichoccurredinpatientswithrenalinsufficiency.Deathshavebeenreportedin

somesuchpatients(seesection4.4and4.5).

Aftertakingthisproduct,somecasesofgranulocytopeniahaveoccurred.;Thesesymptomsdisappearafterstopping

thetreatment(seesection4.4).

4.9Overdose

Symptomsofintoxification:

Reportsindicatethattheingestionoflargeamountsofclarithromycincanbeexpectedtoproducegastro-intestinal

symptoms.Symptomsofoverdosemaylargelycorrespondtotheprofileofadversereactions.Onepatientwhohada

historyofbipolardisorderingested8gramsofclarithromycinandshowedalteredmentalstatus,paranoidbehaviour,

hypokaliaemiaandhypoxaemia.

Therapyofintoxification:

Thereisnospecificantidoteonoverdose.Serumlevelsofclarithromycincannotbereducedbyhaemodialysisor

peritonealdialysis.

Adversereactionsaccompanyingoverdosageshouldbetreatedbygastriclavageandsupportivemeasures.Severe

acuteallergicreactionsmaybeseenveryrarely,e.g.anaphylacticshock.Atthefirstsignsofhypersensitivityreactions

therapywithclarithromycinmustbediscontinuedandtherequiredmeasuresshouldbeinitiatedimmediately.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Generalproperties

ATCClassification:

Pharamacotherapeuticgroup:Macrolides

ATCCode:J01FA09

Modeofaction:

Clarithromycin,asemi-syntheticderivativeoferythromycin,exertsitsantibacterialactionbybindingtothe50s

ribosomalsub-unitofsusceptiblebacteriaandsuppressesproteinsynthesis.Itishighlypotentagainstawidevarietyof

aerobicandanaerobicgram-positiveandgram-negativeorganisms.Theminimuminhibitoryconcentrations(MICs)of

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The14-hydroxymetaboliteofclarithromycinalsohasantimicrobialactivity.TheMICsofthismetaboliteareequalor

two-foldhigherthantheMICsoftheparentcompound,exceptforH.influenzaewherethe14-hydroxymetaboliteis

two-foldmoreactivethantheparentcompound.

PK/PDRelationship

Clarithromycinisextensivelydistributedinbodytissuesandfluids.Becauseofhightissuepenetration,intracellular

concentrationsarehigherthanserumconcentrations.

Themostimportantpharmacodynamicparametersforpredictingmacrolideactivityarenotconclusivelyestablished.

ThetimeaboveMIC(T/MIC)maycorrelatebestwithefficacyforclarithromycin,howeversinceclarithromycin

concentrationsachievedinrespiratorytissuesandepithelialliningfluidsexceedthoseinplasma,usingparameters

basedonplasmaconcentrationsmayfailtopredictaccuratelytheresponseforrespiratorytractinfections.

MechanismofResistance:

Resistancemechanismsagainstmacrolideantibioticsincludealterationofthetargetsiteoftheantibioticorarebased

onthemodificationand/oractiveeffluxoftheantibiotic.

Resistancedevelopmentcanbemediatedviachromosomesorplasmids,beinducedtoexistconstitutively.Macrolide-

resistantbacteriagenerateenzymeswhichleadtomethylationofresidualadenineatribosomalRNAandconsequently

toinhibitionoftheantibioticbindingtotheribosome.Macrolide-resistantorganismsaregenerallycross-resistantto

lincosamidesandstreptogramineBbasedonmethylationoftheribosomalbindingsite.Clarithromycinranksamong

thestronginducersofthisenzymeaswell.Furthermore,macrolideshaveabacteriostaticactionbyinhibitingthe

peptidyltransferaseofribosomes.

Acompletecross-resistanceexistsamongclarithromycin,erythromycinandazithromycin.Methicillin-resistant

staphyllococciandpenicillin-resistantStreptococcuspneumoniaareresistanttomacrolidessuchasclarithromycin.

Breakpoints:

Thefollowingbreakpointsforclarithromycin,separatingsusceptibleorganismsfromresistantorganisms,havebeen

establishedbytheEuropeanCommitteeforAntimicrobialSusceptibilityTesting(EUCAST)2010-04-27(v1.1)

A.Non-speciesrelatedbreakpointshavebeendeterminedmainlyonthebasisofPK/PDdataandareindependentof

MICdistributionsofspecificspecies.Theyareforuseonlyforspeciesnotmentionedinthetableorfootnotes

However,pharmacodynamicdataforcalculationofmacrolide,lincosaminesandstreptograminsnon-speciesrelated

breakpointsarenotrobust,henceIE.

B.Erythromycincanbeusedtodeterminethesusceptibilityofthelistedbacteriatotheothermacrolides(azithromycin,

clarithromycinandroxithromycin

C.ClarithromycinisusedfortheeradicationofH.pylori(MIC ≤0.25mg/Lforwildtypeisolates).

D.ThecorrelationbetweenH.influenzaemacrolideMICsandclinicaloutcomeisweak.Therefore,breakpointsfor

macrolidesandrelatedantibioticsweresettocategorisewildtypeH.influenzaeasintermediate.

ClarithromycinisusedfortheeradicationofH.pylori;minimuminhibitoryconcentration(MIC) ≤0.25µg/mlwhich

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Theprevalenceofacquiredresistanceratesmayvarygeographicallyandwithtimeforselectedspeciesandlocal

informationonresistanceisdesirable,particularlywhentreatingsevereinfections.Asnecessary,expertadviceshould

besoughtwhenthelocalprevalenceofresistanceissuchthattheutilityofanagentinatleastsometypesofinfections

isquestionable.

Susceptibility:

Theprevalenceofacquiredresistancemayvarygeographicallyandwithtimeforselectedspeciesandlocalinformation

onresistanceisdesirable,particularlywhentreatingsevereinfections.Asnecessary,expertadviceshouldbesought

whenthelocalprevalanceofresistanceissuchthattheutilityoftheagentinatleastsometypesofinfectionsis

questionable.

Commonlysusceptiblespecies

Aerobic,Gram-positivemicroorganisms

StreptococcusgroupF

Corynebacteriumdiptheriae

Aerobic,Gram-negativemicroorganisms

Bordetellapertusis

Moraxellacatarrhalis

Pasteurellamultocida

Legionellaspp.

Anaerobicmicroorganisms

Clostridiumspp.,otherthanC.difficile

Othermicroorganisms

Mycoplasmapneumoniae

Chlamydiatrachomatis

Clamydophilapneumoniae

Clamydophilapsitacci

Mycobacteriumspp.

Speciesforwhichacquiredresistancemaybeaproblem#

Aerobic,Gram-positivemicroorganisms

StreptococcusgroupA*,C,G

StreptococcusgroupB

Streptococcusviridans

Enterococcusspp +

Staphylococcusaureus,methicillin-susceptibleandmethicillin-resistant+

Streptococcuspneumoniae*+

Staphylococcusepidermidis+

Aerobic,Gram-negativemicroorganisms

Haemophilusinfluenzae$

Helicobacterpylori

Anaerobicmicroorganisms

Bacteroidesspp.

Peptococcus/Peptostreptococcusspp.

Inherentlyresistantmicroorganisms

Aerobic,Gram-negativemicroorganisms

Pseudomonasaeruginosa

Acinetobacter

Enterobacteriacea

Anaerobicmicroorganisms

Fusobacteriumspp.

Othermicroorganisms

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≥10%resistanceinatleastonecountryoftheEuropeanUnion

*Speciesagainstefficacyhasbeendemonstratedinclinicalinvestigations(ifsusceptible)

+Indicatesspeciesforwhichahighrateofresistance(i.e.greaterthan50%)havebeenobservedinoneormore

area/country/region(s)oftheEU

§BreakpointsformacrolidesandrelatedantibioticsweresettocategorisewildtypeH.influenzaeasintermediate

Otherinformation:

SusceptibilityandresistanceofStreptococcuspneumoniaeandStreptococcusspp.toclarithromycincanbepredicted

bytestingerythromycin.

Mostavailableclinicalexperiencefromcontrolledrandomisedclinicaltrialsindicatethatclarithromycin500mgtwice

dailyincombinationwithanotherantibiotice.g.amoxicillinormetronidazoleande.g.omeprazole(givenatapproved

levels)for7daysachieve>80%H.pylorieradicationrateinpatientswithgastro-duodenalulcers.Asexpected,

significantlylowereradicationrateswereobservedinpatientswithbaselinemetronidazole-resistantH.pyloriisolates.

Hence,localinformationontheprevalenceofresistanceandlocaltherapeuticguidelinesshouldbetakenintoaccount

inthechoiceofanappropriatecombinationregimenforH.pylorieradicationtherapy.Furthermore,inpatientswith

persistentinfection,potentialdevelopmentofsecondaryresistance(inpatientswithprimarysusceptiblestrains)toan

antimicrobialagentshouldbetakenintotheconsiderationsforanewretreatmentregimen.

5.2Pharmacokineticproperties

Absorption:

Clarithromycinisrapidlyandwellabsorbedfromthegastrointestinaltract–primarilyinthejejunum–butundergoes

extensivefirst-passmetabolismafteroraladministration.Theabsolutebioavailabilityofa250-mgclarithromycintablet

isapproximately50%.Foodslightlydelaystheabsorptionbutdoesnotaffecttheextentofbioavailability.Therefore,

clarithromycintabletsmaybegivenwithoutregardtofood.Duetoitschemicalstructure(6-O-Methylerythromycin)

clarithromycinisquiteresistanttodegradationbystomachacid.Peakplasmalevelsof1–2µg/mlclarithromycinwere

observedinadultsafteroraladministrationof250mgtwicedaily.Afteradministrationof500mgclarithromycintwice

dailythepeakplasmalevelwas2.8µg/ml.

Afteradministrationof250mgclarithromycintwicedailythemicrobiologicallyactive14-hydroxymetaboliteattains

peakplasmaconcentrationsof0.6µg/ml.Steadystateisattainedwithin2daysofdosing.

Distribution:

Clarithromycinpenetrateswellintodifferentcompartments,withanestimatedvolumeofdistributionof200-400L.

Clarithromycinprovidesconcentrationsinsometissuesthatareseveraltimeshigherthanthecirculatinglevelofthe

activesubstance.Increasedlevelshavebeenfoundinbothtonsilsandlungtissue.Clarithromycinalsopenetratesthe

gastricmucus.

Clarithromycinisapproximately70%boundtoplasmaproteinsattherapeuticlevels.

Biotransformationandelimination:

Clarithromycinisrapidlyandextensivelymetabolisedintheliver.MetabolismisintheliverinvolvingtheP450

cytochromesystem.Threemetabolitesaredescribed:N-demethylclarithromycin,decladinosylclarithromycinand14-

hydroxyclarithromycin.

Thepharmacokineticsofclarithromycinisnon-linearduetosaturationofhepaticmetabolismathighdoses.

Eliminationhalf-lifeincreasedfrom2-4hoursfollowingadministrationof250mgclarithromycintwicedailyto5

hoursfollowingadministrationof500mgclarithromycintwicedaily.Thehalf-lifeoftheactive14-hydroxymetabolite

rangesbetween5to6hoursfollowingadministrationof250mgclarithromycintwicedaily.

Approximately20-40%ofclarithromycinisexcretedastheunchangedactivesubstanceintheurine.Thisproportionis

increasedwhenthedoseisincreased.Anadditional10%to15%isexcretedintheurineas14-hydroxymetabolite.The

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Totalplasmaclearancehasbeenestimatedtoapproximately700ml/min(11.7ml/s),witharenalclearanceof

approximately170ml/min(2.8ml/s).

SPECIALPOPULATIONS:

Renalimpairment:Reducedrenalinsufficiencyfunctionresultsinincreasedplasmalevelsofclarithromycinandthe

activemetabolitelevelsinplasma.

5.3Preclinicalsafetydata

In4-week-studiesinanimals,toxicityofclarithromycinwasfoundtoberelatedtothedoseandtothedurationofthe

treatment.Inallspecies,thefirstsignsoftoxicitywereobservedintheliver,inwhichlesionswereseenwithin14days

indogsandmonkeys.Thelevelsofsystemicexposureatwhichthistoxicityoccurredarenotknownindetail,buttoxic

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

includedthestomach,thymusandotherlymphoidtissuesaswellasthekidneys.Atneartherapeuticdosesconjunctival

injectionandlacrimationoccurredonlyindogs.Atadoseof400mg/kg/daysomedogsandmonkeysdevelopedcorneal

opacitiesand/oroedema.

Invitroandinvivostudiesshowedthatclarithromycindidnothavegenotoxicpotential.

Studiesonreproductiontoxicityshowedthatadministrationofclarithromycinatdoses2xtheclinicaldoseinrabbit(iv)

and10xtheclinicaldoseinmonkey(po)resultedinanincreasedincidenceofspontaneousabortions.Thesedoseswere

relatedtomaternaltoxicity.Noembryotoxicityorteratogenicitywasgenerallynotedinratstudies.However,

cardiovascularmalformationswereobservedintwostudiesinratstreatedwithdosesof150mg/kg/d.Inmiceatdoses

70xtheclinicaldose,cleftpalateoccurredatvaryingincidences(3-30%).

Clarithromycinhasbeenfoundinthemilkoflactatinganimals.

In3-dayoldmiceandrats,theLD

valueswereapproximatelyhalfthoseinadultanimals.Juvenileanimalspresented

similartoxicityprofilestomatureanimalsalthoughenhancednephrotoxicityinneonatalratshasbeenreportedinsome

studies.Slightreductionsinerythrocytes,plateletsandleukocyteshavealsobeenfoundinjuvenileanimals.

Clarithromycinhasnotbeentestedforcarcinogenicity.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Cellulose,microcrystalline

Croscarmellosesodium

ColloidalAnhydroussilica

Magnesiumstearate

Povidone(K-30)

Film-coat:

Hypromellose

PropyleneGlycol

TitaniumDioxide(E171)

HydroxypropylCellulose

Vanillin

Sorbicacid

Ironoxideyellow(E172)

6.2Incompatibilities

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6.3Shelflife

3years

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

PVC/PVdC/Aluminiumblister:

Packsizes:

250mg:

1,2,4,5,6,7,8,10,12,14,15,16,20,21,24,28,30,32,40,42,45,49,50,56,60,72,75,90,100,120,140,250,

500or1000filmcoatedtablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Anyunusedproductorwastematerialshouldbedisposedoffinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

PfizerHealthcareIreland

9Riverwalk

NationalDigitalPark

CitywestBusinessCampus

Dublin24

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA822/103/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:29thJune2011

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