CLARITHYROMYCIN

Main information

  • Trade name:
  • CLARITHYROMYCIN Granules for Oral Suspension 250/5 Mg/Ml
  • Dosage:
  • 250/5 Mg/Ml
  • Pharmaceutical form:
  • Granules for Oral Suspension
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CLARITHYROMYCIN Granules for Oral Suspension 250/5 Mg/Ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0711/197/002
  • Authorization date:
  • 03-02-2012
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Clarithromycin250mg/5mlGranulesforOralSuspension

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Afterreconstitution1mloralsuspensioncontains50mgclarithromycin,5mloralsuspensioncontains250mg

clarithromycin.

Theproductcontains2.4gsucroseper5mlready-for-usesuspension.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Granulesfororalsuspension.

Whitetobeigegranules.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Clarithromycin50mg/mlgranulesfororalsuspensionisindicatedinadults,adolescentsandchildren,6monthsto12

years,forthetreatmentofthefollowingacuteandchronicinfections,whencausedbyclarithromycinsusceptible

organisms.

Infectionsoftheupperrespiratorytractsuchastonsillitis/pharyngitis,asanalternativewhenbetalactam

antibioticsarenotappropriate.

Acuteotitismediainchildren.

Infectionsofthelowerrespiratorytractsuchascommunityacquiredpneumonia.

Sinusitisandacuteexacerbationofchronicbronchitisinadultsandadolescentsover12yearsofage

Skininfectionsandsofttissueinfectionsofmildtomoderateseverity.

Inappropriatecombinationwithantibacterialtherapeuticregimensandanappropriateulcerhealingmedicinalproduct

fortheeradicationofHelicobacterpyloriinadultpatientswithH.pyloriassociatedulcers.Seesection4.2.

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantibacterialagents.

4.2Posologyandmethodofadministration

ThedosageofClarithromycin50mg/mlgranulesfororalsuspensiondependsontheclinicalconditionofthepatient

andhastobedefinedinanycasebythephysician.

Adultsandadolescents:

Standarddosage:Theusualdoseis250mgtwicedaily.

Highdosagetreatment(severeinfections):Theusualdosemaybeincreasedto500mgtwicedailyinsevereinfections.

EliminationofHelicobacterpyloriinadults:

Inpatientswithgastro-duodenalulcersduetoH.pyloriinfectionclarithromycinaspartofthefirstlinetripletherapyis

giveninadosageof500mgtwicedaily.ThenationalrecommendationsforHelicobacterpylorieradicationhavetobe

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Dosageinrenalfunctionalimpairment:

Themaximumrecommendeddosagesshouldbereducedproportionatelytorenalimpairment.

Atcreatinineclearancerateoflessthan30ml/min,thedosageshouldbehalvedto250mgdailyorinthemostsevere

infectionsto250mgtwicedaily.Thedurationoftreatmentshouldnotexceed14daysinthesepatients.

Children6monthsto12yearsofage:

Therecommendeddoseis7.5mg/kgtwiceaday.

Weight Age Dosage

12–19kg 2–4years 2.5mltwicedaily

20–29kg 4–8years 3.75mltwicedaily

30–40kg 8–12years 5mltwicedaily

Childrenweighinglessthan8kgshouldbetreatedbasedontheirbodyweight.

Clinicaltrialshavebeenconductedusingclarithromycinpediatricsuspensioninchildren6monthsto12yearsofage.

Therefore,childrenunder12yearsofageshoulduseclarithromycinpediatricsuspension(granulesfororal

suspension).

Thereislimitedexperienceoftreatmentofchildrenbelow6monthsofage.

Fortheindicationcommunityacquiredpneumoniaeffectinchildrenunder3yearsofageisnotdocumented.

Inrenalinsufficiency,especiallyifthecreatinineclearanceis<30ml/min,thedosemustbehalved,i.e.7.5mg/kgonce

aday,andthedurationoftreatmentshouldnotexceed14days.

Durationoftherapy:

ThedurationoftherapywithClarithromycin50mg/mlgranulesfororalsuspensiondependsontheclinicalcondition

ofthepatient.Thedurationoftherapyhasinanycasetobedeterminedbythephysician.

Theusualdurationoftreatmentofchildrenupto12yearsofageis5to10days.

Theusualdurationoftreatmentofadultsandadolescentsis6to14days.

Therapyshouldbecontinuedatleastfor2daysaftersymptomshavesubsided.

Instreptococcuspyogenes(asabeta-haemolyticstreptococcal)infectionsthedurationoftherapyshouldbeat

least10days.

CombinationtherapyfortheeradicationofH.pyloriinfection,e.g.clarithromycin500mgtwicedailyin

combinationwithamoxicillin1000mgtwicedailyandomeprazole20mgtwicedailyshouldbecontinuedfor7

days.

Methodofadministration:

Beforeadministrationthegranulesmustbereconstitutedwithwater,seesection6.6.

ForadministrationafterreconstitutionanoralPE/PP-measuringsyringeoraPP-measuringspoonareused.

Granulesoftheoralsuspensioncancauseabitteraftertastewhenremaininginthemouth.Thiscanbeavoidedby

eatingordrinkingsomethingimmediatelyaftertheintakeofthesuspension.

Clarithromycinmaybegivenirrespectiveoffoodintake.Fooddoesnotaffecttheextentofbioavailability.Fooddoes

onlyslightlydelaytheonsetofabsorptionofclarithromycin.

4.3Contraindications

Clarithromycin50mg/mlgranulesfororalsuspensionmustnotbeusedinpatientswithahypersensitivitytotheactive

substance,othermacrolideantibioticsortoanyoftheexcipients.

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resultinergottoxicity.Concomitantadministrationofclarithromycinandanyofthefollowingactivesubstancesis

contraindicated:astemizole,cisapride,pimozideandterfenadine.ThismayresultinQTprolongationandcardiac

arrhythmiasincludingventriculartachycardia,ventricularfibrillationandTorsadedePointes(seesection4.5).

Clarithromycin50mg/mlgranulesfororalsuspensionmustnotbeadministeredtohypokalemicpatients(riskof

prolongationofQT-time,seesection4.4).

ClarithromycinmustnotbegiventopatientswithhistoryofQTprolongationorventricularcardiacarrhythmia,

includingtorsadesdepointe(seesections4.4and4.5).

ClarithromycinmustnotbeusedconcomitantlywithHMG-CoAreductaseinhibitors(statins),lovastatinor

simvastatin,duetotheriskofrhabdomyolysis.Treatmentwiththeseagentsshouldbediscontinuedduring

clarithromycintreatment(seesection4.4).

Clarithromycinmustnotbeusedinpatientswhosufferfromseverehepaticfailureincombinationwithrenal

impairment.

4.4Specialwarningsandprecautionsforuse

Thephysicianshouldnotprescribeclarithromycintopregnantwomenwithoutcarefullyweighingthebenefitsagainst

risk,particularlyduringthefirstthreemonthsofpregnancy(seesection4.6).

Intheeventofsevereacutehypersensitivityreactions,suchasanaphylaxis,Stevens-JohnsonSyndrome,andtoxic

epidermalnecrolysis,clarithromycintherapyshouldbediscontinuedimmediatelyandappropriatetreatmentshouldbe

urgentlyinitiated.

Clarithromycinismainlyexcretedbytheliver.Therefore,cautionshouldbetakeninadministeringclarithromycinto

patientswithimpairedhepaticfunction.

Casesoffatalhepaticfailure(seesection4.8)havebeenreported.Somepatientsmayhavehadpre-existinghepatic

diseaseormayhavebeentakingotherhepatotoxicmedicinalproducts.Patientsshouldbeadvisedtostoptreatmentand

contacttheirdoctorifsignsandsymptomsofhepaticdiseasedevelop,suchasanorexia,jaundice,darkurine,pruritus,

ortenderabdomen.

Whenrenalfunctionispoor,dosageofclarithromycinshouldbesuitablyreduceddependingonthedegreeofthe

impairment(seesection4.2).Inelderlypatients,thepossibilityofrenalimpairmentshouldbeconsidered.Cautionis

advisedwithsevererenalinsufficiency.

ClarithromycintherapyforH.pylorimayselectfordrug-resistantorganisms.

Patientswhoarehypersensitivetolincomycinorclindamycinmayalsobehypersensitivetoclarithromycin.Therefore,

cautionisrequiredwhenprescribingclarithromycinforsuchpatients.

Attentionshouldalsobepaidtothepossibilityofcrossresistancebetweenclarithromycinandothermacrolidedrugs,as

wellaslincomycinandclindamycin.

Prolongedorrepeateduseofclarithromycinmayresultinsuperinfectionswithnon-susceptiblebacteriaorfungi.In

caseofsuperinfection,clarithromycintherapyshouldbestoppedandappropriatetherapyshouldbeinstituted.

Pseudomembranouscolitishasbeenreportedwithnearlyallantibacterialagents,includingmacrolides,andmayrange

inseverityfrommildtolife-threatening.Clostridiumdifficile-associateddiarrhea(CDAD)hasbeenreportedwithuse

ofnearlyallantibacterialagentsincludingclarithromycin,andmayrangeinseverityfrommilddiarrheatofatalcolitis.

Treatmentwithantibacterialagentsaltersthenormalfloraofthecolon,whichmayleadtoovergrowthofC.difficile.

CDADmustbeconsideredinallpatientswhopresentwithdiarrheafollowingantibioticuse.Carefulmedicalhistoryis

necessarysinceCDADhasbeenreportedtooccurovertwomonthsaftertheadministrationofantibacterialagents.

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testingshouldbeperformedandadequatetreatmentinitiated.Drugsinhibitingperistalsisshouldbeavoided.

DuetoariskofincreasedQT-interval,clarithromycinshouldbeusedwithcautioninpatientswithacoronaryartery

disease,severecardiacinsufficiency,non-compensatedhypokalemiaand/orhypomagnesemia,bradycardia(<50bpm),

orwhenco-administeredwithothermedicinalproductswithaQT-prolongingeffect(seesection4.5).Clarithromycin

mustnotbeusedinpatientswithcongenitalordocumentedacquiredQTprolongationorhistoryofventricular

arrhythmia(seesection4.3).

Therehavebeenpost-marketingreportsofcolchicinetoxicitywithconcomitantuseofclarithromycinandcolchicine,

especiallyintheelderly,someofwhichoccurredinpatientswithrenalinsufficiency.Deathshavebeenreportedin

somesuchpatients(seesection4.5).Ifconcomitantadministrationofcolchicineandclarithromycinisnecessary,

patientsshouldbemonitoredforclinicalsymptomsofcolchicinetoxicity.

Cautionisadvisedregardingconcomitantadministrationofclarithromycinandtriazolobenzodiazepines,suchas

triazolam,andmidazolam(seesection4.5).

Cautionisadvisedregardingconcomitantadministrationofclarithromycinwithotherototoxicdrugs,especiallywith

aminoglycosides.Monitoringofvestibularandauditoryfunctionshouldbecarriedoutduringandaftertreatment.

Clarithromycinshouldbeusedwithcautionwheneverindicatedforuseinpatientsreceivingtreatmentwithaninducer

ofCYP3A4(seesection4.5).

ClarithromycinisaninhibitorofCYP3A4,andconcomitantusewithothermedicinalproductsthataremetabolisedtoa

largeextentbythisenzymeshouldberestrictedtosituationswhereitisclearlyindicated(seesection4.5).

HMG-CoAreductaseinhibitors:Concomitantuseofclarithromycinwithlovastatinorsimvastatiniscontraindicated

(seesection4.3).Aswithothermacrolides,clarithromycinhasbeenreportedtoincreaseconcentrationsofHMG-CoA

reductaseinhibitors(seesection4.5).Rarereportsofrhabdomyolysishavebeenreportedinpatientstakingthesedrugs

concomitantly.Patientsshouldbemonitoredforsignsandsymptomsofmyopathy.Rarereportsofrhabdomyolysis

havealsobeenreportedinpatientstakingatorvastatinorrosuvastatinconcomitantlywithclarithromycin.Whenused

withclarithromycin,atorvastatinorrosuvastatinshouldbeadministeredinthelowestpossibledoses.Adjustmentofthe

statindoseoruseofastatinthatisnotdependentonCYP3Ametabolism(e.g.fluvastatinorpravastatin)shouldbe

considered.

Oralhypoglycemicagents/Insulin:Theconcomitantuseofclarithromycinandoralhypoglycemicagentsand/orinsulin

canresultinsignificanthypoglycemia.Withcertainhypoglycemicdrugssuchasnateglinide,pioglitazone,repaglinide

androsiglitazone,inhibitionofCYP3Aenzymebyclarithromycinmaybeinvolvedandcouldcausehypolgycemia

whenusedconcomitantly.Carefulmonitoringofglucoseisrecommended.

Oralanticoagulants:ThereisariskofserioushemorrhageandsignificantelevationsinInternationalNormalizedRatio

(INR)andprothrombintimewhenclarithromycinisco-administeredwithwarfarin(seesection4.5).INRand

prothrombintimesshouldbefrequentlymonitoredwhilepatientsarereceivingclarithromycinandoralanticoagulants

concurrently.

ExacerbationoraggravationofMyastheniagravismayoccur.

Pneumonia:InviewoftheemergingresistanceofStreptococcuspneumoniaetomacrolides,itisimportantthat

sensitivitytestingbeperformedwhenprescribingclarithromycinforcommunity-acquiredpneumonia.Inhospital-

acquiredpneumonia,clarithromycinshouldbeusedincombinationwithadditionalappropriateantibiotics.

Skinandsofttissueinfectionsofmildtomoderateseverity:TheseinfectionsaremostoftencausedbyStaphylococcus

aureusandStreptococcuspyogenes,bothofwhichmayberesistanttomacrolides.Therefore,itisimportantthat

sensitivitytestingbeperformed.Incaseswherebeta–lactamantibioticscannotbeused(e.g.allergy),otherantibiotics,

suchasclindamycin,maybethedrugoffirstchoice.Currently,macrolidesareonlyconsideredtoplayaroleinsome

skinandsofttissueinfections,suchasthosecausedbyCorynebacteriumminutissimum(erythrasma),acnevulgaris,and

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Thismedicinalproductcontains2.4gsucroseper5mlready-for-usesuspension.Thisshouldbetakenintoaccountin

patientswithdiabetesmellitus.

Patientswithrarehereditaryproblemsoffructoseintolerance,glucose-galactosemalabsorptionorsucrase-isomaltase

insufficiencyshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Theuseofthefollowingdrugsisstrictlycontraindicatedduetothepotentialforseveredruginteractioneffects:

Cisapride,pimozide,astemizoleandterfenadine

Elevatedcisapridelevelshavebeenreportedinpatientsreceivingclarithromycinandcisaprideconcomitantly.This

mayresultinQTprolongationandcardiacarrhythmiasincludingventriculartachycardia,ventricularfibrillationand

torsadesdepointes.Similareffectshavebeenobservedinpatientstakingclarithromycinandpimozideconcomitantly

(seesection4.3).

Macrolideshavebeenreportedtoalterthemetabolismofterfenadineresultinginincreasedlevelsofterfenadinewhich

hasoccasionallybeenassociatedwithcardiacarrhythmiassuchasQTprolongation,ventriculartachycardia,ventricular

fibrillationandtorsadesdepointes(seesection4.3).Inonestudyin14healthyvolunteers,theconcomitant

administrationofclarithromycinandterfenadineresultedinatwotothreefoldincreaseintheserumleveloftheacid

metaboliteofterfenadineandinprolongationoftheQTintervalwhichdidnotleadtoanyclinicallydetectableeffect.

Similareffectshavebeenobservedwithconcomitantadministrationofastemizoleandothermacrolides.

Ergotamine/dihydroergotamine

Postmarketingreportsindicatethatco-administrationofclarithromycinwithergotamineordihydroergotaminehasbeen

associatedwithacuteergottoxicitycharacterizedbyvasospasm,andischemiaoftheextremitiesandothertissues

includingthecentralnervoussystem.Concomitantadministrationofclarithromycinandthesemedicinalproductsis

contraindicated(seesection4.3).

HMG–CoAreductaseinhibitors

Concomitantuseofclarithromycinwithlovastatinorsimvastatiniscontraindicated(seesections4.3and4.4).

Theeffectofothermedicinalproductsonclarithromycin

ClarithromycinisaninhibitorofthemetabolisingenzymeCYP3A4andthetransportproteinP-glycoprotein.The

degreeofinhibitionwithdifferentCYP3A4substratesisdifficulttopredict.Hence,clarithromycinshouldnotbeused

duringtreatmentwithothermedicinalproductsthataresubstratesforCYP3A4,unlessplasmalevels,therapeuticeffect

oradverseeventsoftheCYP3A4substratecanbecloselymonitored.Adosereductionmaybenecessaryformedicinal

productsthataresubstratesforCYP3A4ifco-administeredwithclarithromycin.Alternatively,treatmentwiththese

productsmaybeinterruptedduringclarithromycintreatment.

ClarithromycinismetabolisedbytheenzymeCYP3A4.Hence,stronginhibitorsofthisenzymemayinhibitthe

metabolismofclarithromycin,resultinginincreasedplasmaconcentrationsofclarithromycin.

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

inducethemetabolismofclarithromycin.Thismayresultinsub-therapeuticlevelsofclarithromycinleadingtoa

reducedefficacy.Whenclarithromycinisclearlyindicateditmightbenecessarytoincreasethedoseofclarithromycin

andmonitortheefficacyandsafetyofclarithromycincarefully.Furthermoremonitoringtheplasmalevelsofthe

CYP3A4inducermightbenecessarybecausethelattercouldbeincreasedowingtotheinhibitionofCYP3A4by

clarithromycin(seealsotherelevantproductinformationfortheCYP3A4induceradministered).

Concomitantadministrationofrifabutinandclarithromycinresultedinanincreaseanddecrease,respectively,inserum

levels,followedbyanincreasedriskofuveitis.

Thefollowingdrugsareknownorsuspectedtoaffectcirculatingconcentrationsofclarithromycin;clarithromycin

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Efavirenz,nevirapine,rifampicin,rifabutinandrifapentine

StronginducersofthecytochromeP450metabolismsystemsuchasefavirenz,nevirapine,rifampicin,rifabutin,and

rifapentinemayacceleratethemetabolismofclarithromycinandthuslowertheplasmalevelsofclarithromycin,while

increasingthoseof14-OH-clarithromycin,ametabolitethatisalsomicrobiologicallyactive.Sincethemicrobiological

activitiesofclarithromycinand14-OH-clarithromycinaredifferentfordifferentbacteria,theintendedtherapeutic

effectcouldbeimpairedduringconcomitantadministrationofclarithromycinandenzymeinducers.

Fluconazole

Concomitantadministrationoffluconazole200mgdailyandclarithromycin500mgtwicedailyto21healthy

volunteersledtoincreasesinthemeansteady-stateminimumclarithromycinconcentration(C

)andareaunderthe

curve(AUC)of33%and18%respectively.Steadystateconcentrationsoftheactivemetabolite14-OH-clarithromycin

werenotsignificantlyaffectedbyconcomitantadministrationoffluconazole.Noclarithromycindoseadjustmentis

necessary.

Ritonavir

Ritonavir(200mgthreetimesdaily)havebeenshowntoinhibitthemetabolismofclarithromycin(500mgtwice

daily),withanincreaseinC

,C

andAUCof31,182and77%,respectively,whenco-administeredwithritonavir.

Formationoftheactive14-OH-hydroxymetabolitewasalmostcompletelyinhibited.Ageneraldosereductionis

probablynotrequiredinpatientswithnormalrenalfunction,butthedailydoseofclarithromycinshouldnotexceed1

g.Dosereductionshouldbeconsideredinpatientswithrenalimpairment.Forpatientswithacreatinineclearanceof30

to60ml/min,theclarithromycindoseshouldbereducedwith50%,andatacreatinineclearanceof<30ml/minthe

doseshouldbereducedwith75%.

Similardoseadjustmentsshouldbeconsideredinpatientswithreducedrenalfunctionwhenritonavirisusedasa

pharmacokineticenhancerwithotherHIVproteaseinhibitorsincludingatazanavirandsaquinavir(seesectionbelow,

Bi-directionaldruginteractions).

InteractionineradicationofH.pyloriregimens

Althoughtheplasmaconcentrationsofclarithromycinandomeprazolemaybeincreasedwhentheyareadministered

concurrently,noadjustmenttothedosageisnecessary.Atthedosagesrecommended,thereisnoclinicallysignificant

interactionbetweenclarithromycinandlansoprazole.Increasedplasmaconcentrationsofclarithromycinmayalsooccur

whenitisco-administeredwithantacidsorranitidine.Noadjustmenttothedosageisnecessary.Thereareno

pharmacokineticinteractionswithrelevantantibioticswhichareusedinH.pylorieradicationtherapy.

Effectofclarithromycinonothermedicinalproducts

CYP3A-basedinteractions

Co-administrationofclarithromycin,knowntoinhibitCYP3A,andadrugprimarilymetabolizedbyCYP3Amaybe

associatedwithelevationsindrugconcentrationsthatcouldincreaseorprolongboththerapeuticandadverseeffectsof

theconcomitantdrug.Clarithromycinshouldbeusedwithcautioninpatientsreceivingtreatmentwithotherdrugs

knowntobeCYP3Aenzymesubstrates,especiallyiftheCYP3Asubstratehasanarrowsafetymargin(e.g.

carbamazepine)and/orthesubstrateisextensivelymetabolizedbythisenzyme.

Dosageadjustmentsmaybeconsidered,andwhenpossible,serumconcentrationsofdrugsprimarilymetabolizedby

CYP3Ashouldbemonitoredcloselyinpatientsconcurrentlyreceivingclarithromycin.

ThefollowingdrugsordrugclassesareknownorsuspectedtobemetabolizedbythesameCYP3Aisozyme:

alprazolam,astemizole,carbamazepine,cilostazol,cisapride,cyclosporine,disopyramide,ergotalkaloids,lovastatin,

methylprednisolone,midazolam,omeprazole,oralanticoagulants(e.g.warfarin),pimozide,quinidine,rifabutin,

sildenafil,simvastatin,sirolimus,tacrolimus,terfenadine,triazolamandvinblastine.Drugsinteractingbysimilar

mechanismsthroughotherisozymeswithinthecytochromeP450systemincludephenytoin,theophyllineand

valproate.

Antiarrhythmics

Caseswithtorsadesdepointeshasbeenreportedinpatientswhereclarithromycinhasbeenco-administeredwith

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disopyramidcloselymonitoredtoallowdoseadjustment.ElectrocardiogramsshouldbemonitoredforQTprolongation

duringco-administrationofclarithromycinwiththesedrugs.

Cautioniswarrantedwhenclarithromyinisadministeredtopatientstreatedtakingothermedicinalproductswiththe

potentialtoprolongQT(seesection4.4).

Cyclosporin,tacrolimusandsirolimus

Concomitantuseoforalclarithromycinandcyclosporinortacrolimushaveresultedinmorethana2-foldincreaseof

theC

-levelsofbothcyclosporinandtacrolimus.Similareffectsarealsoexpectedforsirolimus.Wheninitiating

treatmentwithclarithromycininpatientsalreadyreceivinganyoftheseimmunosuppressiveagents,cyclosporin,

tacrolimusorsirolimusplasmalevelsmustbecloselymonitoredandtheirdosesdecreasedasnecessary.When

clarithromycinisdiscontinuedinthesepatients,closemonitoringofplasmalevelsofcyclosporin,tacrolimusor

sirolimus,isagainnecessarytoguidedoseadjustment.

Warfarin

Theuseofclarithromycininpatientsreceivingwarfarinmayresultinpotentiationoftheeffectsofwarfarin.

Prothrombintimeshouldbefrequentlymonitoredinthesepatients(seesection4.4and4.8).

Omeprazole

Clarithromycin(500mgevery8hours)wasgivenincombinationwithomeprazole(40mgdaily)tohealthyadult

subjects.Thesteady-stateplasmaconcentrationsofomeprazolewereincreased(C

,AUC

,andt

increasedby

30%,89%,and34%,respectively),bytheconcomitantadministrationofclarithromycin.Themean24-hourgastricpH

valuewas5.2whenomeprazolewasadministeredaloneand5.7whenomeprazolewasco-administeredwith

clarithromycin.

Sildenafil,tadalafil,andvardenafil

Eachofthesephosphodiesteraseinhibitorsismetabolized,atleastinpart,byCYP3A,andCYP3Amaybeinhibitedby

concomitantlyadministeredclarithromycin.Co-administrationofclarithromycinwithsildenafil,tadalafilorvardenafil

wouldlikelyresultinincreasedphosphodiesteraseinhibitorexposure.Reductionofsildenafil,tadalafilandvardenafil

dosagesshouldbeconsideredwhenthesedrugsareco-administeredwithclarithromycin.

Theophylline,carbamazepine

Resultsofclinicalstudiesindicatetherewasamodestbutstatisticallysignificant(p<0.05)increaseofcirculating

theophyllineorcarbamazepinelevelswheneitherofthesedrugswereadministeredconcomitantlywithclarithromycin.

Dosereductionmayneedtobeconsidered.

Tolterodine

Theprimaryrouteofmetabolismfortolterodineisviathe2D6isoformofcytochromeP450(CYP2D6).However,ina

subsetofthepopulationdevoidofCYP2D6,theidentifiedpathwayofmetabolismisviaCYP3A.Inthispopulation

subset,inhibitionofCYP3Aresultsinsignificantlyhigherserumconcentrationsoftolterodine.Areductionin

tolterodinedosagemaybenecessaryinthepresenceofCYP3Ainhibitors,suchasclarithromycinintheCYP2D6poor

metabolizerpopulation.

Triazolobenzodiazepines(e.g.alprazolam,midazolam,triazolam)

Whenmidazolamwasco-administeredwithclarithromycintablets(250mgtwicedaily),midazolamAUCwas

increased2.7-foldafterintravenousadministrationofmidazolamand7-foldafteroraladministration.Concomitant

administrationoforalmidazolamandclarithromycinshouldbeavoided.Ifintravenousmidazolamisco-administered

withclarithromycin,thepatientmustbecloselymonitoredtoallowdoseadjustment.Thesameprecautionsshouldalso

applytootherbenzodiazepinesthataremetabolisedbyCYP3A4,especiallytriazolambutalsoalprazolam.For

benzodiazepineswhicharenotmetabolisedbyCYP3A4(temazepam,nitrazepam,lorazepam)aninteractionwith

clarithromycinisunlikely.

Therehavebeenpost-marketingreportsofdruginteractionsandcentralnervoussystem(CNS)effects(e.g.somnolence

andconfusion)withtheconcomitantuseofclarithromycinandtriazolam.MonitoringthepatientforincreasedCNS

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Otherdruginteractions

Colchicin

ColchicineisasubstrateforbothCYP3Aandtheeffluxtransporter,P-glycoprotein(Pgp).Clarithromycinandother

macrolidesareknowntoinhibitCYP3AandPgp.Whenclarithromycinandcolchicineareadministeredtogether,

inhibitionofPgpand/orCYP3Abyclarithromycinmayleadtoincreasedexposuretocolchicine.Patientsshouldbe

monitoredforclinicalsymptomsofcolchicinetoxicity(seesection4.4).

DigoxinandotheractivesubstancestransportedbyP-glycoprotein

ClarithromycinisapotentinhibitorofthetransportproteinP-glycoprotein(Pgp).Thiscouldgiverisetoincreased

plasmaconcentrationsofactivesubstanceswhicharetransportedbythistransporterandmayalsoincreasedistribution

ofsuchactivesubstancestoorganshavingPgpasandistributionbarriere.g.CNS.TheconcentrationofthePgp

substratedigoxinmaybeincreasedwhenco-administeredwithclarithromycin.Elevateddigoxinserumconcentrations

inpatientsreceivingclarithromycinanddigoxinconcomitantlyhavebeenreportedinpostmarketingsurveillance.

Somepatientshaveshownclinicalsignsconsistentwithdigoxintoxicity,includingpotentiallyfatalarrhythmias.Serum

digoxinconcentrationsshouldbecarefullymonitoredwhilepatientsarereceivingdigoxinandclarithromycin

simultaneously.

Zidovudine

SimultaneousoraladministrationofclarithromycintabletsandzidovudinetoHIVinfectedadultpatientsmayresultin

decreasedsteady-statezidovudinelevels.Becauseclarithromycinappearstointerferewiththeabsorptionof

simultaneouslyadministeredoralzidovudine,thisinteractioncanbelargelyavoidedbystaggeringthedosesof

clarithromycinandzidovudinetoallowfora4-hourintervalbetweeneachmedication.Thisinteractiondoesnotappear

tooccurinpaediatricHIV-infectedpatientstakingclarithromycinsuspensionwithzidovudineordideoxyinosine.This

interactionisunlikelywhenclarithromycinisadministeredviaintravenousinfusion.

PhenytoinandValproate

TherehavebeenspontaneousorpublishedreportsofinteractionsofCYP3Ainhibitors,includingclarithromycinwith

drugsnotthoughttobemetabolizedbyCYP3A(e.g.phenytoinandvalproate).Serumleveldeterminationsare

recommendedforthesedrugswhenadministeredconcomitantlywithclarithromycin.Increasedserumlevelshavebeen

reported.

Bi-directionaldruginteractions

Atazanavir

BothclarithromycinandatazanaviraresubstratesandinhibitorsofCYP3A,andthereisevidenceofabi-directional

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

resultedina2-foldincreaseinexposuretoclarithromycinanda70%decreaseinexposureto14-OH-clarithromycin,

witha28%increaseintheAUCofatazanavir.Becauseofthelargetherapeuticwindowforclarithromycin,nodosage

reductionshouldbenecessaryinpatientswithnormalrenalfunction.Forpatientswithmoderaterenalfunction

(creatinineclearance30to60mL/min),thedoseofclarithromycinshouldbedecreasedby50%.Forpatientswith

creatinineclearance<30mL/min,thedoseofclarithromycinshouldbedecreasedby75%usinganappropriate

clarithromycinformulation.Dosesofclarithromycingreaterthan1000mgperdayshouldnotbeco-administeredwith

proteaseinhibitors.

Itraconazole

BothclarithromycinanditraconazolearesubstratesandinhibitorsofCYP3A,leadingtoabidirectionaldrug

interaction.Clarithromycinmayincreasetheplasmalevelsofitraconazole,whileitraconazolemayincreasetheplasma

levelsofclarithromycin.Patientstakingitraconazoleandclarithromycinconcomitantlyshouldbemonitoredcloselyfor

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Saquinavir

BothclarithromycinandsaquinaviraresubstratesandinhibitorsofCYP3A,andthereisevidenceofabi-directional

druginteraction.Concomitantadministrationofclarithromycin(500mgtwicedaily)andsaquinavir(softgelatin

capsules,1200mgthreetimesdaily)to12healthyvolunteersresultedinsteady-stateAUCandC

valuesof

saquinavirwhichwere177%and187%higherthanthoseseenwithsaquinaviralone.ClarithromycinAUCandC

valueswereapproximately40%higherthanthoseseenwithclarithromycinalone.Nodoseadjustmentisrequiredwhen

thetwodrugsareco-administeredforalimitedtimeatthedoses/formulationsstudied.Observationsfromdrug

interactionstudiesusingthesoftgelatincapsuleformulationmaynotberepresentativeoftheeffectsseenusingthe

saquinavirhardgelatincapsule.Observationsfromdruginteractionstudiesperformedwithsaquinaviralonemaynotbe

representativeoftheeffectsseenwithsaquinavir/ritonavirtherapy.Whensaquinavirisco-administeredwithritonavir,

considerationshouldbegiventothepotentialeffectsofritonavironclarithromycin.

Verapamil

Hypotension,bradyarrhythmiasandlacticacidosishavebeenobservedinpatientstakingclarithromycinandverapamil

concomitantly.

4.6Fertility,pregnancyandlactation

Pregnancy

Dataontheuseofclarithromycinduringthefirsttrimesterofmorethan200pregnanciesshownoclearevidenceof

teratogeniceffects,orofadverseeffectsonthehealthoftheneonate.Datafromalimitednumberofpregnantwomen

exposedinthefirsttrimesterindicateapossibleincreasedriskofabortions.Todatenootherrelevantepidemiological

dataareavailable.

Datafromanimalstudieshaveshownreproductivetoxicity(seesection5.3).Theriskforhumansisunknown.

Clarithromycinshouldonlybeusedduringpregnancyafteracarefulbenefit/riskassessment.

Lactation

Clarithromycinanditsactivemetaboliteareexcretedinbreastmilk.Therefore,diarrhoeaandfungusinfectionofthe

mucousmembranescouldoccurinthebreast-fedinfant,sothatnursingmighthavetobediscontinued.Thepossibility

ofsensitisationshouldbeborninmind.Thebenefitoftreatmentofthemothershouldbeweighedagainstthepotential

riskfortheinfant.

4.7Effectsonabilitytodriveandusemachines

Therearenodataavailableontheeffectofclarithromycinontheabilitytodriveorusemachines.Whenperforming

theseactivitiesthepossibleoccurrenceoftheadversereactions;dizziness,vertigo,confusionanddisorientationshould

betakenintoaccount.

4.8Undesirableeffects

a.Summaryofthesafetyprofile

Themostfrequentandcommonadversereactionsrelatedtoclarithromycintherapyforbothadultandpediatric

populationsareabdominalpain,diarrhea,nausea,vomitingandtasteperversion.Theseadversereactionsareusually

mildinintensityandareconsistentwiththeknownsafetyprofileofmacrolideantibiotics(seesectionbofsection4.8).

Therewasnosignificantdifferenceintheincidenceofthesegastrointestinaladversereactionsduringclinicaltrials

betweenthepatientpopulationwithorwithoutpreexistingmycobacterialinfections.

b.Tabulatedsummaryofadversereactions

Inthissectionundesirableeffectsaredefinedasfollows:

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Common(1/100to<1/10)

Uncommon(1/1,000to<1/100)

Rare(1/10,000to<1/1,000)

Veryrare(<1/10,000),notknown(cannotbeestimatedfromtheavailabledata)

Infectionsandinfestations

Common:Oralmonilia

Uncommon:Candidiasis,infection,vaginalinfection

Notknown:Erysipelas,erythrasma

Aswithotherantibiotics,prolongedusemayresultintheovergrowthofnon-susceptibleorganisms.

Bloodandlymphaticsystemdisorders

Uncommon:Leucopenia,thrombocythemia

Veryrare:Thrombocytopenia

Notknown:Agranulocytosis

Immunesystemdisorders

Uncommon:Allergicreactionsrangingfromurticariaandmildskineruptionstoanaphylaxis

Metabolismandnutritiondisorders

Uncommon:Anorexia,decreasedappetite

Psychiatricdisorders

Common:Insomnia

Uncommon:Anxietynervousness,screaming

Veryrare:Hallucinations,psychoticdisorder,disorientation,depersonalisation,abnormaldreamsandconfusionalstate

Notknown:Depression

Nervoussystemdisorders

Common:Headache,smellalteration,tasteperversion,dysgeusia

Uncommon:Dizziness,tremor

Veryrare:Paraesthesia,convulsions

Notknown:Ageusia,parosmia,anosmia

Earandlabyrinthdisorders

Uncommon:Vertigo,hearingimpaired,tinnitus

Veryrare:Reversiblehearingloss

Notknown:Deafness

Cardiacdisorders

Uncommon:Palpitations

Veryrare:QTprolongation,ventriculartachycardiaandTorsadesdePointes

Gastrointestinaldisorders

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

discoloration

Uncommon:Gastritis,constipation,drymouth,eructation,flatulence

Veryrare:Pancreatitis.Pseudomembranouscolitishasbeenreportedveryrarelywithclarithromycin,andmayrangein

severityfrommildtolifethreatening.

Hepatobiliarydisorders

Uncommon:Hepaticdysfunction,whichisusuallytransientandreversible,hepatitisandcholestasiswithorwithout

jaundice

Veryrare:Fatalhepaticfailurehasbeenreportedparticularlyinpatientswithpre-existingliverdiseaseortakingother

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Skinandsubcutaneoustissuedisorders

Common:Rash,hyperhidrosis

Uncommon:Pruritus,urticaria,rashmaculo-papular

Veryrare:Stevens-Johnsonsyndromeandtoxicepidermalnecrolysis

Notknown:Drugrashwitheosinophiliaandsystemicsymptoms(DRESS),acne

Musculoskeletal,connectivetissueandbonedisorders

Uncommon:Arthralgia,myalgia,musclespasms

Notknown:Myopathy

Renalandurinarydisorders

Veryrare:Interstitialnephritis,renalfailure.

Generaldisordersandadministrationsiteconditions

Uncommon:Pyrexia,asthenia

Investigations

Common:Elevatedbloodureanitrogen,liverfunctiontestabnormal

Uncommon:Prolongationofprothrombintime,elevatedserumcreatinine,alanineaminotransferaseincreased,

aspartateaminotransferaseincreased

Veryrare:Hypoglycaemiahasbeenobservedespeciallyafterconcomitantadministrationwithantidiabeticmedicinal

productsandinsulin

Notknown:Urinecolorabnormal

c.Descriptionofselectedadversereactions

Inveryrareinstances,hepaticfailurewithfataloutcomehasbeenreportedandgenerallyhasbeenassociatedwith

seriousunderlyingdiseasesand/orconcomitantmedications(seesection4.4).

AspecialattentiontodiarrheashouldbepaidasClostridiumdifficile-associateddiarrhea(CDAD)hasbeenreported

withuseofnearlyallantibacterialagentsincludingclarithromycin,andmayrangeinseverityfrommilddiarrheato

fatalcolitis(seesection4.4).

Pseudomembranouscolitishasbeenreportedwithnearlyallantibacterialagents,includingclarithromycin,andmay

rangeinseverityfrommildtolifethreatening.Therefore,itisimportanttoconsiderthisdiagnosisinpatientswho

presentwithdiarrheasubsequenttotheadministrationofantibacterialagents(seesection4.4).

Intheeventofsevereacutehypersensitivityreactions,suchasanaphylaxis,Stevens-JohnsonSyndromeandtoxic

epidermalnecrolysis,clarithromycintherapyshouldbediscontinuedimmediatelyandappropriatetreatmentshouldbe

urgentlyinitiated(seesection4.4).

Aswithothermacrolides,QTprolongation,ventriculartachycardia,andtorsadedepointeshaverarelybeenreported

withclarithromycin(seesection4.4and4.5).

Insomeofthereportsofrhabdomyolysis,clarithromycinwasadministeredconcomitantlywithstatins,fibrates,

colchicineorallopurinol(seesection4.3and4.4).

Therehavebeenpost-marketingreportsofcolchicinetoxicitywithconcomitantuseofclarithromycinandcolchicine,

especiallyinelderlyand/orpatientswithrenalinsufficiency,somewithafataloutcome(seesections4.4and4.5).

Therehavebeenrarereportsofhypoglycemia,someofwhichhaveoccurredinpatientsonconcomitantoral

hypoglycemicagentsorinsulin(seesection4.4and4.5).

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andconfusion)withtheconcomitantuseofclarithromycinandtriazolam.MonitoringthepatientforincreasedCNS

pharmacologicaleffectsissuggested(seesection4.5).

ThereisariskofserioushemorrhageandsignificantelevationsinINRandprothrombintimewhenclarithromycinis

co-administeredwithwarfarin.INRandprothrombintimesshouldbefrequentlymonitoredwhilepatientsarereceiving

clarithromycinandoralanticoagulantsconcurrently(seesection4.4and4.5).

Specialpopulation:AdverseReactionsinImmunocompromisedPatients(seesectione)

d.Paediatricpopulations

Clinicaltrialshavebeenconductedusingclarithromycinpaediatricsuspensioninchildren6monthsto12yearsofage.

Therefore,childrenunder12yearsofageshoulduseclarithromycinpaediatricsuspension.

Frequency,typeandseverityofadversereactionsinchildrenareexpectedtobethesameasinadults.

e.Otherspecialpopulations

Immunocompromisedpatients

InAIDSandotherimmunocompromisedpatientstreatedwiththehigherdosesofclarithromycinoverlongperiodsof

timeformycobacterialinfections,itwasoftendifficulttodistinguishadverseeventspossiblyassociatedwith

clarithromycinadministrationfromunderlyingsignsofHumanImmunodeficiencyVirus(HIV)diseaseorintercurrent

illness.

Inadultpatients,themostfrequentlyreportedadversereactionsbypatientstreatedwithtotaldailydosesof1000mg

and2000mgofclarithromycinwere:nausea,vomiting,tasteperversion,abdominalpain,diarrhea,rash,flatulence,

headache,constipation,hearingdisturbance,SerumGlutamicOxaloaceticTransaminase(SGOT)andSerumGlutamic

PyruvateTransaminase(SGPT)elevations.Additionallow-frequencyeventsincludeddyspnoea,insomniaanddry

mouth.Theincidenceswerecomparableforpatientstreatedwith1000mgand2000mg,butweregenerallyabout3to

4timesasfrequentforthosepatientswhoreceivedtotaldailydosesof4000mgofclarithromycin.

Intheseimmunocompromisedpatients,evaluationsoflaboratoryvaluesweremadebyanalysingthosevaluesoutside

theseriouslyabnormallevel(i.e.theextremehighorlowlimit)forthespecifiedtest.Onthebasisofthesecriteria,

about2%to3%ofthosepatientswhoreceived1000mgor2000mgofclarithromycindailyhadseriouslyabnormal

elevatedlevelsofSGOTandSGPT,andabnormallylowwhitebloodcellandplateletcounts.Alowerpercentageof

patientsinthesetwodosagegroupsalsohadelevatedBloodUreaNitrogenlevels.Slightlyhigherincidencesof

abnormalvalueswerenotedforpatientswhoreceived4000mgdailyforallparametersexceptWhiteBloodCell.

4.9Overdose

Symptomsofintoxication:

Reportsindicatethattheingestionoflargeamountsofclarithromycincanbeexpectedtoproducegastrointestinal

symptoms.Symptomsofoverdosemaylargelycorrespondtotheprofileofadversereactions.Onepatientwhohada

historyofbipolardisorderingested8gramsofclarithromycinandshowedalteredmentalstatus,paranoidbehaviour,

hypokaliaemiaandhypoxaemia.

Therapyofintoxication:

Thereisnospecificantidoteonoverdose.Serumlevelsofclarithromycincannotbereducedbyhaemodialysisor

peritonealdialysis.

Adversereactionsaccompanyingoverdoseshouldbetreatedbygastriclavageandsupportivemeasures.Severeacute

allergicreactionsmaybeseenveryrarely,e.g.anaphylacticshock.Atfirstsignsofhypersensitivityreactionstherapy

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Generalproperties

Pharmacological-therapeuticalgroup:

Macrolides.ATCCodeJ01FA09.

Mechanismofaction:

Clarithromycin,asemi-syntheticderivativeoferythromycin,exertsitsanti-bacterialactionbybindingtothe50s

ribosomalsub-unitofsusceptiblebacteriaandsuppressesproteinsynthesis.Itishighlypotentagainstawidevarietyof

aerobicandanaerobicgram-positiveandgram-negativeorganisms.Theminimuminhibitoryconcentrations(MICs)of

clarithromycinaregenerallytwo-foldlowerthantheMICsoferythromycin.

The14-hydroxymetaboliteofclarithromycinalsohasantimicrobialactivity.TheMICsofthismetaboliteareequalor

two-foldhigherthantheMICsoftheparentcompound,exceptforHaemophilusinfluenzaewherethe14-hydroxy

metaboliteistwo-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-resistanttolincosamidesandstreptogramineBbasedonmethylation

oftheribosomalbindingsite.Clarithromycinranksamongthestronginducersofthisenzymeaswell.Furthermore,

macrolideshaveabacteriostaticactionbyinhibitingthepeptidyltransferaseofribosomes.

Acompletecross-resistanceexistsamongclarithromycin,erythromycinandazithromycin.Methicillin-resistantand

oxacillin-resistantstaphylococci(MRSA)andpenicillin-resistantStreptococcuspneumoniaeareresistanttoall

currentlyavailableBeta-lactamantibioticsandmacrolidessuchasclarithromycin.

Breakpoints

Thefollowingbreakpointsforclarithromycin,separatingsusceptibleorganismsfromresistantorganisms,havebeen

establishedbytheEuropeanCommitteeforAntimicrobialSusceptibilityTesting(EUCAST)2010-12-20(v1.2):

Species-relatedbreakpointsfor

clarithromycin B,C

Pathogens Susceptible

(mg/L) Resistant>(mg/L)

Enterobacteriaceae - -

Pseudomonasspp. - -

Acinetobacterspp. - -

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A.Non-speciesrelatedbreakpointshavebeendeterminedmainlyonthebasisofPK/PDdataandareindependentofMICdistributionsof

specificspecies.Theyareforuseonlyforspeciesnotmentionedinthetableorfootnotes.However,pharmacodynamicdataforcalculationof

macrolide,lincosaminesandstreptograminsnon-speciesrelatedbreakpointsarenotrobust,henceIE.

B.Erythromycincanbeusedtodeterminethesusceptibilityofthelistedbacteriatotheothermacrolides

(azithromycin,clarithromycinandroxithromycin

C.ClarithromycinisusedfortheeradicationofH.pylori(MIC0.25mg/Lforwildtypeisolates).

D.ThecorrelationbetweenH.influenzaemacrolideMICsandclinicaloutcomeisweak.Therefore,breakpointsformacrolidesandrelated

antibioticsweresettocategorisewildtypeH.influenzaeasintermediate.

“IE"indicatesthatthereisinsufficientevidencethatthespeciesinquestionisagoodtargetfortherapywiththedrug.

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

hasbeenestablishedasthesusceptiblebreakpointbytheClinicalandLaboratoryStandardsInstitute(CLSI).

Susceptibility

Theprevalenceofacquiredresistancemayvarygeographicallyandwithtimeforselectedspeciesandlocalinformation

onresistanceisdesirable,particularlywhentreatingsevereinfections.Asnecessary,expertadviceshouldbesought

whenthelocalprevalenceofresistanceissuchthattheutilityoftheagentinatleastsometypesofinfectionsis

questionable.

Pathogensforwhichresistancemaybeaproblem:prevalenceofresistanceisequaltoorgreaterthan10%inatleast

Enterococcusspp. - -

StreptococcusgroupsA,B,

C,G 0,25 0.5

Streptococcuspneumoniae D 0.25 0.5

Otherstreptococci IE IE

Haemophilusinfluenzae 1 32

Moraxellacatarrhalis 0.25 0.5

Neisseriagonorrhoeae - -

Neisseriameningitidis - -

Gram-positiveanaerobes

(exceptClostridiumdifficile) - -

Gram-negativeanaerobes - -

Non-speciesrelatedbreak-

points A IE IE

Commonlysusceptiblespecies

AerobicGram-positivemicroorganisms

Corynebacteriumdiphteriae

StreptococcusGroupF

AerobicGram-negativemicroorganisms

Bordetellapertussis

Legionellaspp.

Moraxellacatarrhalis

Pasteurellamultocida

Anaerobes

Clostridumspp.otherthanC.difficile

Othermicroorganisms

Chlamydiatrachomatis

Chlamydiapneumoniae

Clamydophilapsitacci

Mycobacteriumspp.

Mycoplasmapneumoniae

Speciesforwhichacquiredresistancemaybeaproblem

AerobicGram-positivemicroorganisms

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10%resistanceinatleastonecountryoftheEuropeanUnion

*Speciesagainstefficacyhasbeendemonstratedinclinicalinvestigations(ifsusceptible)

+Indicatesspeciesforwhichahighrateofresistance(i.e.greaterthan50%)havebeenobservedinoneormorearea/country/region(s)ofthe

§BreakpointsformacrolidesandrelatedantibioticsweresettocategorisewildtypeH.influenzaeasintermediate

Otherinformation

SusceptibilityandresistanceofStreptococcuspneumoniaeandStreptococcusspp.toclarithromycincanbepredicted

bytestingerythromycin.

Mostavailableclinicalexperiencefromcontrolledrandomisedclinicaltrialsindicatethatclarithromycin500mgtwice

dailyincombinationwithanotherantibiotice.g.amoxicillinormetronidazoleande.g.omeprazole(givenatapproved

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

significantlylowereradicationrateswereobservedinpatientswithbaselinemetronidazole-resistantH.pyloriisolates.

Hence,localinformationontheprevalenceofresistanceandlocaltherapeuticguidelinesshouldbetakenintoaccount

inthechoiceofanappropriatecombinationregimenforH.pylorieradicationtherapy.Furthermore,inpatientswith

persistentinfection,potentialdevelopmentofsecondaryresistance(inpatientswithprimarysusceptiblestrains)toan

antimicrobialmedicinalproductshouldbetakenintotheconsiderationsforanewretreatmentregimen.

5.2Pharmacokineticproperties

Absorption:

Clarithromycinisrapidlyandwellabsorbedfromthegastrointestinaltract–primarilyinthejejunum-butundergoes

extensivefirst-passmetabolismafteroraladministration.Theabsolutebioavailabilityofa250-mgclarithromycintablet

isapproximately50%.Thebioavailabilityofthesuspensionisidenticaltoorslightlyhigherthanthebioavailabilityof

thetablets.Thepharmacokineticprofileofthesuspensioninchildrencorrespondstothepharmacokineticprofileofthe

suspensioninadults.Foodslightlydelaystheabsorptionbutdoesnotaffecttheextentofbioavailability.Therefore,

clarithromycinmaybegivenwithoutregardtofood.Duetoitschemicalstructure(6-O-Methylerythromycin)

clarithromycinisquiteresistanttodegradationbystomachacid.Peakplasmalevelsof1–2µg/mlclarithromycinwere

observedinadultsafteroraladministrationof250mgtwicedaily.Afteradministrationof500mgclarithromycintwice

dailythepeakplasmalevelwas2.8µg/ml.Inchildrenthefollowingsteady-stateparameterswereobservedafterthe

ninthdoseinadoseregimenof7.5mg/kgtwicedailyonaverageforclarithromycin:C

4.60µg/ml,AUC15.7

µg.hour/mlandT

Staphylococcusaureus(methicillin-susceptibleandmethicillin-resistant+)

Staphylococcusepidermidis+

StreptococcusGroupA*,B,C,G

Streptococcusviridans

Streptococcuspneumoniae*+

AerobicGram-negativemicroorganisms

Haemophilusinfluenzae§

Helicobacterpylori

Anaerobes

Bacteroidesspp.

Peptococcus/Peptostreptococcusspp.

Inherentlyresistantorganisms

AerobicGram-negativemicroorganisms

Acinetobacter

Enterobacteriacea

Pseudomonasaeruginosa

Anaerobes

Fusobacteriumspp.

Othermicroorganisms

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µg/ml,6.69µg.hour/mland2.7hours.

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.Witha250mgevery12hoursdosing,thehalf-

lifeoftheactive14-hydroxymetaboliterangesbetween5to6hoursfollowingadministrationof250mg

clarithromycintwicedaily.

Approximately20-40%ofclarithromycinisexcretedastheunchangedactivesubstanceintheurine.Thisproportionis

increasedwhenthedoseisincreased.Anadditional10%to15%isexcretedintheurineas14-hydroxymetabolite.The

restisexcretedinthefaeces.Renalinsufficiencyincreasesclarithromycinlevelsinplasma,ifthedoseisnotdecreased.

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.Thesystemiclevelsofexposure,relatedtothistoxicity,arenotknownindetail,buttoxicdoses

(300mg/kg/day)wereclearlyhigherthanthetherapeuticdosesrecommendedforhumans.Othertissuesaffected

includedthestomach,thymusandotherlymphoidtissuesaswellasthekidneys.Atneartherapeuticdosesconjunctival

injectionandlacrimationoccurredonlyindogs.Atamassivedoseof400mg/kg/daysomedogsandmonkeys

developedcornealopacitiesand/oroedema.

Invitroandinvivostudiesshowedthatclarithromycindidnothavegenotoxicpotential.

Studiesonreproductiontoxicityshowedthatadministrationofclarithromycinatdoses2xtheclinicaldoseinrabbit(iv)

and10xtheclinicaldoseinmonkey(po)resultedinanincreasedincidenceofspontaneousabortions.Thesedoseswere

relatedtomaternaltoxicity.Noembryotoxicityorteratogenicitywasgenerallynotedinratstudies.However,

cardiovascularmalformationswereobservedintwostudiesinratstreatedwithdosesof150mg/kg/d.Inmiceatdoses

70xtheclinicaldosecleftpalateoccurredatvaryingincidence(3-30%).

Clarithromycinhasbeenfoundinthemilkoflactatinganimals.

In3-dayoldmiceandrats,theLD

valueswereapproximatelyhalfthoseinadultanimals.Juvenileanimalspresented

similartoxicityprofilestomatureanimalsalthoughenhancednephrotoxicityinneonatalratshasbeenreportedinsome

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Clarithromycinhasnotbeentestedforcarcinogenicity.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Poloxamer188

PovidoneK30(E1201)

Hypromellose(E464)

Macrogol6000

Titaniumdioxide(E171)

Methacrylicacid–ethylacrylatecopolymer(1:1)

Triethylcitrate(E1505)

Glycerolmonostearate

Polysorbate80(E433)

Sucrose

Maltodextrin

Potassiumsorbate(E202)

Colloidalanhydroussilica(E551)

Xanthangum(E415)

Fruitpunchflavouring(naturalandartificialflavouringsubstancesincludingmaltodextrin,modifiedstarchand

maltol).

6.2Incompatibilities

Notapplicable.

6.3Shelflife

3years.

Afterreconstitution14days.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

Afterreconstitution:Donotstoreabove25°C.

6.5Natureandcontentsofcontainer

60ml,120mland240mlHDPEbottleswithchildresistantPP-screwclosures,anoralPE/PP-measuringsyringe

(5ml)withfillingmarksat2.5ml,3.75mland5.0mlandaPE/PP-measuringspoonwithfillingmarksat1.25ml,2.5

mland5.0ml.

1bottlecontains

47.8ggranulesfororalsuspensionfor70mlready-for-usesuspension(requiredwateramount:39.9ml)or

68.3ggranulesfororalsuspensionfor100mlready-for-usesuspension(requiredwateramount:57.0ml).

Irish Medicines Board

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Date Printed 07/02/2012 CRN 2087147 page number: 17

6.6Specialprecautionsfordisposalandotherhandling

Thebottleshouldbefilledwithtwo-thirdsoftheoverallrequiredquantityofwater,thenthoroughlyshakenandfilled

withwateruptothemarkandshakenagain.Thebottleshouldbeshakenvigorouslybeforeeachapplication.

Afterreconstitutionwithwaterthemedicinalproductresultsinawhitetobeigesuspension.

Ifthedoseistobegivenusingtheoraldosingsyringe,thesyringeadaptorshouldbeinsertedintothebottleneck.

7MARKETINGAUTHORISATIONHOLDER

RowexLtd

Bantry,

Co.Cork,

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA711/197/002

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:3rdFebruary2012

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 07/02/2012 CRN 2087147 page number: 18