CLARIE LA

Main information

  • Trade name:
  • CLARIE LA
  • Dosage:
  • 500 Milligram
  • Pharmaceutical form:
  • Tablet Prolonged Release
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CLARIE LA
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0749/125/001
  • Authorization date:
  • 01-10-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ClarieLA500mgProlonged-releaseTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

EachtabletcontainsClarithromycincitrateequivalenttoClarithromycin500mg

Excipients:Eachtabletcontainslactose

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Prolonged-releasetablet

Yellow,oblongprolonged-releasetablet.

4CLINICALPARTICULARS

4.1TherapeuticIndications

ClarieLAisindicatedinthefollowinginfectionscausedbysusceptibleorganisms:

-Communityacquiredpneumonia

-Acuteexacerbationofchronicbronchitis

-Acutebacterialsinusitis(adequatelydiagnosed)

-Bacterialpharyngitisandtonsillitis

-Skinandsofttissueinfections(mildtomoderateseverity)

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantibacterialagents.

ClarieLAisindicatedinadultsandchildren12yearsandolder.

4.2Posologyandmethodofadministration

Adults:TheusualrecommendeddosageofClarieLAinadultsisone500mgprolonged-releasetabletdailytobetaken

withfood.

Inmoresevereinfections,thedosagecanbeincreasedtotwo500mgprolonged-releasetabletstakenasonedosedaily.

Dosemustbetakenatthesametimeeveryday.

Tabletsmustbeswallowedwhole.

Theusualdurationoftreatmentis6to14days.

Childrenolderthan12years:Asforadults.

Childrenyoungerthan12years:UseofClarieLAisnotrecommendedforchildrenyoungerthan12years.

Clarithromycinsuspensionshouldbeusedinthisagegroup.

Patientswithrenalimpairment:ClarieLAshouldnotbeusedinpatientswithrenalimpairment(creatinineclearance

lessthan30ml/min).Clarithromycinimmediate-releasetabletsshouldbeusedinthispatientpopulation(seesection

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 30/08/2011 CRN 2096241 page number: 1

Patientswithhepaticimpairment:CautionshouldbeexercisedwhenadministratingClarieLAinpatientswith

hepaticimpairment(seesection4.4).

4.3Contraindications

Clarithromyciniscontra-indicatedinpatientswithknownhypersensitivitytomacrolideantibioticdrugs.

Concomitantadministrationofclarithromycinandanyofthefollowingdrugsiscontraindicated:cisapride,pimozide,

astemizole,terfenadine,andergotamineordihydroergotamine.(seesection4.5).

Asthedosecannotbereducedfrom500mgdaily,ClarieLAiscontraindicatedinpatientswithcreatinineclearance

lessthan30ml/min.

4.4Specialwarningsandprecautionsforuse

Clarithromycinisprincipallyexcretedbytheliverandkidneys.Therefore,cautionshouldbeexercisedinadministering

theantibiotictopatientswithimpairedhepaticfunction.Cautionshouldalsobeexercisedwhenadministering

clarithromycintopatientswithmoderatetosevererenalimpairment(seealsosection4.3).

Therehavebeenpost-marketingreportsofcolchicinetoxicitywithconcomitantuseofclarithromycinandcolchicine,

especiallyinelderlyand/orpatientswithrenalinsufficiency,somewithafataloutcome(seesections4.5and4.8).

Pseudomembranouscolitishasbeenreportedwithnearlyallantibacterialagents,includingclarithromycin,andmay

rangeinseverityfrommildtolifethreatening.Therefore,itisimportanttoconsiderthisdiagnosisinpatientswho

presentwithdiarrhoeasubsequenttotheadministrationofantibacterialagents.

Long-termusemay,aswithotherantibiotics,resultincolonizationwithincreasednumbersofnon-susceptiblebacteria

andfungi.Ifsuperinfectionsoccur,appropriatetherapyshouldbeinstituted.

ClarieLAcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiency

orglucose-galactosemalabsorptionshouldnottakethismedicine.

Clarithromycinshouldnotbegiventopatientswithuncorrectedhypokalaemia(riskofQTintervalprolongation).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Useofthefollowingdrugsisstrictlycontraindicatedduetothepotentialforseveredruginteractioneffects:

Cisapride,pimozide,andterfenadine

Clarithromycinhasbeenreportedtoelevateplasmalevelsofcisapride,pimozide,astemizole,andterfenadine.

Increasedlevelsofthesedrugsmayresultinincreasedriskofventricularrhythmdisorders,especiallyTorsadesde

Pointes.

Concomitantadministrationofclarithromycinandanyofthesemedicinalproductsiscontraindicated(seesection4.3).

Ergotamine/dihydroergotamine

Post-marketingreportsindicatethatco-administrationofclarithromycinwithergotamineordihydroergotaminehas

beenassociatedwithacuteergottoxicitycharacterizedbyvasospasm,andischemiaoftheextremitiesandothertissues

includingthecentralnervoussystem.Concomitantadministrationofclarithromycinandthesemedicinalproductsis

contraindicated(seesection4.3).

Effectofothermedicinalproductsonclarithromycin

ClarithromycinismetabolisedviaenzymeCYP3A4.Therefore,stronginhibitorsofthisenzymemayinhibit

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 30/08/2011 CRN 2096241 page number: 2

Thefollowingdrugsareknownorsuspectedtoaffectcirculatingconcentrationsofclarithromycin;clarithromycin

dosageadjustmentorconsiderationofalternativetreatmentsmayberequired:

Fluconazole

Concomitantadministrationoffluconazole200mgdailyandclarithromycin500mgtwicedailyto21healthy

volunteersledtoincreasesinthemeansteady-stateminimumclarithromycinconcentration(Cmin)andareaunderthe

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

hydroxyclarithromycinwerenotsignificantlyaffectedbyconcomitantadministrationoffluconazole.Noclarithromycin

doseadjustmentisnecessary.

Ritonavir

Co-administrationofclarithromycinandritonavirincreasestheareaunderthecurve(AUC),maximumconcentration

(Cmax)andtheminimumconcentration(Cmin)ofclarithromycin.Becauseofthelargetherapeuticwindowfor

clarithromycin,nodosagereductionshouldbenecessaryinpatientswithnormalrenalfunction.

Forpatientswithmoderaterenalfunction(creatinineclearance30to60ml/min),thedoseofclarithromycinshouldbe

decreasedby50%.

Forpatientswithcreatinineclearance<30ml/min,thedoseofclarithromycinshouldbedecreasedby75%usingan

appropriateclarithromycinformulation,suchasclarithromycinimmediatereleasetablets,orclarithromycinsachet,or

clarithromycin,paediatricsuspensions(notallpresentationsmaybemarketed).

Dosesofclarithromycingreaterthan1000mgperdayshouldnotbecoadministeredwithproteaseinhibitors(see

section4.2).

Similardoseadjustmentsshouldbeconsideredinpatientswithreducedrenalfunctionwhenritonavirisusedasa

pharmacokineticenhancerwithotherHIVproteaseinhibitorsincludingatazanavirandsaquinavir(seesectionbelow,

bidirectionalpharmacokineticinteractions).

StronginducersofthecytochromeP450metabolismsystemsuchasefavirenz,nevirapine,rifampicin,rifabutin,and

rifapentinemayacceleratethemetabolismofclarithromycinandthuslowertheplasmalevelsofclarithromycin,while

increasingthoseof14(R)-hydroxyclarithromycin,ametabolitethatisalsomicrobiologicallyactive.Sincethe

microbiologicalactivitiesofclarithromycinand14(R)-hydroxy-clarithromycinaredifferentfordifferentbacteria,the

intendedtherapeuticeffectcouldbeimpairedduringconcomitantadministrationofclarithromycinandenzyme

inducers.

Effectofclarithromycinonothermedicinalproducts

CYP3A-basedInteractions

Co-administrationofclarithromycin,knowntoinhibitCYP3A,andadrugprimarilymetabolizedbyCYP3Amaybe

associatedwithelevationsindrugconcentrationsthatcouldincreaseorprolongboththerapeuticandadverseeffectsof

theconcomitantdrug.

ClarithromycinshouldbeusedwithcautioninpatientsreceivingtreatmentwithotherdrugsknowntobeCYP3A

enzymesubstrates,especiallyiftheCYP3Asubstratehasanarrowsafetymargin(e.g.,carbamazepine)and/orthe

substrateisextensivelymetabolizedbythisenzyme.

Dosageadjustmentsmaybeconsidered,andwhenpossible,serumconcentrationsofdrugsprimarilymetabolizedby

CYP3Ashouldbemonitoredcloselyinpatientsconcurrentlyreceivingclarithromycin.

Antiarrhythmics

Therehavebeenpost-marketingreportsoftorsadedepointesoccurringwithconcurrentuseofclarithromycinand

quinidineordisopyramide.ElectrocardiogramsshouldbemonitoredforQTcprolongationduringco-administrationof

clarithromycinwiththesedrugs.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 30/08/2011 CRN 2096241 page number: 3

Carbamazepine

Duringtherapywithclarithromycin,themetabolismofcarbamazepinemaybeinhibited.

Consequentlytheserumconcentrationsofcarbamazepinemaybeincreased,anddosereductionmayneedtobe

considered.

HMG-CoAReductaseInhibitors(e.g.,lovastatin,simvastatin)

Clarithromycininhibitsthemetabolizationofanumberof3-hydroxy-3-methylglutarylcoenzymeA(HMG-CoA)

reductaseinhibitors.Thismayresultinelevatedplasmalevelsofthesedrugs.

Inrarecases,theoccurrenceofrhabdomyolysiswasreportedwithconcomitantadministrationofclarithromycinand

HMG-CoAreductaseinhibitors(statins),suchaslovastatinorsimvastatin.

Patientsshouldbemonitoredforsignsandsymptomsofmyopathy.Adjustmentofthestatindosageoruseofastatin

thatislessdependentonCYP3Ametabolism,e.g.,pravastatin,shouldbeconsidered.

Clarithromycinmaycausesimilarinteractionswithatorvastatin.

Oralanticoagulants(e.g.,warfarin,acenocoumarol)

Inisolatedcases,patientsreceivingcombinationtherapywithclarithromycinandoralanticoagulantsmayexperience

increasedpharmacologiceffectsandeventoxiceffectsofthesedrugs.

Internationalnormalizedratio(INR)orProthrombintimesshouldbecarefullymonitoredwhilepatientsare

simultaneouslyreceivingclarithromycinandoralanticoagulants.

Sildenafil,tadalafil,andvardenafil

Eachofthesephosphodiesteraseinhibitorsismetabolized,atleastinpart,byCYP3A,andCYP3Amaybeinhibitedby

concomitantlyadministeredclarithromycin.

Co-administrationofclarithromycinwithsildenafil,tadalafilorvardenafilwouldlikelyresultinincreased

phosphodiesteraseinhibitorexposure.

Reductionofsildenafil,tadalafilandvardenafildosagesshouldbeconsideredwhencoadministeredwith

clarithromycin.

Theophylline

Duringtherapywithclarithromycin,themetabolismoftheophyllinemaybeinhibited.

Consequentlytheserumconcentrationsoftheophyllinemaybeincreased,anddosereductionmayneedtobe

considered.

Tolterodine

Theprimaryrouteofmetabolismfortolterodineisviathe2D6isoformofcytochromeP450(CYP2D6).However,ina

subsetofthepopulationdevoidofCYP2D6,theidentifiedpathwayofmetabolismisviaCYP3A.

Inthispopulationsubset,inhibitionofCYP3Aresultsinsignificantlyhigherserumconcentrationsoftolterodine.A

reductionintolterodinedosagemaybenecessaryinthepresenceofCYP3Ainhibitors,suchasclarithromycin.

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

Whenmidazolamwasco-administeredwithclarithromycintablets(500mgtwicedaily),midazolamAUCwas

increased2.7-foldafterintravenousadministrationofmidazolamand7-foldafteroraladministration.

Concomitantadministrationoforalmidazolamandclarithromycinshouldbeavoided.Ifintravenousmidazolamisco-

administeredwithclarithromycin,thepatientmustbecloselymonitoredtoallowdoseadjustment.

ThesameprecautionsshouldalsoapplytootherbenzodiazepinesthataremetabolisedbyCYP3A,includingtriazolam

andalprazolam.

ForbenzodiazepineswhicharenotmetabolisedbyCYP3A(temazepam,nitrazepam,lorazepam)aninteractionwith

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 30/08/2011 CRN 2096241 page number: 4

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

somnolenceandconfusion)withtheconcomitantuseofclarithromycinandtriazolam.Monitoringthepatientfor

increasedCNSpharmacologicaleffectsissuggested.

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.

Ciclosporin,tacrolimusandsirolimus

Concomitantadministrationoftheoralformofclarithromycinwithciclosporinortacrolimusresultsinamorethan

two-foldincreaseofCminplasmaconcentrationsofciclosporinandtacrolimus.Similareffectscanalsobeexpected

withsirolimus.

Plasmalevelsofciclosporin,tacrolimusorsirolimusshouldbethoroughlymonitoredwhencommencingtreatment

withclarithromycininpatientsonanyoftheabovementionedimmunosuppresants,andtheirdosesshouldbedecreased,

ifnecessary.

Clarithromycindiscontinuationinthosepatientsalsorequiresathoroughmonitoringofciclosporin,tacrolimusor

sirolimusplasmalevelstoguidedoseadjustment.

TherehavebeenspontaneousorpublishedreportsofdruginteractionsofCYP3Ainhibitors,includingclarithromycin,

withciclosporin,tacrolimus,methylprednisolone,vinblastine,andcilostazol.

OtherInteractions

Colchicine

ColchicineisasubstrateforbothCYP3Aandtheeffluxtransporter,P-glycoprotein(Pgp).Clarithromycinandother

macrolidesareknowntoinhibitCYP3AandPgp.Whenclarithromycinandcolchicineareadministeredtogether,

inhibitionofPgpand/orCYP3Abyclarithromycinmayleadtoincreasedexposuretocolchicine.

Patientsshouldbemonitoredforclinicalsymptomsofcolchicinetoxicity(seesection4.4).

Digoxin

Digoxinisasubstratefortheeffluxtransporter,P-glycoprotein(Pgp).ClarithromycinisknowntoinhibitPgp.When

clarithromycinanddigoxinareadministeredtogether,inhibitionofPgpbyclarithromycinmayleadtoincreased

exposuretodigoxin.Elevateddigoxinserumconcentrationsinpatientsreceivingclarithromycinanddigoxin

concomitantlyhavealsobeenreportedinpostmarketingsurveillance.Somepatientshaveshownclinicalsigns

consistentwithdigoxintoxicity,includingpotentiallyfatalarrhythmias.

Serumdigoxinconcentrationsshouldbecarefullymonitoredwhilepatientsarereceivingdigoxinandclarithromycin

simultaneously.

Zidovudine

Duetoreducedgastrointestinalabsorptionofzidovudineinthepresenceofclarithromycin,reducedserumlevelsof

zidovudinewereobservedinadultsduringconcomitanttherapywithclarithromycinandzidovudine.

Becauseclarithromycinappearstointerferewiththeabsorptionofsimultaneouslyadministeredoralzidovudine,

patientsshouldobservea4-hourintervalbetweentakingthesetwodrugs.

ThisinteractiondoesnotappeartooccurinpediatricHIV-infectedpatientstakingclarithromycinsuspensionwith

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 30/08/2011 CRN 2096241 page number: 5

PhenytoinandValproate

TherehavebeenspontaneousorpublishedreportsofinteractionswithCYP3Ainhibitors,includingclarithromycin,and

drugsnotthoughttobemetabolizedbyCYP3A,includingphenytoinandvalproate.

Serumleveldeterminationsarerecommendedforthesedrugswhenadministeredconcomitantlywithclarithromycin.

Increasedconcentrationshavebeenreported.

Bidirectionalpharmacokineticinteractions

Atazanavir

Co-administrationofclarithromycin(500mgtwicedaily)withatazanavir(400mgoncedaily)resultedina2-fold

increaseinexposuretoclarithromycinanda70%decreaseinexposureto14(R)-hydroxy-clarithromycin,witha28%

increaseintheAUCofatazanavir.

Becauseofthelargetherapeuticwindowforclarithromycin,nodosagereductionshouldbenecessaryinpatientswith

normalrenalfunction.

Forpatientswithmoderaterenalfunction(creatinineclearance30to60ml/min),thedoseofclarithromycinshouldbe

decreasedby50%.

Forpatientswithcreatinineclearance<30ml/min,thedoseofclarithromycinshouldbedecreasedby75%usingan

appropriateclarithromycinformulation,suchasclarithromycinimmediatereleasetablets,orclarithromycinsachet,or

clarithromycinpaediatricsuspensions(notallpresentationsmaybemarketed).

Dosesofclarithromycingreaterthan1000mgperdayshouldnotbeco-administeredwithproteaseinhibitors(seealso

section4.2).

Atazanavirisco-administeredwithritonavirintheEU,thereforethecommentsforthismedicinalproductshouldalso

betakenintoaccount.

Itraconazole

BothclarithromycinanditraconazolearesubstratesandinhibitorsofCYP3A,leadingtoabidirectionaldrug

interaction:Clarithromycinmayincreasetheplasmalevelsofitraconazole,whileitraconazolemayincreasetheplasma

levelsofclarithromycin.

Patientstakingitraconazoleandclarithromycinconcomitantlyshouldbemonitoredcloselyforsignsorsymptomsof

increasedorprolongedpharmacologiceffect.

Saquinavir

BothclarithromycinandsaquinaviraresubstratesandinhibitorsofCYP3A,andthereisevidenceofabidirectional

druginteraction.

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

healthyvolunteersresultedinsteady-stateareaunderthecurve(AUC)andmaximumconcentration(Cmax)valuesof

saquinavirwhichwere177%and187%higherthanthoseseenwithsaquinaviralone.

ClarithromycinAUCandCmaxvalueswereapproximately40%higherthanthoseseenwithclarithromycinalone.

Nodoseadjustmentisrequiredwhenthetwodrugsareco-administeredforalimitedtimeatthedoses/formulations

studied.

Observationsfromdruginteractionstudiesusingthesoftgelatincapsuleformulationmaynotberepresentativeofthe

effectsseenusingthesaquinavirhardgelatincapsule.Observationsfromdruginteractionstudiesdonewithunboosted

saquinavirmaynotberepresentativeoftheeffectsseenwithsaquinavir/ritonavirtherapy.Whensaquinavirisco-

administeredwithritonavir,considerationshouldbegiventothepotentialeffectsofritonavironclarithromycin(see

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 30/08/2011 CRN 2096241 page number: 6

4.6Fertility,pregnancyandlactation

Pregnancy

Thesafetyofclarithromycinforuseduringpregnancyandbreastfeedingofinfantshasnot

beenestablished.Clarithromycinshouldthusnotbeusedduringpregnancyorlactationunlessthebenefitisconsidered

tooutweightherisk.

Dataontheuseofclarithromycinduringthefirsttrimesterofmorethan200pregnanciesshownoclearevidenceof

teratogeniceffectsoradverseeffectsonthehealthoftheneonate.Datafromalimitednumberofpregnantwomen

exposedinthefirsttrimesterindicateapossibleincreasedriskofabortions.Todatenootherrelevantepidemiological

dataareavailable.

Datafromanimalstudieshaveshownreproductivetoxicity(seesection5.3).Theriskforhumansisunknown.

Clarithromycinshouldnotbegiventopregnantwomenunlessitisclearlyneeded.

Lactation

Clarithromycinanditsactivemetaboliteareexcretedinbreastmilk.Therefore,diarrhoeaandfungusinfectionofthe

mucousmembranescouldoccurinthebreast-fedinfant,sothatnursingmighthavetobediscontinued.Thepossibility

ofsensitisationshouldbeborneinmind.Thebenefitoftreatmentofthemothershouldbeweighedagainstthepotential

riskfortheinfant.

4.7Effectsonabilitytodriveandusemachines

Therearenodataontheeffectofthisproductonthedrivingability.Whendrivingorusingmachines,oneshouldtake

intoaccountthatdizzinessmayoccur.

4.8Undesirableeffects

Clinicalexperience

ThemostcommonlyreportedADRweregastro-intestinaldisorders(nausea,diarrhoea,dyspepsia,abdominalpain).

FrequenciesofADRs:

Verycommon(1/10);common(1/100to<1/10);uncommon(1/1000to<1/100);rare(1/10,000to<1/1,000);

veryrare(1/10,000),notknown(cannotbeestimatedfromtheavailabledata).

Investigations

Common:Elevatedbloodureanitrogen

Uncommon:Prothrombintimeprolongation,elevatedserumcreatinine,changesinliverfunctiontests(elevated

transaminaseslevels),alanineaminotransferaseincreased,alkalinephosphateincreased,aspartateaminotransferase

increased,bloodlactatedehydrogenaseincreased,prothrombindecreased.

Veryrare:Hypoglycaemiahasbeenreportedinparticularinconcomitantadministrationofantidiabeticagentsand

insulin.

Cardiacdisorders

Veryrare:QTintervalprolongation,ventriculartachycardia,torsadesdepointes.

Bloodandlymphaticsystemdisorders

Uncommon:Leucopenia.anaemia,eosinophilia,hypochromicanaemia,thrombocythaemia

Veryrare:Thrombocytopenia.

Nervoussystemdisorders

Common:Headache,smellalteration

Uncommon:Tremor,dizziness

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 30/08/2011 CRN 2096241 page number: 7

Earandlabyrinthdisorders

Uncommon:Tinnitus,vertigo

Veryrare:Reversiblelossofhearing

Notknown:Irreversiblelossofhearing

Gastrointestinaldisorders

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

reversiblediscolorationoftongueandteeth,tasteabnormalities,e.g.metalorbittertaste.

Uncommon:Constipation,drymouth,eructation,flatulence,gastrointestinalhaemorrhage

Veryrare:Pancreatitis.Pseudomembranouscolitiswhichmaybemildtolife-threatening.

Renalandurinarydisorders

Uncommon:Albuminuria,haematuria,pyuria

Veryrare:Interstitialnephritis,renalfailure.

Skinandsubcutaneoustissuedisorders

Uncommon:Dryskin,eczema,hyperhidrosis,pruritus,rash,rashmaculo-papular,rashpustular

Veryrare:Stevens-Johnson´ssyndromeandtoxicepidermalnecrolysis.

Musculoskeletal,connectivetissuedisorders

Uncommon:Arthralgia,myalgia,backpain

Infectionsandinfestations

Common:Moniliasisoforalcavity.

Uncommon:Gastroenteritis,rhinitis,vaginalcandidiasis,vaginalinfection

Long-termusemay,aswithotherantibiotics,resultincolonizationwithincreasednumbersofnon-susceptiblebacteria

andfungi.Ifsuperinfectionsoccur,appropriatetherapyshouldbeinstituted.

Immunesystemdisorders

Uncommon:AllergicreactionsfromurticariaandmildskinrashuptoAnaphylaxis

Hepatobiliarydisorders

Uncommon:Liverdysfunctionwhichusuallyistransientandreversible,hepatitisandcholestasiswithorwithout

jaundice.Hyperbilirubinaemia

Veryrare:Hepaticfailurewithfatalcoursehasbeenreportedparticularlyinpatientswithpreexistinghepaticdiseaseor

inpatientsreceivingotherhepatotoxicmedicinalproducts.

Psychiatricdisorders

Uncommon:Depression,insomnia,nervousness,somnolence

Veryrare:Anxiety,hallucinations,psychosis,disorientationanddepersonalisation,nightmares,confusion.

Metabolismandnutritiondisorders

Uncommon:Anorexia,hyperchloraemia,hyperuricaemia,hypocalcaemia,increasedappetite

Eyedisorders

Uncommon:Conjunctivitis,visualdisturbance

Vasculardisorders

Uncommon:Vasodilatation

Respiratory,thoracicandmediastinaldisorders

Uncommon:Asthma,dyspnoea

Reproductivesystemandbreastdisorders

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 30/08/2011 CRN 2096241 page number: 8

Generaldisordersandadministrationsiteconditions

Uncommon:Asthenia,chestpain,faceoedema,malaise,pain,thirst

Pseudomembranouscolitishasbeenreportedwithnearlyallantibacterialagents,includingclarithromycin,andmay

rangeinseverityfrommildtolifethreatening.Therefore,itisimportanttoconsiderthisdiagnosisinpatientswho

presentwithdiarrhoeasubsequenttotheadministrationofantibacterialagents.

Therehavebeenpost-marketingreportsofcolchicinetoxicitywithconcomitantuseofclarithromycinandcolchicine,

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

4.9Overdose

Reportsindicatethattheingestionoflargeamountsofclarithromycincanbeexpectedtoproducegastro-intestinal

symptoms.Onepatientwhohadahistoryofbipolardisorderingested8gramsofclarithromycinandshowedaltered

mentalstatus,paranoidbehaviour,hypokalaemiaandhypoxaemia.Adversereactionsaccompanyingoverdosageshould

betreatedbygastriclavageandsupportivemeasures.

Aswithothermacrolides,clarithromycinserumlevelsarenotexpectedtobeappreciablyaffectedbyhaemodialysisor

peritonealdialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

GeneralProperties

ATCclassification

Pharmacotherapeuticgroup:Anti-infectious,ATCcode:J01FA09.

ModeofAction

Clarithromycinisanantibioticbelongingtothemacrolideantibioticsgroup.Itexertsitsantibacterialactionby

inhibitingtheintracellularproteinsynthesisofsusceptiblebacteria.Itselectivelybindstothe50Ssubunitofbacterial

ribosomesandthuspreventsthetranslocationofactivatedaminoacids.

Clarithromycinhasrelevantbactericidalactivityagainstseveralbacterialstrains.

TheorganismsincludeH.influenzae,S.pneumoniae,S.pyogenes,S.aureus,M.catarrhalis,H.pylori,C.pneumoniae,

M.pneumoniae,L.pneumophila,M.avium,andM.intracellulare.

The14(R)-hydroxymetaboliteofclarithromycin,aproductofparentdrugmetabolisminhumans,alsohas

antimicrobialactivity.

Themetaboliteislessactivethantheparentcompoundformostorganisms,includingMycobacteriumspp.

AnexceptionisHaemophilusinfluenzaeagainstwhichthemetaboliteis1to2timesmoreactivethantheparent

compound.Clarithromycincombinedwiththemetaboliteshowedastrain-dependentadditiveorsynergisticeffectboth

invitroandinvivo.

PK/PDRelationship

Clarithromycinisextensivelydistributedinbodytissuesandfluids.Becauseofhightissuepenetration,intracellular

concentrationsarehigherthanserumconcentrations.

Clarithromycinconcentrationsintonsilandwholelungtissueare2-to6-foldhigherthanthoseobservedintheserum.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 30/08/2011 CRN 2096241 page number: 9

Thepharmacokineticsoforallyadministeredmodified-release(LA)clarithromycintabletshavebeenstudiedinadult

humans(refertosection5.2)andcomparedwithclarithromycin250mgand500mgIRtablets.Theextentof

absorption–areaundercurve(AUC)–wasfoundtobeequivalentwhenequaltotaldailydoseswereadministered.The

equivalentAUCswouldbeexpectedtodrivetissuelevelsequivalenttothoseobservedforclarithromycinIRtablets.

MechanismofResistance

AcquiredmacrolideresistanceinS.pneumoniae,S.pyogenes,andS.aureusismediatedprimarilybythepresenceof

oneoftwomechanisms(i.e.ermandmeformsr).

Ribosomalbindingoftheantimicrobialispreventedthroughmethylationoftheribosomebyanenzyme(erm).

Alternativelyaneffluxmechanism(meformsr)canpreventtheantimicrobialfromreachingitsribosomaltargetby

pumpingtheantimicrobialoutofthecell.NoacquiredresistancemechanismshavebeenidentifiedinMoraxellaor

Haemophilusspp.Macrolideresistancemechanismsareequallyeffectiveagainst14-and15-membered

macrolidesincludingerythromycin,clarithromycin,roxithromycin,andazithromycin.Themechanismsforpenicillin

resistanceandmacrolideresistanceareunrelated.

Attentionshouldbepaidtotheerm-mediatedcross-resistancebetweenmacrolidessuchasclarithromycinand

lincosamidessuchaslincomycinandclindamycin.

Breakpoints

AccordingtotheEUCAST2009v1.4thefollowingbreakpointshavebeendefinedforclarithromycin 1,2

IE=Thereisinsufficientevidencethatthespeciesinquestionisagoodtargetfortherapywiththedrug.

Erythromycincanbeusedtodeterminethesusceptibilityofthelistedbacteriatotheothermacrolides(azithromycin,

clarithromycinandroxithromycin).MacrolidesadministeredintravenouslyareactiveagainstLegionellapneumophila

(erythromycinMIC1mg/Lforwildtypeisolates).Macrolideshavebeenusedinthetreatmentofinfectionswith

Campylobacterjejuni(erythromycinMIC4mg/Lforwildtypeisolates).Azithromycinhasbeenusedinthetreatment

MeanClarithromycinConcentration[250mgBID]

TissueType Tissue Serum

Tonsil 1.6µg/g 0.8µg/ml

Lung 8.8µg/g 1.7µg/ml

BACTERIASPECIES MICbreakpoints

S /R>(mg/L)

Acinetobacter -/-

Enterobacteriaceae -/-

Enterococcus -/-

Haemophilusinfluenzae 3 1.0/32

Moraxellacatarrhalis 0.25/0.5

Neisseriagonorrhoeae -/-

Neisseriameningitides -/-

Otherstreptococci IE

Staphylococcusspp 1.0/2.0

Pseudomonas -/-

StreptococcusA,B,C,G 0.25/0.5

Streptococcuspneumoniae 0.25/0.5

Gram-negative,anaerobes -/-

Gram-positive,anaerobes -/-

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 30/08/2011 CRN 2096241 page number: 10

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

ThecorrelationbetweenH.influenzaemacrolideMICsandclinicaloutcomeisweak.Therefore,breakpointsfor

macrolidesandrelatedantibioticsweresettocategorisewildtypeH.influenzaeasintermediate.

Theactivityof14(R)-hydroxy-clarithromycinisgreaterthanthatofclarithromycinagainstHaemophilusinfluenzae.

Studiesdoneinvitrohavesuggestedanadditiveactivityofthe14(R)-hydroxy-clarithromycinandtheparentmolecule

againstH.influenzae.

Susceptibility:

Theprevalenceofresistancemayvarygeographicallyandwithtimeforselectedspeciesandlocalinformationon

resistanceisdesirable,particularlywhentreatingsevereinfections.Asnecessary,expertadviceshouldbesoughtwhen

thelocalprevalenceofresistanceissuchthattheutilityoftheagentinatleastsometypesofinfectionsisquestionable.

*speciesagainstwhichefficacyhasbeendemonstratedinclinicalinvestigations

(ifsusceptible)

+Indicatesspeciesforwhichahighrateofresistance(i.e.greaterthan50%)

hasbeenobservedinoneormorearea/country/region(s)oftheEU

Commonlysusceptiblespecies:

AerobicGram-positivemicro-organisms:

StreptococcusgroupF

AerobicGram-negativemicro-organisms:

Legionellapneumophila

Moraxellacatarrhalis

Legionellaspp.

Anaerobicmicro-organisms:

Clostridiumperfringens

“Other”organisms:

Chlamydiapneumoniae(TWAR)

Chlamydiatrachomatis

Mycoplasmapneumoniae

Speciesforwhichacquiredresistancemaybeaproblem#:

AerobicGram-positivemicro-organisms:

Staphylococcusaureus(resistantorsusceptible*tomethicillin)+

Staphylococcuscoagulasenegative+

StreptococcusgroupB,C,G

Streptococcuspneumoniae*+

Streptococcuspyogenes*

Streptococcusspp

AerobicGram-negativemicro-organisms:

H.influenzae§

Inherentlyresistantorganisms:

AerobicGram-positivemicro-organisms:

Enterococcusspp

AerobicGram-negativemicro-organisms:

Enterobacteriaceae

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 30/08/2011 CRN 2096241 page number: 11

10%resistanceinatleastonecountryoftheEuropeanUnion

5.2Pharmacokineticproperties

Thekineticsoforallyadministeredmodified-releaseclarithromycinhavebeenstudiedinadulthumansandcompared

withclarithromycin250mgand500mgimmediatereleasetablets.Theextentofabsorptionwasfoundtobeequivalent

whenequaltotaldailydoseswereadministered.Theabsolutebioavailabilityisapproximately50%.Littleorno

unpredictedaccumulationwasfoundandthemetabolicdispositiondidnotchangeinanyspeciesfollowingmultiple

dosing.Baseduponthefindingofequivalentabsorptionthefollowinginvitroandinvivodataareapplicabletothe

modified-releaseformulation.

Invitro:Resultsofinvitrostudiesshowedthattheproteinbindingofclarithromycininhumanplasmaaveragedabout

70%atconcentrationsof0.45-4.5µg/ml.Adecreaseinbindingto41%at45.0µg/mlsuggestedthatthebindingsites

mightbecomesaturated,butthisonlyoccurredatconcentrationsfarinexcessoftherapeuticdruglevels.

Invivo:Clarithromycinlevelsinalltissues,exceptthecentralnervoussystem,wereseveraltimeshigherthanthe

circulatingdruglevels.Thehighestconcentrationswerefoundintheliverandlungtissue,wherethetissuetoplasma

ratiosreached10to20.

Thepharmacokineticbehaviourofclarithromycinisnon-linear.Infedpatientsgiven500mgclarithromycinmodified-

releasedaily,thepeaksteadystateplasmaconcentrationofclarithromycinanditsactivemetabolite,14-hydroxy

clarithromycinwere1.3and0.48µg/ml,respectively.Whenthedosagewasincreasedto1000mgdaily,thesesteady-

statevalueswere2.4µg/mland0.67µg/mlrespectively.MetabolismisintheliverinvolvingtheP450cytochrome

system.Threemetabolitesaredescribed:N-demethylclarithromycin,decladinosylclarithromycinand14-hydroxy

clarithromycin.Eliminationhalf-livesoftheparentdrugandmetabolitewereapproximately5.3and7.7hours

respectively.Theapparenthalf-livesofbothclarithromycinanditshydroxylatedmetabolitetendedtobelongerat

higherdoses.

Urinaryexcretionaccountedforapproximately40%oftheclarithromycindose.

Faecaleliminationaccountsforapproximately30%.

5.3Preclinicalsafetydata

Inacutetoxicitystudiesinmouseandrat,themedianlethaldosewasgreaterthanthehighestfeasibledosefor

administration(5g/kg).

Inrepeateddosestudies,toxicitywasrelatedtodose,durationoftreatmentandspecies.Dogsweremoresensitivethan

primatesorrats.Themajorclinicalsignsattoxicdosesincludedemesis,weakness,reducedfoodconsumptionand

weightgain,salivation,dehydrationandhyperactivity.Inallspeciestheliverwastheprimarytargetorganattoxic

doses.Hepatotoxicitywasdetectablebyearlyelevationsofliverfunctiontests.Discontinuationofthedruggenerally

resultedinareturntoortowardnormalresults.Othertissueslesscommonlyaffectedincludedthestomach,thymusand

otherlymphoidtissuesandthekidneys.

Atneartherapeuticdoses,conjunctivalinjectionandlacrimationoccurredonlyindogs.Atamassivedoseof

400mg/kg/day,somedogsandmonkeysdevelopedcornealopacitiesand/oroedema.

Fertilityandreproductionstudiesinratshaveshownnoadverseeffects.Teratogenicitystudiesinrats(Wistar(p.o.)and

Sprague-Dawley(p.o.andi.v.)),NewZealandWhiterabbitsandcynomolgousmonkeysfailedtodemonstrateany

teratogenicityfromclarithromycin.However,afurthersimilarstudyinSprague-Dawleyratsindicatedalow(6%)

incidenceofcardiovascularabnormalitieswhichappearedtobeduetospontaneousexpressionofgeneticchanges.Two

mousestudiesrevealedavariableincidence(3-30%)ofcleftpalateandinmonkeysembryoniclosswasseenbutonly

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 30/08/2011 CRN 2096241 page number: 12

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore

LactoseMonohydrate

Hypromellose

HypromellosePhthalate

Talc

MagnesiumStearate

FilmCoat

Hypromellose

LactoseMonohydrate

Macrogol4000

Macrogol400

QuinolineYellowAluminiumLake(E104)

Talc

TitaniumDioxide(E171)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

2years

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

Storeintheoriginalpackageinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

AvailableinblisterpackofClearPVC/PVdCliddedwithaluminiumfoilforblisterpackof7or14tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 30/08/2011 CRN 2096241 page number: 13

7MARKETINGAUTHORISATIONHOLDER

TevaPharmaB.V.

Computerweg10

3542DRUtrecht

TheNetherlands

8MARKETINGAUTHORISATIONNUMBER

PA749/125/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:1October2010

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 30/08/2011 CRN 2096241 page number: 14