CLARITHROMYCIN

Main information

  • Trade name:
  • CLARITHROMYCIN Coated Tablets 500mg Milligram
  • Dosage:
  • 500mg Milligram
  • Pharmaceutical form:
  • Coated Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CLARITHROMYCIN Coated Tablets 500mg Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0585/011/002
  • Authorization date:
  • 31-03-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Clarithromycin500mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains500mgClarithromycin

Forexcipients,see6.1.

3PHARMACEUTICALFORM

Film-coatedtablets.

Clarithromycin500mgtabletsarewhiteoblong,biconvexfilm-coatedtabletswitha

break-lineononeside

4CLINICALPARTICULARS

4.1TherapeuticIndications

Thetreatmentofinfectionsduetosusceptibleorganisms.Suchinfectionsinclude:

Lowerrespiratorytractinfections(e.g.bronchitis,pneumonia).

Upperrespiratorytractinfections(e.g.pharyngitis,sinusitis).

Skinandsofttissueinfections(e.g.folliculitis,cellulitis,erysipelas).

DisseminatedorlocalisedmycobacterialinfectionsduetoMycobacteriumaviumorMycobacterium

intracellulare.LocalisedinfectionsduetoMycobacteriumchelonae,MycobacteriumfortuitumorMycobacterium

kansasii.

ThepreventionofdisseminatedMycobacteriumaviumcomplexinfectioninHIVinfectedpatientswithCD4

lymphocytecountslessthanorequalto100/mm 3

ClarithromycininthepresenceofacidsuppressionisindicatedfortheeradicationofHelicobacterpylori,

resultingindecreasedrecurrenceofduodenalulcer.(Seefurtherinformation.)

Aswithotherantibiotics,itisrecommendedthatguidelinesontheprevalenceoflocalresistance,andassociated

medicalpracticeregardingtheprescriptionofantibioticsbeconsultedbeforeprescribingClarithromycin.

Furtherinformation:Helicobacterpyloriisstronglyassociatedwithpepticulcerdisease.Ninetyto100%ofpatients

withduodenalulcersareinfectedwiththisagent.EradicationofHelicobacterpylorihasbeenshowntomarkedly

reducetheneedformaintenanceanti-secretorytherapy.

Inawellcontrolleddouble-blindstudy,Helicobacterpyloriinfectedpatientswithduodenalulcerreceived

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ClarithromycinhasbeenusedinothertreatmentregimensfortheeradicationofHelicobacterpylori.Theseregimens

include:clarithromycinplustinidazoleandomeprazole:andclarithromycinplustetracycline,bismuthsalicylateand

ranitidine.

4.2Posologyandmethodofadministration

Theusualrecommendeddosageofclarithromycininadultsis250mgtwicedaily.Inmoresevereinfections,thedosage

canbeincreasedto500mgtwicedaily.Theusualdurationoftherapyis6to14days.

Inpatientswithrenalimpairmentwithcreatinineclearancelessthan30ml/min,thedosageofclarithromycinshouldbe

reducedbyone-half,i.e.250mgoncedaily,250mgtwicedailyinmoresevereinfections.Treatmentsshouldnotbe

continuedbeyond14daysinthesepatients.

Treatmentofmycobacterial(MAC)infections:Therecommendedstartingdoseis500mgtwicedaily.Ifnoclinicalor

bacteriologicresponseisobservedin3to4weeks,thedosemaybeincreasedto1000mgtwicedaily.Treatmentof

disseminatedMACinfectionsinAIDSpatientsshouldbecontinued,aslongasclinicalmicrobiologicalbenefitis

demonstrated.Clarithromycinshouldbeusedinconjunctionwithotherantimycobacterialagents.

Treatmentofothernon-tuberculousmycobacterialinfectionsshouldcontinueatthediscretionofthephysician.

DosageforMACprophylaxis:TherecommendeddosageofClarithromycininadultsis500mgtwicedaily.

EradicationofHelicobacterpylori:

Dualtherapy(14days):Therecommendeddoseofclarithromycinis500mgthreetimesdailyfor14days(seeFurther

information).

Tripletherapy(7days):Clarithromycin(500mg)twicedailyandaprotonpumpinhibitor(attheapproveddailydose)*

shouldbegivenwithamoxicillin1000mgormetronidazole400mgtwicedailyfor7days.

Tripletherapy(7–10days):Clarithromycin(500mg)twicedailyshouldbegivenwithamoxicillin1000mgtwicedaily

andOmeprazole20mgdailyfor7–10days.

*seeindividualSummariesofProductCharacteristicsforthedoserecommendationsforHelicobacterpylori

eradication.

4.3Contraindications

UseinpatientswithknownhypersensitivitytoClarithromycin,othermacrolideantibioticdrugsortoanyofthe

excipients.

Clarithromycinandergotderivativesshouldnotbeco-administered.

Concomitantadministrationofclarithromycinandanyofthefollowingdrugsiscontraindicated:cisapride,pimozide

andterfenadine.Elevatedcisapride,pimozideandterfenadinelevelshavebeenreportedinpatientsreceivingeitherof

thesedrugsandclarithromycinconcomitantly.ThismayresultinQTprolongationandcardiacarrhythmiasincluding

ventricularfibrillationandtorsadesdepointes.Similareffectshavebeenobservedwithconcomitantadministrationof

astemizoleandothermacrolides.

4.4Specialwarningsandprecautionsforuse

Clarithromycinshouldnotbeprescribedtopregnantwomenwithoutcarefullyweighingthebenefitsagainsttherisks,

particularlyduringthefirst3monthsofpregnancy.

Clarithromycinisprincipallyexcretedbytheliverandkidneysothatcautionmustbeexercisedinitsuseinpatients

withimpairedhepaticorrenalfunctionorinthoseconcomitantlyreceivingpotentiallyhepatotoxicdrugs.

Attentionshouldbepaidtothepossibilityofcrossresistancebetweenclarithromycinandothermacrolidedrugs,as

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Prolongedorrepeateduseofclarithromycinmayresultinovergrowthofnon-susceptiblebacteria.Ifsuper-infection

occurs,clarithromycinshouldbediscontinuedandappropriatetherapyinstituted.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Druginteractions:resultsofclinicalstudiesindicatethattherewasamodestbutstatisticallysignificant(p<0.05)

increaseofcirculatingtheophyllineorcarbamazepinelevelswheneitherofthesedrugswereco-administeredwith

clarithromycin.

Aswithothermacrolideantibioticstheuseofclarithromycininpatientsconcurrentlytakingdrugsmetabolisedbythe

cytochromeP450system(e.g.warfarin,ergotalkaloids,triazolam,midazolam,disopyramide,lovastatin,phenytoin,

ciclosporin,tacrolimusandrifabutin)maybeassociatedwithelevationsinserumlevelsoftheseotherdrugs.(Seealso

section4.3,Contraindications.)

Theeffectofdigoxinmaybepotentiatedwithconcomitantadministrationofclarithromycin.Monitoringofserum

digoxinlevelsshouldbeconsidered.

SimultaneousoraladministrationofclarithromycintabletsandzidovudinetoHIV-infectedadultpatientsmayresultin

decreasedsteady-statezidovudineconcentrations.Becauseclarithromycinappearstointerferewiththeabsorptionof

simultaneouslyadministeredoralzidovudine,thisinteractioncanbeavoidedlargelybystaggeringthedosesof

clarithromycinandzidovudine.Todate,thisinteractiondoesnotappeartooccurinpaediatricHIV-infectedpatients

takingclarithromycinsuspensionwithzidovudineordideoxyinosine.

Ritonavirincreasestheareaunderthecurve(AUC),C

andC

ofclarithromycinwhenadministeredconcurrently.

Becauseofthelargetherapeuticwindowforclarithromycin,nodosagereductionshouldbenecessaryinpatientswith

normalrenalfunction.However,forpatientswithrenalimpairment,thefollowingdosageadjustmentsshouldbe

considered:forpatientswithCL

<30to60ml/minthedoseofclarithromycinshouldbereducedby50%.For

patientswithCL

<30ml/minthedoseofclarithromycinshouldbedecreasedby75%.Dosesofclarithromycin

greaterthan1g/dayshouldnotbecoadministeredwithritonavir.

Rhabdomyolysiscoincidentwiththeco-administrationofclarithromycinandHMG-CoAreductaseinhibitors,suchas

lovastatinandsimvastatin,hasrarelybeenreported.

Therearenoknownclinicallysignificantinteractionsbetweenclarithromycinandprotonpumpinhibitors.

Therehavebeenpost-marketingreportsofcolchicinetoxicitywithconcomitantuseofclarithromycinandcolchicines,

especiallyintheelderly,someofwhichoccurredinpatientswithrenalinsufficiency.

4.6Pregnancyandlactation

Thesafetyofclarithromycininduringpregnancyorbreastfeedingofinfantshasnotbeenestablished.Clarithromycinis

excretedintohumanbreastmilk.

4.7Effectsonabilitytodriveandusemachines

Noneknown.

4.8Undesirableeffects

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i.e.nausea,dyspepsia,abdominalpain,vomitinganddiarrhoea.Othersideeffectsincludedheadache,alteredtaste,and

transientelevationsofliverenzymes.

Stomatitis,glossitis,oralmoniliaandtonguediscolourationhavebeenreported.Allergicreactionsrangingfrom

urticariaandmildskineruptionstoanaphylaxisandStevens-Johnsonsyndromehaveoccurredwithorally

administeredclarithromycin.Therehavebeenreportsoftransientcentralnervoussystemside-effectsincluding

dizziness,vertigo,anxiety,insomnia,baddreams,tinnitus,confusion,disorientation,hallucinations,psychosisand

depersonalization,however,acauseandeffectrelationshiphasnotbeenestablished.

Aswithothermacrolides,hepaticdysfunction(whichisusuallyreversible),includingalteredliverfunctiontests,

hepatitisandcholestasiswithorwithoutjaundice,hasbeenreported.Dysfunctionmaybesevereandveryrarelyfatal

hepaticfailurehasbeenreported.

Reportsofalterationofthesenseofsmell,usuallyinconjunctionwithtasteperversionhavealsobeenreceived.There

havebeenreportsoftoothdiscolourationinpatientstreatedwithclarithromycin.Toothdiscolourationisusually

reversiblewithprofessionaldentalcleaning.

Reversiblecasesofhearinglosshavebeenreportedwithclarithromycin.Therehavebeenrarereportsof

hypoglycaemia,someofwhichhaveoccurredinpatientsonconcomitantoralhypoglycaemicagentsorinsulin.Isolated

casesofthrombocytopeniahavebeenreported.

Pseudomembraneouscolitishasbeenreportedrarelywithclarithromycinandmayrangeinseverityfrommildtolife

threatening.

Isolatedcasesofincreasedserumcreatininehavebeenreportedbutanassociationhasnotbeenestablished.

Aswithothermacrolides,QTprolongation,ventriculartachycardiaandTorsadesdePointeshavebeenrarelyreported

withclarithromycin.

Adverseeventsinimmunocompromisedpatients:InAIDSandotherimmunocompromisedpatientstreatedwiththe

higherdosesofclarithromycinoverlongperiodsoftimeformycobacterialinfections,itwasoftendifficultto

distinguishadverseeventspossiblyassociatedwithclarithromycinadministrationfromunderlyingsignsofHIVdisease

orintercurrentillness.

Inadultpatients,themostfrequentlyreportedadverseeventsbypatientstreatedwithtotaldailydosesof1000mgand

2000mgwere:nausea,vomiting,tasteperversion,abdominalpain,diarrhoea,rash,flatulence,headache,constipation,

hearingdisturbance,SGOTandSGPTelevations.Additionallow-frequencyeventsincludeddyspnoea,insomniaand

drymouth.Theincidenceswerecomparableforpatientstreatedwith1000mgand2000mg,butweregenerallyabout3

to4timesasfrequentforthosepatientswhoreceivedtotaldailydosesof4000mgofclarithromycin.

Intheseimmunocompromisedpatientsevaluationsoflaboratoryvaluesweremadebyanalysingthosevaluesoutside

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

about2to3%ofthosepatientswhoreceived1000mgor2000mgofclarithromycindailyhadseriouslyabnormally

elevatedlevelsofSGOTandSGPT,andabnormallylowwhitebloodcellandplateletcounts.Alowerpercentageof

patientsinthesetwogroupsalsohadelevatedBloodUreaNitrogen(BUN)levels.Slightlyhigherincidencesof

abnormalvalueswerenotedforpatientswhoreceived4000mgdailyforallparametersexceptWBC.

4.9Overdose

Reportsindicatethattheingestionoflargeamountsofclarithromycinorallycanbeexpectedtoproducegastrointestinal

symptoms.Onepatientwhohasahistoryofbipolardisorderingested8000mgofclarithromycinandshowedaltered

mentalstatus,paranoidbehaviour,hypokalemiaandhypoxemia.Adversereactionsaccompanyingoverdosageshould

betreatedbytheprompteliminationofunabsorbeddrugandsupportivemeasures.Aswithothermacrolides,

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Clarithromycinisasemi-syntheticmacrolideantibioticobtainedbysubstitutionofthehydroxylgroupinposition6by

aCH

Ogroupintheerythromycinlactonicring.Specifically,Clarithromycinis6-0-MethylErythromycinA.

Clarithromycinexertsitsantibacterialactionbybindingtothe50sribosomalsubunitsofsusceptiblebacteriaand

suppressingproteinsynthesis.

Microbiology:Clarithromycinhasdemonstratedexcellentinvitroactivityagainststandardstrainsofbacteriaand

clinicalisolates.ItishighlypotentagainstawidevarietyofaerobicandanaerobicGram-positiveandGram-negative

organisms.Theminimuminhibitoryconcentrations(MICs)ofclarithromycinaregenerallyonelog 2

dilutionmore

potentthantheMICsoferythromycin.

InvitrodataalsoindicateclarithromycinhasexcellentactivityagainstLegionellapneumophila,andMycoplasma

pneumoniae.ItisbactericidaltoHelicobacterpylori;thisactivityofClarithromycinisgreateratneutralpHthanatacid

pH.Invitroandinvivodatashowthatthisantibiotichasactivityagainstclinicallysignificantmycobacterialspecies.

Theinvitroantibacterialspectrumofclarithromycinisasfollows:

Theprincipalmetaboliteofclarithromycininmanandprimatesisamicrobiologically-activemetabolite,14-OH-

clarithromycin.Themetaboliteisasactiveor1to2foldlessactivethantheparentcompoundformostorganisms,

exceptforHaemophilusinfluenzaeagainstwhichitistwiceasactive.Theparentcompoundandthe14-OH-metabolite

USUALLYSENSITIVEBACTERIA NON-SENSITIVEBACTERIA

Streptococcusagalactiae Enterobacteriacae

Streptococcuspyogenes Pseudomonasspecies

Streptococcusviridans

Streptococcuspneumoniae

Haemophilusinfluenzae

Haemophilusparainfluenzae

Neisseriagonorrhoeae

Listeriamonocytogenes

Legionellapneumophila

Pasteurellamultocida

Mycoplasmapneumoniae

Helicobacter(Campylobacter)pylori

Campylobacterjejuni

Chlamydiapneumoniae(TWAR)

Chlamydiatrachomatis

Moraxella(Branhamella)catarrhalis

Bordetellapertussis

Borreliaburgdorferi

Staphylococcusaureus

Clostridiumperfringens

Peptococcusniger

Propionibacteriumacnes

Bacteroidesmelaninogenicus

Mycobacteriumavium

Mycobacteriumleprae

Mycobacteriumkansasii

Mycobacteriumchelonae

Mycobacteriumfortuitum

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InguineapigswithLegionellainfection,anintraperitonealdoseof1.6mg/kg/dayofclarithromycinwasmoreeffective

than50mg/kg/dayoferythromycin.

SusceptibilityTests:Quantitativemethodsthatrequiremeasurementofzonediametersgivethemostpreciseestimate

ofsusceptibilityofbacteriatoantimicrobialagents.Onerecommendedprocedureusesdiscsimpregnatedwith15mcg

ofclarithromycinfortestingsusceptibility(Kirby-Bauerdiffusiontest);interpretationscorrelateinhibitionzone

diametersofthisdisctestwithMICvaluesforclarithromycin.TheMICsaredeterminedbythebrothoragardilution

method.TherecommendedtestmediumforsusceptibilitytestingofHaemophilusinfluenzaeaccordingtotheNational

CommitteeofClinicalLaboratoryStandards(NCCLS)istheHaemophilusTestMedium(H.T.M.).

ThecorrelationofdiscinhibitionzonediameterswithMICsisgiveninthefollowingtable:

ClarithromycinInterpretativeStandards

*HTM=HaemophilusTestMedium

S=Susceptible I=Intermediate R=Resistant

Withtheseprocedures,areportfromthelaboratoryof“susceptible”indicatesthattheinfectingorganismislikelyto

respondtotherapy.Areportof“resistant”indicatesthattheinfectiveorganismsarenotlikelytorespondtotherapy.A

reportof“intermediatesusceptibility”suggeststhatthetherapeuticeffectofthedrugmaybeequivocalorthatthe

organismwouldbesusceptibleifhigherdoseswereused(latteralsoreferredtoasmoderatelysusceptible).

5.2Pharmacokineticproperties

Thenon-linearkineticsoforallyadministeredclarithromycinhavebeenstudiedextensivelyinanumberofanimal

speciesandadulthumans.Thesestudieshaveshownthatclarithromycinisrapidlyandwellabsorbedfromthegastro-

intestinaltractwithanabsolutebioavailabilityofapproximately50%.Noaccumulationwasfoundandthemetabolic

dispositiondidnotchangeinanyspeciesfollowingmultipledosing.

Resultsoftheseanimalstudiesshowedthatclarithromycinlevelsinalltissues,exceptthecentralnervoussystem,were

severaltimeshigherthanthecirculatingdruglevels.Thehighestconcentrationswereusuallyfoundintheliverand

lungwherethetissuetoplasma(T/P)rationsreached10to20.

Invitrostudiesshowedthattheproteinbindingofclarithromycininhumanplasmaaveragedabout70%at

concentrationsof0.45–4.5micrograms/ml.Adecreaseinbindingto41%at45.0micrograms/mlsuggestedthatthe

bindingsitesmightbecomesaturated,butthisonlyoccurredatconcentrationsfarinexcessofthetherapeuticdrug

levels.

Clarithromycinandits14-OH-metabolitedistributereadilyintothebodytissuesandfluids.Limiteddatafromasmall

numberofpatientssuggestthatclarithromycindoesnotachievesignificantlevelsincerebro-spinalfluid(CSF)after

oraldoses(i.e.only1-2%ofserumlevelsarefoundinCSFinpatientswithnormalblood-CSFbarriers).

Concentrationsintissuesareusuallyseveralfoldhigherthanserumconcentrations.Examplesfromtissueandserum

concentrationsarepresentedbelow:

InhibitionZoneDiameter

(mm) MIC(micrograms/ml)

Organisms S I R S I R

AllOrganisms

(exceptHaemophilusandStaphylococci) =18 14-17 =13 =1 2-4 =8

Staphylococci =20 - =19 =0.5 - =1

Haemophilusinfluenzaewhentestedon

HTM* =13 11-12 =10 =8 16 =32

TissueType Tissue(micrograms/g) Serum(micrograms/ml)

Tonsil 1.6 0.8

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WithBIDdosingat250mg,thepeaksteadystateplasmaconcentrationwasattainedin2to3daysandaveragedabout

1micrograms/mlforclarithromycinand0.6mcg/mlfor14-OH-clarithromycin,whiletheeliminationhalf-livesofthe

parentdrugandmetabolitewere3-4hoursand5–6hours,respectively.

WithBIDdosingat500mg,thesteadystateC

forclarithromycinanditshydroxylatedmetaboliteaveraged2.7–1.9

micrograms/mland0.88–0.83micrograms/ml,respectively.Thehalf-lifeoftheparentdrugatthe500mgdoselevel

was4.5–4.8hours,whilethatofthe14-OH-clarithromycinwas6.9–8.7hours.Atsteadystate,the14-OH-

clarithromycinlevelsdidnotincreaseproportionatelywiththeclarithromycindose,andtheapparenthalf-livesofboth

clarithromycinanditshydroxylatedmetabolitetendedtobelongerathigherdoses.Thisnon-linearpharmacokinetic

behaviourofclarithromycin,coupledwiththeoveralldecreaseintheformationof14-hydroxylationandN-

demethylationproductatthehigherdoses,indicatethatthemetabolismofclarithromycinapproachessaturationathigh

doses.

Apharmacokineticstudywasconductedwithclarithromycin500mgt.i.d.andOmeprazole40mgq.i.d.When

clarithromycinwasgivenaloneat500mgq8h,themeansteady-stateC

valuewasapproximately31%higherand

valuewasapproximately119%higherthanwhenclarithromyciniscomparedwithapreviousstudyat500mg

q12h.ThemeanAUC

0-24 forclarithromycinwas65%greaterwhen500mgclarithromycinwasgivenq8hratherthan

q12h.NeitherT

norhalf-lifevaluesappearedsubstantiallydifferentbetweentheq8handq12hregimens.

Whenclarithromycinwasadministeredwithomeprazole,increasesinomeprazolehalf-lifeandAUC

0-24 were

observed.Forallsubjectscombined,themeanAUC

0-24 was89%greaterandtheharmonicmeanforomeprazoleT

was34%greaterwhenomeprazolewasadministeredwithclarithromycinthanwhenomeprazolewasadministered

alone.Whenclarithromycinwasadministeredwithomeprazole,thesteadystateC

,CminandAUC

of

clarithromycinwasincreasedby10%,27%and15%,respectively,overvaluesachievedwhenclarithromycinwas

administeredwithplacebo.

Inhumanadultsgivensingleoraldosesof250mgor1200mgclarithromycin,urinaryexcretionaccountedfor37.9%of

thelowerdoseand46.0%ofthehigherdose.Faecaleliminationaccountedfor40.2%and29.1%oftheserespective

doses.

Atsteadystate,clarithromycingastricmucusconcentrationssixhoursafterdosingwhereapproximately25-holdhigher

intheclarithromycin/omeprazolegroupcomparedtotheclarithromycinalonegroup.Sixhourspost-dosing,mean

clarithromycingastrictissueconcentrationswereapproximately2-foldhigherwhenclarithromycinwasgivenwith

omeprazolethanwhenclarithromycinwasgivenwithplacebo.

Inastudycomparingonegroupofhealthyhumansubjectswithagroupofsubjectswithliverimpairmentwhowere

given250mgofclarithromycinBIDfor2daysandasingle250mgdoseonthethirdday,steadystateplasmalevelsand

systemicclearanceofclarithromycinwerenotsignificantlydifferentbetweenthetwogroups.Incontrast,steadystate

concentrationsofthe14-OHmetaboliteweremarkedlylowerinthegroupofhepatic-impairedsubjects.Thisdecreased

metabolicclearanceoftheparentcompoundby14-hydroxylationwaspartiallyoffsetbyanincreaseintherenal

clearanceofparentdrug,resultingincomparablesteadystatelevelsofparentdruginthehepaticimpairedandhealthy

subjects.Theseresultsindicatethatnoadjustmentofdosageisnecessaryforsubjectswithmoderateorseverehepatic

impairmentbutwithnormalrenalfunction.

Astudywasconductedtoevaluateandcomparethepharmacokineticprofileofmultiple500mgoraldosesof

clarithromycininsubjectswithnormalanddecreasedrenalfunction.Plasmalevels,half-life,C

andC

were

higherforbothclarithromycinandits14-OHmetaboliteandAUCwaslargerinsubjectswithrenalimpairment.K

elim

andurinaryexcretionwerelower.Theextenttowhichtheseparametersdifferedwascorrelatedwiththedegreeofrenal

impairment:themoreseveretherenalimpairment,themoresignificantthedifference.

Pharmacokineticsinelderlysubjects:Astudywasalsoconductedtoevaluateandcomparethesafetyand

pharmacokineticprofilesofmultiple500mgoraldosesofclarithromycininhealthyelderlymaleandfemalesubjectsto

thoseinhealthyyoungadultmalesubjects.Intheelderlygroup,circulatingplasmalevelswerehigherandelimination

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However,therewasnodifferencebetweenthetwogroupswhenrenalclearancewascorrelatedwithcreatinine

clearance.Itisconcludedfromtheseresultsthatanyeffectonthehandlingofclarithromycinisrelatedtorenalfunction

andnottoageperse.

Pharmacokineticsinpatientswithmycobacterialinfections:Steady-stateconcentrationsofclarithromycinand14-OH-

clarithromycinobservedfollowingadministrationofusualdosestoadultpatientswithHIVinfectionweresimilarto

thoseobservedinnormalsubjects.However,atthehigherdoseswhichmayberequiredtotreatmycobacterial

infections,clarithromycinconcentrationsweremuchhigherthanthoseobservedattheusualdoses.InadultHIV-

infectedpatientstaking2000mg/dayintwodivideddoses,steady-stateclarithromycinC

valuesrangedfrom5–10

micrograms/ml.C

valuesashighas27micrograms/mlhavebeenobservedinHIV-infectedadultpatientstaking

4000mg/dayintwodivideddoses.Eliminationhalf-livesappearedtobelengthenedatthesehigherdosesascompared

tothoseseenwithusualdosesinnormalsubjects.Thehigherplasmaconcentrationsandlongereliminationhalf-lives

observedatthesedosesareconsistentwiththeknownnon-linearityofclarithromycinpharmacokinetics.

5.3Preclinicalsafetydata

Acute,SubchronicandChronicToxicity:

Studieswereconductedinmice,rats,dogsand/ormonkeyswithclarithromycinadministeredorally.Thedurationof

administrationrangedfromasingleoraldosetorepeateddailyoraladministrationfor6consecutivemonths.

Inacutemouseandratstudies,1rat,butnomice,diedfollowingasinglegavageof5g/kgbodyweight.Themedian

lethaldose,therefore,wasgreaterthan5g/kg,thehighestfeasibledoseforadministration.

Noadverseeffectswereattributedtoclarithromycininprimatesexposedto100mg/kg/dayfor14consecutivedaysor

35mg/kg/dayfor1month.Similarly,noadverseeffectswereseeninratsexposedto75mg/kg/dayfor1month,to35

mg/kg/dayfor3months,or8mg/kg/dayfor6months.Dogsweremoresensitivetoclarithromycin,tolerating50

mg/kg/dayfor14days,10mg/kg/dayfor1and3months,and4mg/kg/dayfor6monthswithoutadverseeffects.

Themajorclinicalsignsattoxicdosesinthesestudiesincludedemesis,weakness,reducedfoodconsumptionand

weightgain,salivation,dehydrationandhyperactivity.Twooftenmonkeysreceiving400mg/kg/daydiedontreatment

day8;yellowdiscolouredfaeceswerepassedonafewisolatedoccasionsbysomesurvivingmonkeysgivenadoseof

400mg/kg/dayfor28days.

Theprimarytargetorganattoxicdosagesinallspecieswastheliver.Thedevelopmentofhepatotoxicityinallspecies

wasdetectablebyearlyelevationofserumconcentrationsofalkalinephosphatase,alanineandaspartat

aminotransferase,gamma-glutamyltransferase,and/orlacticdehydrogenase.Discontinuationofthedruggenerally

resultedinareturntoortowardnormalconcentrationsofthesespecificparameters.

Additionaltissueslesscommonlyaffectedincludedthevariousstudiesincludedthestomach,thymusandother

lymphoidtissuesandthekidneys.Conjunctivalinjectionandlacrimation,followingneartherapeuticdosages,occurred

indogsonly.Atamassivedoseof400mg/kg/day,somedogsandmonkeysdevelopedcornealopacitiesand/or

oedema.

Fertility,ReproductionandTeratogenicity:

Fertilityandreproductionstudieshaveshowndailydosagesof150–160mg/kg/daytomaleandfemaleratscausedno

adverseeffectsontheoestrouscycle,fertility,parturitionandthenumberorviabilityofoffspring.Twoteratogenicity

studiesinbothWistar(p.o.)andSprague-Dawley(p.o.andi.v.)rats,1studyinNewZealandWhiterabbitsandone

studyincynomologousmonkeysfailedtodemonstrateanyteratogenicityfromclarithromycin.Onlyinoneadditional

studyinSprague-Dawleyratsatsimilardosesandessentiallysimilarconditionsdidaverylow,statistically

insignificantincidence(approximately6%)ofcardiovascularanomaliesoccur.Theseanomaliesappearedtobedueto

spontaneousexpressionofgeneticchangeswithinthecolony.

Twomousestudiesinmicealsorevealedavariableincidence(3-30%)ofcleftpalatefollowingdosesof70timesthe

upperrangeoftheusualdailyhumanclinicaldose(500mgBID),butnotatthe35timesthemaximaldailyhuman

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Clarithromycinhasbeenshowntoproduceembryoniclossinmonkeyswhenadministeredatapproximately10times

theupperrangeoftheusualdailyhumandose(500mgBID),startingatgestationday20.Thiseffecthasbeenattributed

tomaternaltoxicityofthedrugatveryhighdoses.Anadditionalstudyinpregnantmonkeysatdosagesof

approximately2.5to5timesthemaximalintendeddailydosageproducednouniquehazardtotheconceptus.

Adominantlethaltestinmicegiven1000mg/kg/day(approximately70timesthemaximalhumandailyclinicaldose)

wasclearlynegativeforanymutagenicactivity,and,inaSegmentIstudyofratstreatedwithupto500mg/kg/day

(approximately35timesthemaximaldailyhumanclinicaldose)for80days,noevidenceoffunctionalimpairmentof

malefertilityduetothislong-termexposuretotheseveryhighdosesofclarithromycinwasexhibited.

Mutagenicity:

Studiestoevaluatethemutagenicpotentialofclarithromycinwereperformedusingbothnonactivatedandrat-liver

microsome-activatedtestsystems(Amestest).Resultsofthesestudiesshowednoevidenceofmutagenicpotentialat

drugconcentrationsof25micrograms/petriplateorless.Ataconcentrationof50micrograms,thedrugwastoxicfor

allstrainstested.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Povidone

Microcrystallinecellulose

Croscarmellosesodium

Colloidalanhydroussilica

Magnesiumstearate

OpadryII31F8914whitecoatingcontaininghypromellose,lactosemonohydrate,titaniumdioxide(E171),macrogol

4000,sodiumcitrate

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

3years

6.4Specialprecautionsforstorage

Donotstoreabove25°C

6.5Natureandcontentsofcontainer

PVC/Aluminiumblister.Cartoncontaining14,20,28,42,84,or168tablets

Notallpacksizesmaybemarketed

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Irish Medicines Board

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7MARKETINGAUTHORISATIONHOLDER

PlivaPharmaLimited

VisionHouse

BedfordRoad

Petersfield

Hampshire

GU323QB

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA0585/011/002

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:31March2006

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 23/09/2007 CRN 2040179 page number: 10