CLARYL

Main information

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

Documents

Localization

  • Available in:
  • CLARYL Coated Tablets 500 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0281/131/002
  • Authorization date:
  • 19-05-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Claryl500mgFilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

EachFilm-coatedtabletcontains500mgofclarithromycin

Forlistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Yellow,oval,biconvexmarkedwith`500`ononesideand‘CL’ontheotherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Clarithromycinisindicatedforthetreatmentofinfectionsduetosusceptibleorganisms.Suchinfectionsinclude:-

Lowerrespiratorytractinfections(e.g.bronchitis,pneumonia).

Upperrespiratorytractinfections(e.g.pharyngitis,sinusitis).

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

DisseminatedorlocalisedmycobacterialinfectionsduetoMycobacteriumaviumorMycobacterium

intracellulare.LocalisedinfectionsduetoMycobacteriumchelonae,Mycobacteriumfortuitumor

Mycobacteriumkansasii.

ClarithromycinisindicatedforthepreventionofdisseminatedMycobacteriumaviumcomplexinfectioninHIV

-infectedpatientswithCD4lymphocytecountslessthanorequalto100/mm³.

ClarithromycininthepresenceofacidsuppressionisindicatedfortheeradicationofH.pylori,resultingin

decreasedrecurrenceofduodenalulcer.(Seefurtherinformation).

Aswithotherantibiotics,itisrecommendedthatguidelinesontheprevalenceoflocalresistance,andassociated

medicalpracticeregardingtheprescriptionofantibiotics,beconsultedbeforeprescribingclarithromycin.

FurtherInformation:H.pyloriisstronglyassociatedwithpepticulcerdisease.90to100%ofpatientswithduodenal

ulcersareinfectedwiththisagent.EradicationofH.pylorihasbeenshowntomarkedlyreducetherateofduodenal

ulcerrecurrence,therebyreducingtheneedformaintenanceanti-secretorytherapy.Inawellcontrolleddouble-blind

study,H.pyloriinfectedpatientswithduodenalulcerreceivedclarithromycin500mgTIDfor14dayswithomeprazole

40mgdailyfor28days.ClarithromycinhasbeenusedinothertreatmentregimensfortheeradicationofH.pylori.

Theseregimensinclude:Clarithromycinplustinidazoleandomeprazole;andclarithromycinplustetracycline,bismuth

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4.2Posologyandmethodofadministration

Theusualrecommendeddosageofclarithromycininadultsisone250mgtablettwicedaily.Inmoresevereinfections,

thedosagecanbeincreasedto500mgtwicedaily.Theusualdurationoftherapyis6to14days.

Inpatientswithrenalimpairmentwithcreatinineclearancelessthan30ml/min,thedosageofclarithromycinshouldbe

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

continuedbeyond14daysinthesepatients.

Dosageinpatientswithmycobacterialinfections:Therecommendedstartingdoseis500mgtwicedaily.Ifnoclinical

orbacteriologicresponseisobservedin3to4weeks,thedosemaybeincreasedto1000mgtwicedaily.Treatmentof

disseminatedMycobacteriumAviumComplex(MAC)infectionsinAIDSpatientsshouldbecontinued,aslongas

clinicalmicrobiologicalbenefitisdemonstrated.Clarithromycinshouldbeusedinconjunctionwithother

antimycobacterialagents.

Treatmentofothernon-tuberculousmycobacterialinfectionsshouldcontinueatthediscretionofthephysician.

DosageforMACprophylaxis:Therecommendeddosageofclarithromycininadultsis500mgtwicedaily.

EradicationofH.pylori:

DualTherapy(14days):Therecommendeddoseofclarithromycinis500mgthreetimesdailyfor14days.(see

FurtherInformationabove).

TripleTherapy(7days):Clarithromycin(500mg)twicedailyandaprotonpumpinhibitor(attheapproveddailydose)

*shouldbegivenwithamoxycillin1000mgtwicedailyfor7days.

TripleTherapy(7days):Clarithromycin(500mg)twicedailyandaprotonpumpinhibitor(attheapproveddailydose)

*shouldbegivenwithmetronidazole400mgtwicedailyfor7days.

TripleTherapy(7-10days):Clarithromycin(500mg)twicedailyshouldbegivenwithamoxycillin1000mgtwice

dailyandomeprazole20mgdailyfor7-10days.

*seeindividualdatasheets/SPCsforthedoserecommendationsforH.pylorieradication.

4.3Contraindications

Useinpatientswithknownhypersensitivitytomacrolideantibioticdrugs.

Clarithromycinandergotderivativesshouldnotbeco-administered.

Concomitantadministrationofclarithromycinandanyofthefollowingdrugsiscontra-indicated:cisapride,pimozide

andterfenadine.Elevatedcisapride,pimozideandterfenadinelevelshavebeenreportedinpatientsreceivingeitherof

thesedrugsandclarithromycinconcomitantly.ThismayresultinQTprolongationandcardiacarrhythmiasincluding

ventricularfibrillationandtorsadedepointes.Similareffectshavebeenobservedwithconcomitantadministrationof

astemizoleandothermacrolides.

4.4Specialwarningsandprecautionsforuse

Clarithromycinisexcretedprincipallybytheliverandkidneysothatcautionmustbeexercisedinitsuseinpatients

withimpairedhepaticorrenalfunctionorinthoseconcomitantlyreceivingpotentiallyhepatotoxicdrugs.

Attentionshouldbepaidtothepossibilityofcrossresistancebetweenclarithromycinandothermacrolidedrugs,as

wellaslincomycinandclindamycin.

Prolongedorrepeateduseofclarithromycinmayresultinovergrowthofnon-susceptiblebacteria.Ifsuper-infections

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Resultsofclinicalstudiesindicatethattherewasamodestbutstatisticallysignificant(p<0.05)increaseofcirculating

theophyllineorcarbamazepinelevelswheneitherofthesedrugsareadministeredconcomitantlywithclarithromycin.

Aswithothermacrolideantibioticstheuseofclarithromycininpatientsconcurrentlytakingdrugsmetabolisedbythe

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

cyclosporin,tacrolimusandrifabutin)maybeassociatedwithelevationsinserumlevelsoftheseotherdrugs.(Seealso

section4.3,Contraindications).

Theeffectsofdigoxinmaybepotentiatedwithconcomitantadministrationofclarithromycin.Monitoringofserum

digoxinlevelsshouldbeconsidered.

SimultaneousoraladministrationofclarithromycintabletsandzidovudinetoHIV-infectedadultpatientsmayresultin

decreasedsteady-statezidovudineconcentrations.Becauseclarithromycinappearstointerferewiththeabsorptionof

simultaneouslyadministeredoralzidovudine,thisinteractioncanbelargelyavoidedbystaggeringthedosesof

clarithromycinandzidovudine.Todate,thisinteractiondoesnotappeartooccurinpaediatricHIV-infectedpatients

takingclarithromycinsuspensionwithzidovudineordideoxyinosine.

Ritonavirincreasestheareaunderthecurve(AUC),C

andC

ofclarithromycinwhenadministeredconcurrently.

Becauseofthelargetherapeuticwindowforclarithromycin,nodosagereductionshouldbenecessaryinpatientswith

normalrenalfunction.However,forpatientswithrenalimpairment,thefollowingdosageadjustmentsshouldbe

considered:ForpatientswithCL

30to60ml/minthedoseofclarithromycinshouldbereducedby50%.Forpatients

withCL

<30ml/minthedoseofclarithromycinshouldbedecreasedby75%.Dosesofclarithromycingreaterthan1

g/dayshouldnotbeco-administeredwithritonavir.

Rhabdomyolysisconincidentwiththeco-administrationofclarithromycinandHMG-CoAreductaseinhibitors,suchas

lovastatinandsimvastatin,hasrarelybeenreported.

Therearenoknownclinicallysignificantinteractionsbetweenclarithromycinandprotonpumpinhibitors.

4.6Pregnancyandlactation

Safeuseinpregnancyhasnotbeenestablished.Useinwomenbreastfeedinginfantsisnotrecommended.Someanimal

studieshavesuggestedateratogeniceffectatdosessignificantlyinexcessofthoserecommendedforclinicaluse.

clarithromycinhasbeenfoundinthemilkoflactatinganimalsandhumans.

4.7Effectsonabilitytodriveandusemachines

Noneknown.

4.8Undesirableeffects

ThemostfrequentlyreportedsideeffectsofClarithromycininclinicalstudiesweregastrointestinal-relatedcomplaints,

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

transientelevationsofliverenzymes.

Stomatitis,glossitis,oralmoniliaandtonguediscolourationhavebeenreported.

AllergicreactionsrangingfromurticariaandmildskineruptionstoanaphylaxisandStevens-JohnsonSyndrome/toxic

epidermalnecrolysishaveoccurredwithorallyadministeredclarithromycin.Therehavebeenreportsoftransient

centralnervoussystemsideeffectsincludingdizziness,vertigo,anxiety,insomnia,baddreams,tinnitus,confusion,

disorientation,hallucinations,psychosis,anddepersonalisation,however,acauseandeffectrelationshiphasnotbeen

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Aswithothermacrolides,hepaticdysfunction(whichisusuallyreversible),includingalteredliverfunctiontests,

hepatitisandcholestasiswithorwithoutjaundice,hasbeenreported.Dysfunctionmaybesevereandveryrarelyfatal

hepaticfailurehasbeenreported.

Reportsofalterationofthesenseofsmell,usuallyinconjunctionwithtasteperversionhavealsobeenreceived.There

havebeenreportsoftoothdiscolourationinpatientstreatedwithclarithromycin.Toothdiscolourationisusually

reversiblewithprofessionaldentalcleaning.

Reversiblecasesofhearinglosshavebeenreportedwithclarithromycin.Therehavebeenrarereportsof

hypoglycaemia,someofwhichhaveoccurredinpatientsonconcomitantoralhypoglycaemicagentsorinsulin.Isolated

casesofthrombocytopeniahavebeenreported.

Pseudomembranouscolitishasbeenreportedrarelywithclarithromycinandmayrangeinseverityfrommidtolife

threatening.

Isolatedcasesofincreasedserumcreatininehavebeenreportedbutanassociationhasnotbeenestablished.

Aswithothermacrolides,QTprolongation,ventriculartachycardiaandTorsadedePointeshavebeenrarelyreported

withclarithromycin.

Adverseeventsinimmunocompromisedpatients:InAIDSandotherimmunocompromisedpatientstreatedwiththe

higherdosesofclarithromycinoverlongperiodsoftimeformycobacterialinfections,itwasoftendifficultto

distinguishadverseeventspossiblyassociatedwithclarithromycinadministrationfromunderlyingsignsofHIVdisease

orintercurrentillness.Inadultpatients,themostfrequentlyreportedadverseeventsbypatientstreatedwithtotaldaily

dosesof1000mgand2000mgofclarithromycinwere:nausea,vomiting,tasteperversion,abdominalpain,diarrhoea,

rash,flatulence,headache,constipation,hearingdisturbance,SGOTandSGPTelevations.Additionallow-frequency

eventsincludeddyspnoea,insomniaanddrymouth.Theincidenceswerecomparableforpatientstreatedwith1000mg

and2000mg,butweregenerallyabout3to4timesasfrequentforthosepatientswhoreceivedtotaldailydosesof

4000mgofclarithromycin.

Intheseimmunocompromisedpatientsevaluationsoflaboratoryvaluesweremadebyanalysingthosevaluesoutside

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

about2%to3%ofthosepatientswhoreceived1000mgor2000mgofclarithromycindailyhadseriouslyabnormal

elevatedlevelsofSGOTandSGPT,andabnormallylowwhitebloodcellandplateletcounts.

AlowerpercentageofpatientsinthesetwodosagegroupsalsohadelevatedBloodUreaNitrogen(BUN)levels.

Slightlyhigherincidencesofabnormalvalueswerenotedforpatientswhoreceived4000mgdailyforallparameters

exceptWBC.

4.9Overdose

Reportsindicatethattheingestionoflargeamountsofclarithromycinorallycanbeexpectedtoproducegastrointestinal

symptoms.Adversereactionsaccompanyingoverdosageshouldbetreatedbytheprompteliminationofunabsorbed

drugandgeneralsupportivemeasures.Aswithothermacrolides,clarithromycinserumlevelsarenotexpectedtobe

appreciablyaffectedbyhaemodialysisorperitonealdialysis.

Onepatientwhohasahistoryofbipolardisorderingested8gramsofclarithromycinandshowedalteredmentalstatus,

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Clarithromycinisasemi-syntheticderivativeoferythromycinA.Itexertsitsantibacterialactionbybindingtothe50s

ribosomalsub-unitofsusceptiblebacteriaandsuppressesproteinsynthesis.Itishighlypotentagainstawidevarietyof

aerobicandanaerobicgram-positiveandgram-negativeorganisms.Theminimuminhibitoryconcentrations(MICs)of

clarithromycinaregenerallytwo-foldlowerthantheMICsoferythromycin.

The14-hydroxymetaboliteofclarithromycinalsohasantimicrobialactivity.TheMICsofthismetaboliteareequalor

two-foldhigherthantheMICsoftheparentcompound,exceptforH.influenzaewherethe14-hydroxymetaboliteis

two-foldmoreactivethantheparentcompound.

Clarithromycinisusuallyactiveagainstthefollowingorganismsinvitro:-

GrampositiveBacteria:Staphylococcusaureus(methicillinsusceptible);Streptococcuspyogenes(GroupAbeta-

hemolyticstreptococci);alpha-hemolyticstreptococci(viridansgroup);Streptococcus(Diplococcus)pneumoniae;

Streptococcusagalactiae;Listeriamonocytogenes.

Gram-negativeBacteria:Haemophilusinfluenzae;Haemophilusparainfluenzae;Moraxella(Branhamella)catarrhalis;

Neisseriagonorrhoeae;Legionellapneumophila;Bordetellapertussis;Helicobacterpylori;Campylobacterjejuni.

Mycoplasma:Mycoplasmapneumoniae;Ureaplasmaurealyticum.

OtherOrganisms:Chlamydiatrachomatis;Mycobacteriumavium;Mycobacteriumleprae.

Anaerobes:Macrolide-susceptibleBacteroidesfragilis;Clostridiumperfringens;Peptococcusspecies;

Peptostreptococcusspecies;Propionibacteriumacnes.

Clarithromycinhasbactericidalactivityagainstseveralbacterialstrains.TheorganismsincludeHaemophilus

influenzae,Streptococcuspneumoniae,Streptococcuspyogenes,Streptococcusagalactiae,Moraxella(Branhamella)

catarrhalis,Neisseriagonorrhoeae,H.pyloriandCampylobacterspp.

H.pyloriisassociatedwithacidpepticdiseaseincludingduodenalulcerandgastriculcerinwhichabout95%and80%

ofpatientsrespectivelyareinfectedwiththeagent.H.pyloriisalsoimplicatedasamajorcontributionfactorinthe

developmentofgastricandulcerrecurrenceinsuchpatients.

Clarithromycinhasbeenusedinsmallnumbersofpatientsinothertreatmentregimens.Possiblekineticinteractions

havenotbeenfullyinvestigated.Theseregimensinclude:

Clarithromycinplustinidazoleandomeprazole;clarithromycinplustetracycline,bismuthsubsalicylateandranitidine;

clarithromycinplusranitidinealone.

ClinicalstudiesusingvariousdifferentH.pylorieradicationregimenshaveshownthateradicationofH.pylori

preventsulcerrecurrence.

5.2Pharmacokineticproperties

Clarithromycinisrapidlyandwellabsorbedfromthegastro-intestinaltractafteroraladministrationofclarithromycin

tablets.Themicrobiologicallyactivemetabolite14-hydroxyclarithromycinisformedbyfirstpassmetabolism.

Clarithromycinmaybegivenwithoutregardtomealsasfooddoesnotaffecttheextentofbioavailabilityof

clarithromycintablets.Fooddoesslightlydelaytheonsetofabsorptionofclarithromycinandformationofthe14-

hydroxymetabolite.Thepharmacokineticsofclarithromycinarenonlinear;however,steady-stateisattainedwithin2

daysofdosing.At250mgb.i.d.15-20%ofunchangeddrugisexcretedintheurine.With500mgb.i.d.dailydosing

urinaryexcretionisgreater(approximately36%).The14-hydroxyclarithromycinisthemajorurinarymetaboliteand

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5-10%oftheparentdrugisrecoveredfromthefaeces.

Whenclarithromycin500mgisgiventhreetimesdaily,theclarithromycinplasmaconcentrationsareincreasedwith

respecttothe500mgtwicedailydosage.

Clarithromycinprovidestissueconcentrationsthatareseveraltimeshigherthanthecirculatingdruglevels.Increased

levelshavebeenfoundinbothtonsillarandlungtissue.Clarithromycinis80%boundtoplasmaproteinsattherapeutic

levels.

Clarithromycinalsopenetratesthegastricmucus.Levelsofclarithromyciningastricmucusandgastrictissueare

higherwhenclarithromycinisco-administeredwithomeprazolethanwithclarithromycinisadministeredalone.

5.3Preclinicalsafetydata

Inacutemouseandratstudies,themedianlethaldosewasgreaterthanthehighestfeasibledoseforadministration(5

g/kg).

Inrepeateddosestudies,toxicitywasrelatedtodose,durationoftreatmentandspecies.Dogsweremoresensitivethan

primatesorrats.Themajorclinicalsignsattoxicdosesincludedemesis,weakness,reducedfoodconsumptionand

weightgain,salivation,dehydrationandhyperactivity.Inallspeciestheliverwastheprimarytargetorganattoxic

doses.Hepatotoxicitywasdetectablebyearlyelevationsofliverfunctiontests.Discontinuationofthedruggenerally

resultedinareturntoortowardnormalresults.Othertissueslesscommonlyaffectedincludedthestomach,thymusand

otherlymphoidtissuesandthekidneys.Atneartherapeuticdoses,conjunctivalinjectionandlacrimationoccurredonly

indogs.Atamassivedoseof400mg/kg/day,somedogsandmonkeysdevelopedcornealopacitiesand/oroedema.

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

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

teratogenicityforclarithromycin.However,afurthersimilarstudyinSprague-Dawleyratsindicatedalow(6%)

incidenceofcardiovascularabnormalitieswhichappearedtobeduetospontaneousexpressionofgeneticchanges.Two

mousestudiesrevealedavariableincidence(3-30%)ofcleftpalateandembryoniclosswasseeninmonkeysbutonly

atdoselevelswhichwereclearlytoxictothemothers.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Microcrystallinecellulose

Starch,pregelatinised

Croscarmellosesodium

Povidone(k-value81.0–96.3)

Talc

Magnesiumstearate

Silica,colloidalanhydrous

Titaniumdioxide(E171)

Polydextrose(E1200)

Hypromellose((E464)

Triacetin(E1518)

Macrogol

Quinolineyellow(E104)

6.2Incompatibilities

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6.3ShelfLife

3years.

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

Al/PVC/PVdCStriporHDPETabletContainerwithLDPECap

Packsizes:7,14,21,28,30,50,100,250,500or1000tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

PinewoodLaboratoriesLimited

Ballymacarbry

Clonmel

Co.Tipperary

8MARKETINGAUTHORISATIONNUMBER

PA0281/131/002

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:13January2006

10DATEOFREVISIONOFTHETEXT

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