AZITHROMYCIN TEVA

Main information

  • Trade name:
  • AZITHROMYCIN TEVA
  • Dosage:
  • 200 MG/5ml
  • Pharmaceutical form:
  • Powder for Oral Suspension
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • AZITHROMYCIN TEVA
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0749/039/001
  • Authorization date:
  • 14-09-2007
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

AzithromycinTeva200mg/5mlpowderfororalsuspension

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each5mlofreconstitutedoralsuspensioncontains200mgazithromycinasdihydrate.

Each1mlofreconstitutedoralsuspensioncontains40mgazithromycinasdihydrate.

Excipients

Each5mlofreconstitutedoralsuspensioncontains3.78gofsucrose.

Each1mlofreconstitutedoralsuspensioncontains0.756gofsucrose.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Powderfororalsuspension.

Whitetoyellowish-whitepowder.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Azithromycinisindicatedforthefollowingbacterialinfectionsinducedbymicro -organismssusceptibleto

azithromycin(seesections4.4and5.1):

Infectionsofthelowerrespiratorytract:acutebronchitisandmildtomoderatecommunity-acquiredpneumonia

Infectionsoftheupperrespiratorytract:sinusitisandpharyngitis/tonsillitis

Acuteotitismedia

Infectionsoftheskinandsofttissueofmildtomoderateseveritye.g.folliculitis,cellulites,erysipelas

UncomplicatedChlamydiatrachomatisurethritisandcervicitis.

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantibacterialagents.

Azithromycinisnotthefirstchoicefortheempiricaltreatmentofinfectionsinareaswheretheprevalenceofresistant

isolatesis10%ormore(seesection5.1).

4.2Posologyandmethodofadministration

Azithromycinsuspensionshouldbegivenasasingledailydose.Thesuspensioncanbetakenwithorwithoutfood.

Thedurationoftreatmentineachoftheinfectiousdiseasesisgivenbelow.

Childrenandadolescentsover45kgbodyweight,adultsandtheelderly

Thetotaldosageofazithromycinis1500mgwhichisspreadoverthreedays(500mgoncedaily).Alternatively,the

dosagecanbespreadoverfivedays(500mgasasingledoseonthefirstdayandthereafter250mgoncedaily).

InuncomplicatedChlamydiatrachomatisurethritisandcervicitisthedosageis1000mgasasingleoraldose.

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Otherpharmaceuticalformsareavailabletotreatpatientsweighingmorethan45kg.

Childrenunder45kgbodyweight

Azithromycinsuspensionshouldbeusedforchildrenunder45kg.Thefollowingrecommendationsrefertothe

reconstituted40mg/ml(200mg/5ml)suspension.

WithasonlyexceptionthetreatmentofStreptococcipharyngitis,thetotaldoseinchildren1yearandolderis30

mg/kg,tobeadministeredasonesingledailydoseof10mg/kgforthreedays.Asanalternativeazithromycincanalso

beadministeredoveraperiodof5dayswithonesingledoseof10mg/kgonday1,followedbyonesingledailydose

of5mg/kgondays2through5.

Forchildrenwithaweightof10to15kgazithromycinsuspensionshouldbemeasuredasaccuratelyaspossiblewith

theassistanceoftheencloseddosagesyringe,whichisgraduatedin0.5mldivisions,providing20mgofazithromycin

ineverydivision.

Forchildrenwhoweighmorethan15kg,azithromycinsuspensionshouldbeadministeredwiththeassistanceofthe

dosagespoon,whichprovides2.5,3.75or5mldoses,correspondingto100,150or200mgofazithromycin,

respectivelyaccordingtothefollowingschedule:

*Separatedosagerecommendationsapplyforstreptococcalpharyngitisandaredescribedbelow.

ForthetreatmentofStreptococcipharyngitisinchildrenaged2yearsormore:Azithromycininasingledoseof10

mg/kgor20mg/kgforthreedays,inwhichthemaximumdailydoseof500mgshouldnotbeexceeded.However,

penicillinremainsthefirstchoiceforthetreatmentofStreptococcuspyogenespharyngitis,amongwhichthe

prophylaxisforacuterheumatism(seesection4.1).

Themaximumdosageinchildrencorrelateswiththecommondosageinadultswith1500mgazithromycin.

Sinusitis

Forthetreatmentofsinusitis,limiteddataisavailableforthetreamentofchildrenunder16yearsofage.

Elderly

Nodoseadjustmentsarerequiredforelderlypatients.

Patientswithrenalimpairment

Nodoseadjustmentisnecessaryinpatientswithmildtomoderaterenalimpairment(GFR10-80ml/min)(seesection

Weight(kg) 3-daytreatment* 5-daytreatment* Contentbottle

10-15 Oncedaily10mg/kg

ondays1through3 Oncedaily10mg/kgonday1,

followedbyoncedaily5mg/kgon

days2through5 15ml

16-25 Oncedaily200mg

(5ml)ondays1

through3 Oncedaily200mg(5ml)onday1,

followedbyoncedaily100mg(2.5

ml)ondays2through5 15ml

26-35 Oncedaily300mg

(7.5ml)ondays1

through3 Oncedaily300mg(7.5ml)onday1,

followedbyoncedaily150mg(3.75

ml)ondays2through5 22.5ml

35-45 Oncedaily400mg

(10ml)ondays1

through3 Oncedaily400mg(10ml)onday1,

followedbyoncedaily200mg(5ml)

ondays2through5 30ml

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Patientswithhepaticimpairment

Adoseadjustmentisnotnecessaryforpatientswithmildtomoderatelyimpairedliverfunction(Child-PughclassAor

B)(seesections4.3and4.4).

4.3Contraindications

Hypersensitivitytoazithromycin,erythromycin,anymacrolideorketolideantibioticortoanyoftheexcipients.

4.4Specialwarningsandprecautionsforuse

Allergicreactions

Inrarecasesazithromycinisreportedtohavecausedseriousallergicreactions(rarelyfatal)suchasangioneuroticoedemaand

anaphylaxis.Someofthesereactionshavecausedrecurrentsymptomsandhaverequiredlongerobservationandtreatment.

Renalimpairment

Nodoseadjustmentisnecessaryinpatientswithmildtomoderaterenalimpairment(GFR10-80ml/min).Cautionisadvisedin

patientswithsevererenalimpairment(GFR<10ml/min)assystemicexposuremaybeincreased(33%increaseshavebeen

observed)(seesection5.2).

Hepaticfailure

Sinceliveristheprincipalrouteofeliminationforazithromycin,theuseofazithromycinshouldbeundertakenwithcautionin

patientswithsignificanthepaticdisease.Casesoffulminanthepatitispotentiallyleadingtolife-threateningliverfailurehavebeen

reportedwithazithromycin(seeSection4.8).Somepatientsmayhavehadpre-existinghepaticdiseaseormayhavebeentaking

otherhepatotoxicmedicinalproducts.

Incaseofsignsandsymptomsofliverdysfunction,suchasrapiddevelopingastheniaassociatedwithjaundice,darkurine,

bleedingtendencyorhepaticencephalopathy,liverfunctiontests/investigationsshouldbeperformedimmediately.Azithromycin

administrationshouldbestoppedifliverdysfunctionhasemerged.

Ergotalkaloidsandazithromycin

Theconcurrentuseofergotalkaloidsandmacrolideantibioticshasbeenfoundtoacceleratethedevelopmentofergotism.The

interactionsbetweenergotalkaloidsandazithromycinhavenotbeenstudied.Thedevelopmentofergotismishoweverpossible,

sothatazithromycinandergotalkaloidderivativesshouldnotbeadministeredsimultaneously.

QTprolongation

ProlongedcardiacrepolarisationandQTinterval,impartingariskofdevelopingcardiacarrhythmiaandtorsadesdepointes,have

beenseenintreatmentwithothermacrolides.Asimilareffectwithazithromycincannotbecompletelyruledoutinpatientsat

increasedriskforprolongedcardiacrepolarisation(seesection4.8).Therefore:

AzithromycinshouldnotbeusedinpatientswithcongenitalordocumentedacquiredQTprolongation.

AzithromycinshouldnotbeusedconcurrentlywithotheractivesubstancesthatprolongQTintervalsuchas

antiarrhythmicsofclassesIAandIII,cisaprideandterfenadine(seesection4.5).

Azithromycinshouldnotbeusedinpatientswithelectrolytedisturbance,particularlyincasesofhypokalaemiaand

hypomagnesaemia

Azithromycinshouldnotbeusedinpatientswithclinicallyrelevantbradycardia,cardiacarrhythmiaorseverecardiac

insufficiency.

Thefollowingshouldbeconsideredbeforeprescribingazithromycin:

Azithromycinpowderfororalsuspensionisnotsuitablefortreatmentofsevereinfectionswhereahighconcentrationofthe

antibioticinthebloodisrapidlyneeded.

InareaswithahighincidenceoferythromycinAresistance,itisespeciallyimportanttotakeintoconsiderationtheevolutionof

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Asforothermacrolides,highresistanceratesofStreptococcuspneumoniae(>30%)havebeenreportedforazithromycininsome

Europeancountries(seesection5.1).ThisshouldbetakenintoaccountwhentreatinginfectionscausedbyStreptococcus

pneumoniae.

Themaincausativeagentofsofttissueinfections,Staphylococcusaureus,isfrequentlyresistanttoazithromycin.Therefore,

susceptibilitytestingisconsideredapreconditionfortreatmentofsofttissueinfectionswithazithromycin.

Pharyngitis/tonsillitis

AzithromycinisnotthesubstanceoffirstchoiceforthetreatmentofpharyngitisandtonsillitiscausedbyStreptococcuspyogenes.

Forthisandfortheprophylaxisofacuterheumaticfeverpenicillinisthetreatmentoffirstchoice.

Sinusitis

Often,azithromycinisnotthesubstanceoffirstchoiceforthetreatmentofsinusitis.

Acuteotitismedia

Often,azithromycinisnotthesubstanceoffirstchoiceforthetreatmentofacuteotitismedia.

Infectedburnwounds

Azithromycinisnotindicatedforthetreatmentofinfectedburnwounds.

Sexuallytransmitteddisease

IncaseofsexuallytransmitteddiseasesaconcomitantinfectionbyT.pallidumshouldbeexcluded.

Superinfections

Attentionshouldbepaidtopossiblesymptomsofsuperinfectionscausedbynon-sensitivecausalagentssuchasfungi.A

superinfectionmayrequireaninterruptionoftheazithromycintreatmentandinitiationofadequatemeasures.

Neurologicalorpsychiatricdiseases

Azithromycinshouldbeadministeredwithcautiontopatientssufferingfromneurologicalorpsychiatricdiseases.

Myastheniagravis

Exacerbationsofthesymptomsofmyastheniagravisandnewonsetofmyastheniasyndromehavebeenreportedinpatients

receivingazithromycin(seesection4.8).

Clostridiumdifficile -associateddiarrhoea

Clostridiumdifficile -associateddiarrhoea(CDAD)hasbeenreportedwiththeuseofnearlyallantibacterialagents,including

azithromycin,andmayrangeinseverityfrommilddiarrhoeatofatalcolitis.Treatmentwithantibacterialagentsaltersthenormal

floraofthecolonleadingtoovergrowthofC.difficile.

C.difficileproducestoxinsAandBwhichcontributetothedevelopmentofCDAD.Hypertoxin -producingstrainsofC.difficile

causeincreasedmorbidityandmortality,astheseinfectionscanberefractorytoantimicrobialtherapyandmayrequirecolectomy.

CDADmustbeconsideredinallpatientswhopresentwithdiarrhoeafollowingantibioticuse.Acarefulmedicalhistoryis

necessarysinceCDADhasbeenreportedtooccurovertwomonthsaftertheadministrationofantibacterialagents.Should

pseudomembranouscolitisbeinducedbyazithromycin,thenanti-peristalticsshouldbecontraindicated.

Long-termuse

Thereisnoexperienceregardingthesafetyandefficacyoflong-termuseofazithromycinforthementionedindications.Incaseof

rapidrecurrentinfections,treatmentwithanotherantibioticshouldbeconsidered.

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ThesafetyandefficacyofazithromycinforthepreventionortreatmentofMycobacteriumaviumcomplex(MAC)infectionin

childrenhavenotbeenestablished.

Sucrose

Thismedicinalproductcontainssucrose.

Patientswithrarehereditaryproblemsoffructoseintolerance,glucose-galactosemalabsorptionorsucrase-isomaltase

insufficiencyshouldnottakethismedicine.

Thesucrosecontentshouldbetakenintoaccountinpatientswithdiabetesmellitus.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Antacids

Whenstudyingtheeffectofsimultaneouslyadministeredantacidonthepharmacokineticsofazithromycin,nooverallchangehas

beenobservedinthebioavailability,althoughthepeakconcentrationsofazithromycinmeasuredintheplasmadidfallby

approximately25%.Azithromycinshouldbetakenatleast1hourbeforeor2hoursaftertheantacid.

Cetirizine

Inhealthyvolunteers,co -administrationofa5-dayregimenofazithromycinwithcetirizine20mgatsteady-stateresultedinno

pharmacokineticinteractionandnosignificantchangesintheQTinterval.

Digoxin

Insomepatientscertainmacrolideantibioticshavebeenreportedtohaveimpairedthemetabolismofdigoxinintheintestine.

Consequently,inthecaseofpatientsreceivingtherelatedazalideazithromycinanddigoxin,thepossibilityofariseinthedigoxin

concentrationsshouldbeborneinmind.

Zidovudine

1000mgsingledosesand1200mgor600mgmultipledosesofazithromycinhadonlyaslighteffectuponthepharmacokinetics

ofzidovudineoritsglucuronidemetaboliteintheplasmaoruponexcretionintheurine.However,theadministrationof

azithromycinincreasedtheconcentrationsofphosphorylatedzidovudine,theclinicallyactivemetabolite,inmononuclearcellsin

theperipheralcirculation.Theclinicalsignificanceofthisfindingisunclear,butitmaybeofbenefittopatients.

Didanosine(dideoxyinosine)

Dailydosagesof1200mgazithromycinco-administeredwith400mg/daydidanosinein6HIV -positivevolunteersappearedto

havenoeffectonthesteady -statepharmacokineticsofdidanosinecomparedtoplacebo.

AzithromycindoesnotinteractsignificantlywiththehepaticcytochromeP450system.Itisnotbelievedtobesubjecttothe

pharmacokineticinteractionsseenwitherythromycinandothermacrolides.HepaticcytochromeP450inductionorinactivationvia

cytochrome -metabolitecomplexdoesnotoccurwithazithromycin.

Ergot

Thecombineduseofergotderivativesandazithromycinmayintheorycauseergotism,andconsequentlytheircombineduseis

notrecommended(seealsosection4.4).

Pharmacokineticstudieshavebeenconductedbetweenazithromycinandthefollowingagentsknowntoundergosignificant

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Atorvastatin

-administrationofatorvastatin(10mgdaily)andazithromycin(500mgdaily)didnotaltertheplasmaconcentrationof

atorvastatin(basedonanHMG -CoAreductaseinhibitionassay).

Carbamazepine

Inapharmacokineticinteractionstudyinhealthyvolunteers,nosignificanteffectwasobservedontheplasmalevelsof

carbamazepineoritsactivemetaboliteinpatientsreceivingconcomitantazithromycin.

Cimetidine

Inapharmacokineticstudyinvestigatingtheeffectsofasingledoseofcimetidine,given2hoursbeforeazithromycin,onthe

pharmacokienticsofazithromycin,noalterationofazithromycinpharmacokineticswasseen.

Coumarin-likeoralanticoagulants

Inapharmacokineticinteractionstudy,azithromycindidnotalterthenaticoagulanteffectofsingle15mgdoseofwarfarin

administeredtohealthyvolunteers.Therehavebeenreportsreceivedinthepost -marketingperiodofpotentiatedanticoagulation

subsequenttoco -administrationofazithromycinandcoumarin-typeoralanticoagulants.Althoughacausalrelationshiphasnot

beenestablished,considerationshouldbegiventothefrequencyofprothrombintimemonitoringwhenazithromycinisusedin

patientsreceivingcoumarin -typeoralanticoagulants.

Ciclosporin

Inapharmacokineticstudywithhealthyvolunteersgivenoralazithromycin500mg/dayfor3daysthenasingle10mg/kgoral

doseofciclosporin,theresultingciclosporinC

andAUC

werefoundtobesignificantlyelevated.Consequently,caution

shouldbeexercisedbeforeconsideringconcurrentadministrationoftheseagents.Ifcombinationtreatmentisnecessary,the

ciclosporinlevelsshouldbecarefullymonitoredandthedosageshouldbeadjustedaccordingly.

Efavirenz

-administrationofa600mgsingledoseofazithromycinand400mgefavirenzdailyfor7daysdidnotresultinanyclinically

significantpharmacokineticinteractions.

Fluconazole

-administrationofasingledoseof1,200mgazithromycindidnotalterthepharmacokineticsofasingledoseof800mg

fluconazole.Totalexposureandhalf -lifeofazithromycinwereunchangedbytheco-administrationoffluconazole,however,a

clinicallyinsignificantdecreaseinC

(18%)ofazithromycinwasobserved.

Indinavir

-administrationofasingledoseof1,200mgazithromycinhadnostatisticallysignificanteffectonthepharmacokineticsof

indinaviradministeredas800mgthreetimesdailyfor5days.

Methylprednisolone

Inapharmacokineticinteractionstudyinhealthyvolunteers,azithromycinhadnosignificanteffectonthepharmacokineticsof

methylprednisolone.

Midazolam

Inhealthyvolunteers,co -administrationofazithromycin500mg/dayfor3daysdidnotcauseclinicallysignificantchangesinthe

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Nelfinavir

-administrationofazithromycin(1,200mg)andnelfinaviratsteady-state(750mgthreetimesdaily)resultedinincreased

azithromycinconcentrations.Noclinicallysignificantadverseeffectswereobservedandnodoseadjustmentisrequired.

Rifabutin

-administrationofazithromycinandrifabutindidnotaffecttheserumconcentrationsofeitheragent.

Neutropeniawasobservedinsubjectsreceivingconcomitanttreatmentofazithromycinandrifabutin.Althoughneutropeniahas

beenassociatedwiththeuseofrifabutin,acausalrelationshiptocombinationwithazithromycinhasnotbeenestablished(see

section4.8).

Sildenafil

Innormalhealthymalevolunteers,therewasnoevidenceofaneffectofazithromycin(500mgdailyforthreedays)ontheAUC

andC

ofsildenafiloritsmajorcirculatingmetabolite.

Terfenadine

Inpharmacokineticstudiestherearenoreportsofinteractionsbetweenazithromycinandterfenadine.

Therehavebeenrarecasesreportedwherethepossibilityofsuchaninteractioncouldnotbeentirelyexcluded;howevertherewas

nospecificevidencethatsuchaninteractionhadoccurred.

Azithromycinshouldbeadministeredwithcautionincombinationwithterfenadine.

Theophylline

Thereisnoevidenceofaclinicallysignificantpharmacokineticinteractionwhenazithromycinandtheophyllineare

-administeredtohealthyvolunteers.

Triazolam

In14healthyvolunteers,co -administrationofazithromycin500mgonday1and250mgonday2with0.125mgtriazolamon

day2hadnosignificanteffectonanyofthepharmacokineticvariablesfortriazolamcomparedtotriazolamandplacebo.

Trimethoprim/sulphamethoxazole

-administrationoftrimethoprim/sulphamethoxazoleDS(160mg/800mg)for7dayswithazithromycin1,200mgonday7had

nosignificanteffectonpeakconcentrations,totalexposureorurinaryexcretionofeithertrimethoprimorsulphamethoxazole.

Azithromycinserumconcentrationsweresimilartothoseseeninotherstudies.

Cisapride

CisaprideismetabolizedintheliverbytheenzymeCYP3A4.Becausemacrolidesinhibitthisenzyme,concomitantadministration

ofcisapridemaycausetheincreaseofQTintervalprolongation,ventriculararrhythmiasandtorsadedepointes.

Astemizol,alfentanil

Nodataareavailableoninteractionswithastemizolandalfentanil.Cautionshouldbeexercisedwithconcomitantuseofthese

agentsandazithromycininviewofthedescribedpotentationofitseffectduringconcomitantuseofthemacrolideantibiotic

erythromycin.

SubstancesthatprolongtheQTinterval

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4.6Fertility,pregnancyandlactation

Pregnancy

Animalreproductionstudieshavebeenperformedatdosesuptomoderatelymaternallytoxicdoseconcentrations.Inthese

studies,noevidenceofharmtothefetusduetoazithromycinwasfound.Thereare,however,noadequateandwellcontrolled

studiesinpregnantwomen.Asanimalstudiesarenotalwayspredictiveofhumanresponse,azithromycinshouldbeusedduring

pregnancyonlyifclearlyneeded.

Lactation

Thereisnodataonsecretioninbreastmilk.Asmanyagentsareexcretedinbreastmilk,azithromycinshouldnotbeusedinthe

treatmentofalactatingwomanunlessthephysicianfeelsthatthepotentialbenefitsjustifythepotentialriskstotheinfant.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.However,thepossibilityof

undesirableeffectslikedizzinessandconvulsionsshouldbetakenintoaccountwhenperformingtheseactivities.

4.8Undesirableeffects

About13%ofpatientsincludedinclinicaltrialsreportedadverseevents,mostcommonlygastro-intestinaldisorders.

Systemorgan

class Very

common

1/10 Common

1/100,

<1/10 Uncommon

1/1000,1/100 Rare

1/10000,

1/1000 Notknown

Infectionsand

infestations candidiasis

oralcandidiasis

vaginalinfection

Bloodand

lymphatic

system

disorders lymphocyte

count

decreased

eosinophil

count

increased

blood

bicarbonate

decreased leucopenia

neutropenia thrombocytopenia

haemolytic

anaemia

Immune

system

disorders angioedema

hypersensitivity anaphylactic

reaction(see

section4.4)

Psychiatric

disorders nervousness agitation

depersonalisation,

inelderlypatients

deliriummay

occur. aggression

anxiety

Nervous

system

disorders dizziness

headache

paraesthesia

dysgeusia hypoaesthesia

somnolence

insomnia syncope

convulsions

psychomotor

hyperactivity

anosmia

parosmia

ageusia

myasthenia

gravis(see

section4.4)

Eyedisorders visual

impairment

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labyrinth

disorders tinnitus

Cardiac

disorders palpitations torsadesde

pointes

arrhythmia

including

ventricular

tachycardia(see

section4.4)

electrocardiogram

QTprolonged

(seesection4.4)

Vascular

disorders hypotension

Gastrointestinal

disorders diarrhoea

abdominal

pain

nausea

flatulence vomiting

dyspepsia

anorexia gastritis

constipation

loosestools discolourationof

theteeth tongue

discolouration

pancreatitis

pseudomembranous

colitis(see

section4.4)

Hepatobiliary

disorders hepatitis

aspartate

aminotransferase

increased

alanine

aminotransferase

increased

bloodbilirubin

increased hepaticfunction

abnormal hepaticfailure

whichhasrarely

resultedindeath

(seesection4.4)

hepatitis

fulminant

hepaticnecrosis

jaundice

cholestatic

Skinand

subcutaneous

tissue

disorders rash

pruritus Stevens-Johnson

syndrome

photosensitivity

reaction

urticaria maculopapular

rash

toxicepidermal

necrolysis

erythema

multiforme

Musculoskeletal,

connective

tissueand

bone

disorders arthralgia

Renaland

urinarytract

disorders bloodurea

increased

bloodcreatinine

increased interstitial

nephritis

acuterenalfailure

Reproductive

systemand

breast

disorders vaginitis

General

disordersand

administration

site

conditions fatigue chestpain

oedema

malaise

asthenia pain

Investigations bloodpotassium

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4.9Overdose

Theundesirableeffectsatdosagesinexcessoftherecommendeddosagesweresimilartothoseafternormaldosages.

Symptoms

Thetypicalsymptomsofanoverdosewithmacrolideantibioticsincludereversiblelossofhearing,severenausea,

vomitinganddiarrhoea.

Treatment

Incasesofoverdosetheadministrationofmedicinalcharcoalandgeneralsymptomatictreatmentandmeasuresto

supportvitalfunctionsareindicatedwherenecessary.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antibacterialsforsystemicuse;macrolides.

ATCcode:J01FA10.

Azithromycinisamacrolideantibioticbelongingtotheazalidegroup.

ThemoleculeisconstructedbyaddinganitrogenatomtothelactoneringoferythromycinA.Thechemicalnameof

azithromycinis9-deoxy-9a-aza-9a-methyl-9a-homo-erythromycinA.Themolecularweightis749.0.

Modeofaction

Theactionmechanismofazithromycinisbaseduponthesuppressionofbacterialproteinsynthesis,bybindingtothe

50Ssubunitandthusinhibitingthetranslocationofpeptides.

(Cross)-resistance

Generally,theresistanceofdifferentbacterialspeciestomacrolideshasbeenreportedtooccurbythreemechanisms

associatedwithtargetsitealteration,antibioticmodification,oralteredantibiotictransport(efflux).Theeffluxin

streptococciisconferredbythemefgenesandresultsinamacrolide-restrictedresistance(Mphenotype).Target

modificationiscontrolledbyermencodedmethylases.

Acompletecross-resistanceexistsamongerythromycin,azithromycin,othermacrolidesandlincosamidesfor

Streptococcuspneumoniae,beta-haemolyticstreptococciofgroupA,Enterococcusspp.andStaphylococcusaureus,

includingmethicillin-resistantS.aureus(MRSA).

Penicillin-sensitiveS.pneumoniaearemorelikelytobesusceptibletoazithromycinthanarepenicillin-resistantstrains

ofS.pneumoniae.Methicillin-resistantS.aureus(MRSA)islesslikelytobesusceptibletoazithromycinthan

methicillin-sensitiveS.aureus(MSSA).

Theinductionofsignificantresistanceinbothinvitroandinvivomodelsis<1dilutionriseinMICsforS.pyogenes,

H.influenzaeandEnterobacterciaeafterninesub-lethalpassagesofactivesubstanceandthreedilutionincreaseforS.

aureusanddevelopmentofinvitroresistanceduetomutationisrare.

Breakpoints

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EUCAST(2008):

Staphylococcusspp.:susceptible 1mg/landresistant>2mg/l

Haemophilusspp.:susceptible 0.12mg/landresistant>4mg/l

Moraxellacatarrhalis:susceptible 0.5mg/landresistant>0.5mg/l

Streptococcusspp.includinggroupsA,B,C,GandStreptococcuspneumoniae:susceptible 0.25mg/land

resistant>0.5mg/l

Theprevalenceofacquiredresistancemayvarygeographicallyandwithtimeforselectedspeciesandlocalinformation

onresistanceisdesirable,particularlywhentreatingsevereinfections.Asnecessary,expertadviceshouldbesought

whenthelocalprevalenceofresistanceissuchthattheutilityoftheagentinatleastsometypesofinfectionsis

questionable.

Speciesforwhichacquiredresistancemaybeaproblem:prevalenceofresistanceisequaltoorgreaterthan10%inatleastone

countryintheEuropeanUnion.

Table:Antibacterialspectrumofazithromycin

Species

Commonlysusceptiblespecies

AerobicGram-positive

Corynebacteriumdiphteriae

Streptococcuspneumoniae

Erythromycin-sensitive

Penicillin-sensitive

Streptococcuspyogenes

Erythromycin-sensitive

AerobicGram-negative

Bordetellapertussis

Escherichiacoli-ETEC

Escherichiacoli-EAEC

Haemophilusinfluenzae

Haemophilusducreyi

Legionellaspp.

Moraxellacatarrhalis

Erythromycin-sensitive

Erythromycin-intermediate

Pasteurellamultocida

Anaerobic

Fusobacteriumnucleatum

Fusobacteriumnecrophorum

Prevotellaspp.

Porphyromonasspp.

Propionibacteriumspp.

Othermicro-organisms

Chlamydophilapneumoniae

Chlamydiatrachomatis

Listeriaspp.

MycobacteriumaviumComplex

Mycoplasmapneumoniae

Ureaplasmaurealyticum

Speciesforwhichacquiredresistancemaybea

problem

AerobicGram-positive

Staphylococcusaureus

Methicillin-susceptible

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Resistanceisgreaterthan50%.

5.2Pharmacokineticproperties

Absorption

Followingoraladministrationthebio-availabilityofazithromycinisapproximately37%.Peakplasmalevelsare

reachedafter2-3hours.

Distribution

Orallyadministeredazithromyciniswidelydistributedthroughoutthebody.Pharmacokineticstudieshaveshown

considerablyhigherazithromycinconcentrationsinthetissues(upto50timesthemaximumconcentrationobservedin

theplasma)thanintheplasma.Thisindicatesthatthesubstanceisextensivelyboundinthetissues(steady-state

volumeofdistributionapproximately31l/kg).Themeanmaximumconcentrationobserved(C

)afterasingledose

of500mgisapproximately0.4µg/ml,2-3hoursafteradministration.Withtherecommendeddosagenoaccumulation

intheserum/plasmaoccurs.Accumulationdoesoccurinthetissueswherethelevelsaremuchhigherthaninthe

serum/plasma.Threedaysafteradministrationof500mgasasingledoseorindivideddosesconcentrationsof1.3-4.8

µg/g,0.6-2.3µg/g,2.0-2.8µg/gand0-0.3µg/mlarefoundinlung,prostate,tonsilandserumrespectively.

MeanpeakconcentrationsmeasuredinperipheralleukocytesarehigherthantheMIC

ofthemostcommon

Methicillin-susceptible +

Streptococcuspneumoniae

Penicillin-intermediate

Penicillin-resistant

Erythromycin-intermediate

Streptococcuspyogenes

Erythromycin-intermediate

Streptococciviridansgroup

Penicillin-intermediate

AerobicGram-negative

Moraxellacatarrhalis

Erythromycin-resistant

Anaerobic

Peptostreptococcusspp.

Inherentlyresistantorganisms

AerobicGrampositive

Corynebacteriumspp.

Enterococcusspp.

StaphylococciMRSA,MRSE

Streptococcuspneumoniae

Erythromycin-resistant

Penicillin&Erythromycinresistant

Streptococcuspyogenes

Erythromycin-resistant

Streptococciviridansgroup

Penicillin-resistant

Erythromycin-resistant

AerobicGram-negative

Pseudomonasaeruginosa

Anaerobic

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Inexperimentalinvitroandinvivostudies,azithromycinaccumulatesinphagocytes;releaseispromotedbyactive

phagocytosis.Inanimalmodelsthisprocessappearedtocontributetotheaccumulationofazithromycininthetissue.

Thebindingofazithromycintoplasmaproteinsisvariableandvariesfrom52%at0.005µg/mlto18%at0.5µg/ml,

dependingontheserumconcentration.

Metabolismandexcretion

Theterminalplasmaeliminationhalf-lifefollowsthetissuedepletionhalf-lifeof2to4days.Inelderlyvolunteers(>65

years),higher(29%)AUCvalueswerealwaysobservedaftera5-daycoursethaninyoungervolunteers(<45years).

However,thesedifferencesarenotconsideredtobeclinicallyrelevant;nodoseadjustmentisthereforerecommended.

Approximately12%ofanintravenouslyadministereddoseisexcretedinunchangedformwiththeurineoveraperiod

of3days;themajorproportioninthefirst24hours.Concentrationsofupto237µg/mlazithromycin,2daysaftera5-

daycourseoftreatment,havebeenfoundinhumanbile,togetherwith10metabolites(formedbyN-andO-

demethylation,byhydroxylationofthedesosamineandaglyconerings,andbysplittingofthecladinoseconjugate).A

comparisonofHPLCandmicrobiologicaldeterminationsuggeststhatthemetabolitesdonotplayaroleinthemicro-

biologicalactivityofazithromycin.

Pharmacokineticsinspecialpopulations

Renalinsufficiency

Followingasingleoraldoseofazithromycin1g,meanC

andAUC

0-120 increasedby5.1%and4.2%respectively,

insubjectswithmildtomoderaterenalimpairment(glomerularfiltrationrateof10-80ml/min)comparedwithnormal

renalfunction(GFR>80ml/min).Insubjectswithsevererenalimpairment(GFR<10ml/min),themeanC

0-120 increased61%and35%respectivelycomparedtonormal.

Hepaticinsufficiency

Inpatientswithmildtomoderatehepaticimpairment,thereisnoevidenceofamarkedchangeinserum

pharmacokineticsofazithromycincomparedtonormalhepaticfunction.Inthesepatients,urinaryrecoveryof

azithromycinappearstoincreaseperhapstocompensateforreducedhepaticclearance.Therearenodataon

azithromycinuseincasesofmoreseverehepaticimpairment.

Elderly

Thepharmacokineticsofazithromycininelderlymenwassimilartothatofyoungadults;however,inelderlywomen,

althoughhigherpeakconcentrations(increasedby30-50%)wereobserved,nosignificantaccumulationoccurred.

Infants,toddlers,childrenandadolescents

Pharmacokineticshavebeenstudiedinchildrenaged4months–15yearstakingcapsules,granulesorsuspension.At

10mg/kgonday1followedby5mg/kgondays2-5,theC

achievedisslightlylowerthanadultswith224µg/lin

childrenaged0.6-5yearsandafter3daysdosingand383µg/linthoseaged6-15years.Thet

of36hintheolder

childrenwaswithintheexpectedrangeforadults.

5.3Preclinicalsafetydata

Inanimalstudiesusingexposures40timesthoseachievedattheclinicaltherapeuticdosages,azithromycinwasfound

tohavecausedreversiblephospholipidosis,butasaruletherewerenoassociatedtoxicologicalconsequences.The

relevanceofthisfindingtohumansreceivingazithromycininaccordancewiththerecommendationsisunknown.

ElectrophysiologicalinvestigationshaveshownthatazithromycinprolongstheQTinterval.

Carcinogenicpotential

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Mutagenicpotential

Therewasnoevidenceofapotentialforgeneticandchromosomemutationsininvivoandinvitrotestmodels.

Reproductivetoxicity

Noteratogeniceffectswereobservedinembryotoxicitystudiesinratsafteroraladministrationofazithromycin.Inrats,

azithromycindosagesof100and200mg/kgbodyweight/dayledtomildretardationsinfetalossificationandin

maternalweightgain.Inperi-andpostnatalstudiesinrats,mildretardationsfollowingtreatmentwith50mg/kg/day

azithromycinandabovewereobserved.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Silica,colloidalanhydrous(E551)

Sucrose

Xanthangum(E415)

Trisodiumphosphateanhydrous

Hydroxypropylcellulose

Cherryflavouringtrusil

Vanilaflavour

Bananaflavour

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Unopenedbottles:2years

Afterreconstitution(forazithromycin15mland22.5ml):5days

Afterreconstitution(forazithromycin30mland37.5ml):10days

Afterreconstitution:storebelow25°C

6.4Specialprecautionsforstorage

Unopenedbottles:Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

HDPEbottleswithchild-resistantPPclosures.

Packsizes:

Azithromycin600mg/15ml

12.555gofpowderforthepreparationof15mlsuspension

Eachbottlecontainsanoverfillof5mltoensurecompletedosing

Azithromycin900mg/22.5ml

18.8325gofpowderforthepreparationof22.5mlsuspension

Eachbottlecontainsanoverfillof2.5mltoensurecompletedosing

Azithromycin1200mg/30ml

25.110gofpowderforthepreparationof30mlsuspension

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Azithromycin1500mg/37.5ml

31.3875gofpowderforthepreparationof37.5mlsuspension

Eachbottlecontainsanoverfillof5mltoensurecompletedosing

Multi-dosepolystyrenespoon2.5/5mlgraduatedat3.75ml.

Polystyrene/polyethyleneoraldosingsyringe(5ml).Thesyringeisgraduatedatevery0.5ml.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Preparingsuspension:

Firstloosenthepowderbytappingwell.

For15ml(600mg)bottle:add8mlwaterwithdosingsyringe.

For22.5ml(900mg)bottle:add9.5mlwaterwithdosingsyringe.

For30ml(1200mg)bottle:add14.5mlwaterwithdosingsyringe.

For37.5ml(1500mg)bottle:add16.5mlwaterwithdosingsyringe.

Shakewell.

Adviceshouldbegivenastowhetherthedoseshouldbemeasuredusingtheoraldosingsyringeorthespoonprovided

andoncorrectusage.

Afterreconstitution,ayellowish-whitesuspensionwillbeobtained.

7MARKETINGAUTHORISATIONHOLDER

TevaPharmaB.V.

Computerweg10

3542DRUtrecht

TheNetherlands

8MARKETINGAUTHORISATIONNUMBER

PA0749/039/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:14September2007

Dateoflastrenewal:08November2009

10DATEOFREVISIONOFTHETEXT

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