AVELOX

Main information

  • Trade name:
  • AVELOX Film Coated Tablet 400 Milligram
  • Dosage:
  • 400 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • AVELOX Film Coated Tablet 400 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1328/144/001
  • Authorization date:
  • 18-02-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Avelox400mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains400mgmoxifloxacinashydrochloride.

Excipient:Thefilm-coatedtabletcontainslactosemonohydrate(seesection4.4).

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

ProductimportedfromGreece:

Dullredtabletsmarkedwith“M400”ononesideand“BAYER”onthereverse

4CLINICALPARTICULARS

4.1TherapeuticIndications

Avelox400mgfilm-coatedtabletsareindicatedforthetreatmentofthefollowingbacterialinfectionsinpatientsof

18yearsandoldercausedbybacteriasusceptibletomoxifloxacin(seesections4.4,4.8and5.1).Moxifloxacinshould

beusedonlywhenitisconsideredinappropriatetouseantibacterialagentsthatarecommonlyrecommendedforthe

initialtreatmentoftheseinfectionsorwhenthesehavefailed:

Acutebacterialsinusitis(adequatelydiagnosed)

Acuteexacerbationsofchronicbronchitis(adequatelydiagnosed)

Communityacquiredpneumonia,exceptseverecases

Mildtomoderatepelvicinflammatorydisease(i.e.infectionsoffemaleuppergenitaltract,including

salpingitisandendometritis),withoutanassociatedtubo-ovarianorpelvicabscess.

Avelox400mgfilm-coatedtabletsarenotrecommendedforuseinmonotherapyofmildtomoderate

pelvicinflammatorydiseasebutshouldbegivenincombinationwithanotherappropriateantibacterial

agent(e.g.acephalosporin)duetoincreasingmoxifloxacinresistanceofNeisseriagonorrhoeaeunless

moxifloxacin-resistantNeisseriagonorrhoeaecanbeexcluded(seesections4.4and5.1).

Avelox400mgfilm-coatedtabletsmayalsobeusedtocompleteacourseoftherapyinpatientswhohaveshown

improvementduringinitialtreatmentwithintravenousmoxifloxacinforthefollowingindications:

-Community-acquiredpneumonia

-Complicatedskinandskinstructureinfections

Avelox400mgfilm-coatedtabletsshouldnotbeusedtoinitiatetherapyforanytypeofskinandskinstructure

infectionorinseverecommunity-acquiredpneumonia.

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantibacterialagents.

4.2Posologyandmethodofadministration

Dosage(adults)

One400mgfilm-coatedtabletoncedaily.

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Noadjustmentofdosageisrequiredinpatientswithmildtoseverelyimpairedrenalfunctionorinpatientsonchronic

dialysisi.e.haemodialysisandcontinuousambulatoryperitonealdialysis(seesection5.2formoredetails).

Thereisinsufficientdatainpatientswithimpairedliverfunction(seesection4.3).

Otherspecialpopulations

Noadjustmentofdosageisrequiredintheelderlyandinpatientswithlowbodyweight.

Childrenandadolescents

Moxifloxaciniscontraindicatedinchildrenandadolescents(<18years).Efficacyandsafetyofmoxifloxacinin

childrenandadolescentshavenotbeenestablished(seesection4.3).

Methodofadministration

Thefilm-coatedtabletshouldbeswallowedwholewithsufficientliquidandmaybetakenindependentofmeals.

Durationofadministration

Avelox400mgfilm-coatedtabletsshouldbeusedforthefollowingtreatmentdurations:

Acuteexacerbationofchronicbronchitis 5-10days

Communityacquiredpneumonia 10days

Acutebacterialsinusitis 7days

Mildtomoderatepelvicinflammatorydisease14days

Avelox400mgfilm-coatedtabletshavebeenstudiedinclinicaltrialsforupto14daystreatment.

Therecommendeddose(400mgoncedaily)anddurationoftherapyfortheindicationbeingtreatedshouldnotbe

exceeded.

4.3Contraindications

Hypersensitivitytomoxifloxacin,otherquinolonesortoanyoftheexcipients.

Pregnancyandlactation(seesection4.6).

Patientsbelow18yearsofage.

Patientswithahistoryoftendondisease/disorderrelatedtoquinolonetreatment.

Bothinpreclinicalinvestigationsandinhumans,changesincardiacelectrophysiologyhavebeenobservedfollowing

exposuretomoxifloxacin,intheformofQTprolongation.Forreasonsofdrugsafety,moxifloxacinistherefore

contraindicatedinpatientswith:

CongenitalordocumentedacquiredQTprolongation

Electrolytedisturbances,particularlyinuncorrectedhypokalaemia

Clinicallyrelevantbradycardia

Clinicallyrelevantheartfailurewithreducedleft-ventricularejectionfraction

Previoushistoryofsymptomaticarrhythmias

MoxifloxacinshouldnotbeusedconcurrentlywithotherdrugsthatprolongtheQTinterval(seealsosection4.5).

Duetolimitedclinicaldata,moxifloxacinisalsocontraindicatedinpatientswithimpairedliverfunction(ChildPugh

C)andinpatientswithtransaminasesincrease>5foldULN.

4.4Specialwarningsandprecautionsforuse

Hypersensitivityandallergicreactionshavebeenreportedforfluoroquinolonesincludingmoxifloxacinafterfirst

administration.Anaphylacticreactionscanprogresstoalife-threateningshock,evenafterthefirstadministration.

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MoxifloxacinhasbeenshowntoprolongtheQTcintervalontheelectrocardiograminsomepatients.Inthe

analysisofECGsobtainedintheclinicaltrialprogram,QTcprolongationwithmoxifloxacinwas

6msec±26msec,1.4%comparedtobaseline.AswomentendtohavealongerbaselineQTcintervalcompared

withmen,theymaybemoresensitivetoQTc-prolongingmedications.Elderlypatientsmayalsobemore

susceptibletodrug-associatedeffectsontheQTinterval.

Medicationthatcanreducepotassiumlevelsshouldbeusedwithcautioninpatientsreceivingmoxifloxacin.

Moxifloxacinshouldbeusedwithcautioninpatientswithongoingproarrhythmicconditions(especiallywomen

andelderlypatients),suchasacutemyocardialischaemiaorQTprolongationasthismayleadtoanincreased

riskforventriculararrhythmias(incl.torsadedepointes)andcardiacarrest(seealsosection4.3).Themagnitude

ofQTprolongationmayincreasewithincreasingconcentrationsofthedrug.Therefore,therecommendeddose

shouldnotbeexceeded.

Thebenefitofmoxifloxacintreatmentespeciallyininfectionswithalowdegreeofseverityshouldbebalanced

withtheinformationcontainedinthewarningsandprecautionssection.

Ifsignsofcardiacarrhythmiaoccurduringtreatmentwithmoxifloxacin,treatmentshouldbestoppedandan

ECGshouldbeperformed.

Casesoffulminanthepatitispotentiallyleadingtoliverfailure(includingfatalcases)havebeenreportedwith

moxifloxacin(seesection4.8).Patientsshouldbeadvisedtocontacttheirdoctorpriortocontinuingtreatmentif

signsandsymptomsoffulminanthepaticdiseasedevelopsuchasrapidlydevelopingastheniaassociatedwith

jaundice,darkurine,bleedingtendencyorhepaticencephalopathy.

Liverfunctiontests/investigationsshouldbeperformedincaseswhereindicationsofliverdysfunctionoccur.

CasesofbullousskinreactionslikeStevens-Johnsonsyndromeortoxicepidermalnecrolysishavebeenreported

withmoxifloxacin(seesection4.8).Patientsshouldbeadvisedtocontacttheirdoctorimmediatelypriorto

continuingtreatmentifskinand/ormucosalreactionsoccur.

Quinolonesareknowntotriggerseizures.UseshouldbewithcautioninpatientswithCNSdisorderswhichmay

predisposetoseizuresorlowertheseizurethreshold.

Casesofsensoryorsensorimotorpolyneuropathyresultinginparaesthesias,hypoaesthesias,dysaesthesias,or

weaknesshavebeenreportedinpatientsreceivingquinolones.Patientsundertreatmentwithmoxifloxacinshould

beadvisedtoinformtheirdoctorpriortocontinuingtreatmentifsymptomsofneuropathysuchaspain,burning,

tingling,numbness,orweaknessdevelop(seesection4.8).

Antibioticassociateddiarrhoea(AAD)andantibioticassociatedcolitis(AAC),includingpseudomembranous

colitisandClostridiumdifficile-associateddiarrhoea,hasbeenreportedinassociationwiththeuseofbroad

spectrumantibioticsincludingmoxifloxacinandmayrangeinseverityfrommilddiarrhoeatofatalcolitis.

Thereforeitisimportanttoconsiderthisdiagnosisinpatientswhodevelopseriousdiarrhoeaduringorafterthe

useofmoxifloxacin.IfAADorAACissuspectedorconfirmed,ongoingtreatmentwithantibacterialagents,

includingmoxifloxacin,shouldbediscontinuedandadequatetherapeuticmeasuresshouldbeinitiated

immediately.Furthermore,appropriateinfectioncontrolmeasuresshouldbeundertakentoreducetheriskof

transmission.Drugsinhibitingperistalsisarecontraindicatedinpatientswhodevelopseriousdiarrhoea.

Moxifloxacinshouldbeusedwithcautioninpatientswithmyastheniagravisbecausethesymptomscanbe

exacerbated.

Tendoninflammationandrupturemayoccurwithquinolonetherapyincludingmoxifloxacin,particularlyin

elderlypatientsandinthosetreatedconcurrentlywithcorticosteroids.Atthefirstsignofpainorinflammation,

patientsshoulddiscontinuetreatmentwithmoxifloxacinandresttheaffectedlimb(s).

Elderlypatientswithrenaldisordersshouldusemoxifloxacinwithcautioniftheyareunabletomaintainadequate

fluidintake,becausedehydrationmayincreasetheriskofrenalfailure.

Ifvisionbecomesimpairedoranyeffectsontheeyesareexperienced,aneyespecialistshouldbeconsulted

immediately(seesections4.7and4.8).

Quinoloneshavebeenshowntocausephotosensitivityreactionsinpatients.However,studieshaveshownthat

moxifloxacinhasalowerrisktoinducephotosensitivity.Neverthelesspatientsshouldbeadvisedtoavoid

exposuretoeitherUVirradiationorextensiveand/orstrongsunlightduringtreatmentwithmoxifloxacin.

Patientswithafamilyhistoryof,oractualglucose-6-phosphatedehydrogenasedeficiencyareproneto

haemolyticreactionswhentreatedwithquinolones.Therefore,moxifloxacinshouldbeusedwithcautioninthese

patients.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

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Forpatientswithcomplicatedpelvicinflammatorydisease(e.g.associatedwithatubo-ovarianorpelvicabscess),

forwhomanintravenoustreatmentisconsiderednecessary,treatmentwithAvelox400mgfilm-coatedtabletsis

notrecommended.

PelvicinflammatorydiseasemaybecausedbyfluoroquinoloneresistantNeisseriagonorrhoeae.Thereforein

suchcasesempiricalmoxifloxacinshouldbeco-administeredwithanotherappropriateantibiotic(e.g.a

cephalosporin)unlessmoxifloxacin-resistantNeisseriagonorrhoeaecanbeexcluded.Ifclinicalimprovementis

notachievedafter3daysoftreatment,thetherapyshouldbereconsidered.

Duetoadverseeffectsonthecartilageinjuvenileanimals(seesection5.3)theuseofmoxifloxacininchildren

andadolescents<18yearsiscontraindicated(seesection4.3).

MoxifloxacinisnotrecommendedforthetreatmentofMRSAinfections.Incaseofasuspectedorconfirmed

infectionduetoMRSA,treatmentwithanappropriateantibacterialagentshouldbestarted(seesection5.1).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Interactionswithmedicinalproducts

AnadditiveeffectonQTintervalprolongationbetweenmoxifloxacinandthefollowingdrugscannotbeexcluded:

antiarrhythmicsclassIA(e.g.quinidine,hydroquinidine,disopyramide)orantiarrhythmicsclassIII(e.g.amiodarone,

sotalol,dofetilide,ibutilide),neuroleptics(e.g.phenothiazines,pimozide,sertindole,haloperidol,sultopride),tricyclic

antidepressiveagents,certainantimicrobials(sparfloxacin,erythromycinIV,pentamidine,antimalarialsparticularly

halofantrine),certainantihistaminics(terfenadine,astemizole,mizolastine),others(cisapride,vincamineIV,bepridil,

diphemanil).Thiseffectmightleadtoanincreasedriskofventriculararrhythmias,notablytorsadedepointes.

Thereforemoxifloxaciniscontraindicatedinpatientstreatedwiththesedrugs(seealsosection4.3).

Anintervalofabout6hoursshouldbeleftbetweenadministrationofagentscontainingbivalentortrivalentcations

(e.g.antacidscontainingmagnesiumoraluminium,didanosinetablets,sucralfateandagentscontainingironorzinc)

andadministrationofmoxifloxacin.

Concomitantadministrationofcharcoalwithanoraldoseof400mgmoxifloxacinleadstoapronouncedpreventionof

drugabsorptionandareducedsystemicavailabilityofthedrugbymorethan80%.Therefore,theconcomitantuseof

thesetwodrugsisnotrecommended(exceptforoverdosecases,seealsosection4.9).

AfterrepeateddosinginhealthyvolunteersmoxifloxacinincreasedC

ofdigoxinapproximately30%without

affectingAUCortroughlevels.Noprecautionisrequiredforusewithdigoxin.

Instudiesconductedindiabeticvolunteers,concomitantadministrationoforalmoxifloxacinwithglibenclamide

resultedinadecreaseofapproximately21%inthepeakplasmaconcentrationsofglibenclamide.Thecombinationof

glibenclamideandmoxifloxacincouldtheoreticallyresultinamildandtransienthyperglycaemia.However,the

observedpharmacokineticchangesforglibenclamidedidnotresultinchangesofthepharmacodynamicparameters

(bloodglucose,insulin).Thereforenoclinicallyrelevantinteractionwasobservedbetweenmoxifloxacinand

glibenclamide.

ChangesinINR

Alargenumberofcasesshowinganincreaseinoralanticoagulantactivityhavebeenreportedinpatientsreceiving

antibiotics,especiallyfluoroquinolones,macrolides,tetracyclines,cotrimoxazoleandsomecephalosporins.The

infectiousandinflammatoryconditions,ageandgeneralstatusofthepatientappeartoberiskfactors.Underthese

circumstances,itisdifficulttoevaluatewhethertheinfectionortheantibiotictherapycausetheINR(international

normalisedratio)disorder.AprecautionarymeasurewouldbetomorefrequentlymonitortheINR.Ifnecessary,the

oralanticoagulantdosageshouldbeadjustedasappropriate.Evenifduringaninteractionstudyperformedinhealthy

volunteersbetweenmoxifloxacinandwarfarin,negativeresultshavebeenobserved,theprecautionarymeasuresas

abovestatedshouldapplytowarfarinasforotheranticoagulants.

Clinicalstudieshaveshownthattherearenointeractionsfollowingconcomitantadministrationofmoxifloxacinwith:

ranitidine,probenecid,oralcontraceptives,calciumsupplements,morphineadministeredparenterally,theophyllineor

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InvitrostudieswithhumancytochromeP450enzymessupportthisdata.Consideringtheseresultsametabolic

interactionviacytochromeP450enzymesisunlikely.

Interactionwithfood

Moxifloxacinhasnoclinicallyrelevantinteractionwithfoodincludingdairyproducts.

4.6Fertility,pregnancyandlactation

Pregnancy

Theuseofmoxifloxacinduringpregnancyiscontraindicated.Thesafetyofmoxifloxacininhumanpregnancyhasnot

beenevaluated.Reversiblejointinjuriesaredescribedinchildrenreceivingsomequinolones,howeverthiseffecthas

notbeenreportedasoccurringonexposedfoetuses.Animalstudieshaveshownreproductivetoxicity(seesection5.3).

Thepotentialriskforhumansisunknown.

Lactation

Theuseofmoxifloxacinduringbreastfeedingiscontraindicated.Aswithotherquinolones,moxifloxacinhasbeen

showntocauselesionsinthecartilageoftheweightbearingjointsofimmatureanimals.Preclinicaldataindicatethat

moxifloxacinpassesintomilk.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsofmoxifloxacinontheabilitytodriveandusemachineshavebeenperformed.However,

fluoroquinolonesincludingmoxifloxacinmayresultinanimpairmentofthepatient'sabilitytodriveoroperate

machineryduetoCNSreactions(e.g.dizziness;acute,transientlossofvision,seesection4.8)oracuteandshort

lastinglossofconsciousness(syncope,seesection4.8).Patientsshouldbeadvisedtoseehowtheyreactto

moxifloxacinbeforedrivingoroperatingmachinery.

4.8Undesirableeffects

Adversereactionsbasedonallclinicaltrialswithmoxifloxacin400mg(oralandsequentialtherapy)sortedby

frequenciesarelistedbelow:

Apartfromnauseaanddiarrhoeaalladversereactionswereobservedatfrequenciesbelow3%.

SystemOrgan

Class Common

≥1/100to<1/10 Uncommon

≥1/1,000to

<1/100 Rare

≥1/10,000to

<1/1,000 VeryRare

<1/10,000

Infectionsand

Infestations Superinfectionsdue

toresistantbacteria

orfungie.g.oral

andvaginal

candidiasis

Bloodand

LymphaticSystem

Disorders Anaemia

Leucopenia(s)

Neutropenia

Thrombocytopenia

Thrombocythemia

Bloodeosinophilia

Prothrombintime

prolonged/INR

Prothrombinlevel

increased/INR

decreased

Agranulocytosis

ImmuneSystem

Disorders Allergicreaction

(seesection4.4) Anaphylaxisincl.

veryrarelylife-

threateningshock

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Allergicoedema/

angiooedema(incl.

laryngealoedema,

potentiallylife-

threatening,see

section4.4)

Metabolismand

Nutrition

Disorders Hyperlipidemia Hyperglycemia

Hyperuricemia

Psychiatric

Disorders Anxietyreactions

Psychomotor

hyperactivity/

agitation Emotionallability

Depression(invery

rarecases

potentially

culminatinginself-

endangering

behaviour,suchas

suicidalideations/

thoughts,orsuicide

attempts)

Depersonalization

Psychoticreactions

(potentially

culminatinginself-

endangering

behaviour,suchas

suicidalideations/

thoughts,orsuicide

attempts)

NervousSystem

Disorders Headache

Dizziness Par-and

Dysaesthesia

Tastedisorders

(incl.ageusiain

veryrarecases)

Confusionand

disorientation

Sleepdisorders

(predominantly

insomnia)

Tremor

Vertigo

Hypoaesthesia

Smelldisorders

(incl.anosmia)

Abnormaldreams

Disturbed

coordination(incl.

gaitdisturbances,

esp.dueto

dizzinessor

vertigo)

Seizuresincl.grand

malconvulsions

(seesection4.4)

Disturbedattention

Speechdisorders

Hyperaesthesia

EyeDisorders Visualdisturbances

incl.diplopiaand

blurredvision

(especiallyinthe

courseofCNS

reactions,see

section4.4) Transientlossof

vision(especiallyin

thecourseofCNS

reactions,see

sections4.4and

4.7)

Earand

Labyrinth

Disorders Tinnitus

Hearing

impairmentincl.

deafness(usually

reversible)

Cardiacand

Vascular

Disorders QTprolongationin

patientswith

hypokalaemia(see

section4.4) QTprolongation

(seesection4.4)

Palpitations

Tachycardia

Atrialfibrillation

Anginapectoris

Vasodilatation Ventricular

tachyarrhythmias

Syncope(i.e.,acute

andshortlasting

lossof

consciousness)

Hypertension

Hypotension Unspecified

arrhythmias

TorsadedePointes

(seesection4.4)

Cardiacarrest(see

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Respiratory,

Thoracicand

Mediastinal

Disorders Dyspnea(including

asthmatic

conditions)

Gastrointestinal

Disorders Nausea

Vomiting

Gastrointestinaland

abdominalpains

Diarrhoea Anorexia

Constipation

Dyspepsia

Flatulence

Gastritis

Increasedamylase Dysphagia

Stomatitis

Antibiotic

associatedcolitis

(incl.

pseudomembranous

colitis,inveryrare

casesassociated

withlife-

threatening

complications,see

section4.4)

Hepatobiliary

Disorders Increasein

transaminases Hepaticimpairment

(incl.LDH

increase)

Increasedbilirubin

Increasedgamma-

glutamyl-

transferase

Increaseinblood

alkaline

Jaundice

Hepatitis

(predominantly

cholestatic) Fulminanthepatitis

potentiallyleading

tolife-threatening

liverfailure(incl.

fatalcases,see

section4.4)

Skinand

Subcutaneous

TissueDisorders Pruritus

Rash

Urticaria

Dryskin Bullousskin

reactionslike

Stevens-Johnson

syndromeortoxic

epidermal

necrolysis

(potentiallylife-

threatening,see

section4.4)

Musculoskeletal,

ConnectiveTissue

andBone

Disorders Arthralgia

Myalgia Tendonitis(see

section4.4)

Musclecramp

Muscletwitching Tendonrupture(see

section4.4)

Arthritis

Musclerigidity

Exacerbationof

symptomsof

myastheniagravis

(seesection4.4)

RenalandUrinary

Disorders Dehydration Renalimpairment

(incl.increasein

BUNand

creatinine)

Renalfailure(see

section4.4)

GeneralDisorders

and

Administration

SiteConditions Feelingunwell

(predominantly

astheniaorfatigue)

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Therehavebeenveryrarecasesofthefollowingsideeffectsreportedfollowingtreatmentwithotherfluoroquinolones,

whichmightpossiblyalsooccurduringtreatmentwithmoxifloxacin:hypernatraemia,hypercalcaemia,haemolytic

anaemia,rhabdomyolysis,photosensitivityreactions,peripheralneuropathy(seesection4.4).

4.9Overdose

Nospecificcountermeasuresafteraccidentaloverdosearerecommended.Generalsymptomatictherapyshouldbe

initiated.Concomitantadministrationofcharcoalwithadoseof400mgoralmoxifloxacinwillreducesystemic

availabilityofthedrugbymorethan80%.Theuseofcharcoalearlyduringabsorptionmaybeusefultoprevent

excessiveincreaseinthesystemicexposuretomoxifloxacinincasesoforaloverdose.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Quinoloneantibacterials,fluoroquinolones,ATCcode:J01MA14

Mechanismofaction

MoxifloxacinhasinvitroactivityagainstawiderangeofGram-positiveandGram-negativepathogens.

ThebactericidalactionofmoxifloxacinresultsfromtheinhibitionofbothtypeIItopoisomerases(DNAgyraseand

topoisomeraseIV)requiredforbacterialDNAreplication,transcriptionandrepair.ItappearsthattheC8-methoxy

moietycontributestoenhancedactivityandlowerselectionofresistantmutantsofGram-positivebacteriacomparedto

theC8-Hmoiety.ThepresenceofthebulkybicycloaminesubstituentattheC-7positionpreventsactiveefflux,

associatedwiththenorAorpmrAgenesseenincertainGram-positivebacteria.

Pharmacodynamicinvestigationshavedemonstratedthatmoxifloxacinexhibitsaconcentrationdependentkillingrate.

Minimumbactericidalconcentrations(MBC)werefoundtobeintherangeoftheminimuminhibitoryconcentrations

(MIC).

Interferencewithculturetest

MoxifloxacintherapymaygivefalsenegativecultureresultsforMycobacteriumspp.bysuppressionofmycobacterial

growth.

Effectontheintestinalflorainhumans

Thefollowingchangesintheintestinalflorawereseeninvolunteersfollowingoraladministrationofmoxifloxacin:

Escherichiacoli,Bacillusspp.,Enterococcusspp.,andKlebsiellaspp.werereduced,asweretheanaerobes

Bacteroidesvulgatus,Bifidobacteriumspp.,Eubacteriumspp.,andPeptostreptococcusspp..ForBacteroidesfragilis

therewasanincrease.Thesechangesreturnedtonormalwithintwoweeks.

Mechanismofresistance

Resistancemechanismsthatinactivatepenicillins,cephalosporins,aminoglycosides,macrolidesandtetracyclinesdo

notinterferewiththeantibacterialactivityofmoxifloxacin.Otherresistancemechanismssuchaspermeationbarriers

(commoninPseudomonasaeruginosa)andeffluxmechanismsmayalsoeffectsusceptibilitytomoxifloxacin.

InvitroresistancetomoxifloxacinisacquiredthroughastepwiseprocessbytargetsitemutationsinbothtypeII

topoisomerases,DNAgyraseandtopoisomeraseIV.Moxifloxacinisapoorsubstrateforactiveeffluxmechanismsin

Gram-positiveorganisms.

Cross-resistanceisobservedwithotherfluoroquinolones.However,asmoxifloxacininhibitsbothtopoisomeraseIIand

IVwithsimilaractivityinsomeGram-positivebacteria,suchbacteriamayberesistanttootherquinolones,but

(incl.paininback,

chest,pelvicand

extremities)

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InvitroSusceptibilityData

EUCASTclinicalMICbreakpointsformoxifloxacin(31.01.2006):

ClinicalandLaboratoryStandardsInstitute™(CLSI),formerlyNCCLSbreakpointsarepresentedinthebelowtable

forMICtesting(mg/l)ordiscdiffusiontesting(zonediameter[mm])usinga5-µgmoxifloxacindisc.

ClinicalandLaboratoryStandardsInstitute™(CLSI)MICanddiscdiffusionbreakpointsforStaphylococcusspp.and

fastidiousorganisms(M100-S17,2007)andMICbreakpointsforanaerobes(M11-A7,2007):

Theprevalenceofacquiredresistancemayvarygeographicallyandwithtimeforselectedspeciesandlocalinformation

ofresistanceisdesirable,particularlywhentreatingsevereinfections.Asnecessary,expertadviceshouldbesought

wherethelocalprevalenceofresistanceissuchthatutilityoftheagentinatleastsometypesofinfectionsis

Organism Susceptible Resistant

Staphylococcusspp. ≤0.5mg/l >1mg/l

S.pneumoniae ≤0.5mg/l

>0.5mg/l

StreptococcusGroupsA,B,C,G ≤0.5mg/l

>1mg/l

H.influenzaeandM.catarrhalis ≤0.5mg/l

>0.5mg/l

Enterobacteriaceae ≤0.5mg/l >1mg/l

Non-speciesrelatedbreakpoints* ≤0.5mg/l >1mg/l

*Non-speciesrelatedbreakpointshavebeendeterminedmainlyonthebasisof

pharmacokinetic/pharmacodynamicdataandareindependentofMICdistributionsof

specificspecies.Theyareforuseonlyforspeciesthathavenotbeengivenaspecies-

specificbreakpointandarenotforusewithspecieswhereinterpretativecriteriaremain

tobedetermined(Gram-negativeanaerobes).

Organism Susceptible Intermediate Resistant

S.pneumoniae ≤1mg/l

≥18mm 2mg/l

15-17mm ≥4mg/l

≤14mm

Haemophilusspp. ≤1mg/l

≥18mm -

Staphylococcusspp. ≤0.5mg/l

≥24mm 1mg/l

21-23mm ≥2mg/l

≤20mm

Anaerobes ≤2mg/l

4mg/l ≥8mg/l

Commonlysusceptiblespecies

AerobicGram-positivemicro-organisms

Gardnerellavaginalis

Staphylococcusaureus*(methicillin-susceptible)

Streptococcusagalactiae(GroupB)

Streptococcusmillerigroup*(S.anginosus,S.constellatusandS.intermedius)

Streptococcuspneumoniae*

Streptococcuspyogenes*(GroupA)

AerobicGram-negativemicro-organisms

Haemophilusinfluenzae*

Haemophilusparainfluenzae*

Klebsiellapneumoniae* #

Moraxella(Branhamella)catarrhalis*

Anaerobicmicro-organisms

Fusobacteriumspp.

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5.2Pharmacokineticproperties

AbsorptionandBioavailability

Followingoraladministrationmoxifloxacinisrapidlyandalmostcompletelyabsorbed.Theabsolutebioavailability

amountstoapproximately91%.

Pharmacokineticsarelinearintherangeof50-800mgsingledoseandupto600mgoncedailydosingover10days.

Followinga400mgoraldosepeakconcentrationsof3.1mg/larereachedwithin0.5-4hpostadministration.Peak

andtroughplasmaconcentrationsatsteady-state(400mgoncedaily)were3.2and0.6mg/l,respectively.Atsteady-

statetheexposurewithinthedosingintervalisapproximately30%higherthanafterthefirstdose.

Distribution

Moxifloxacinisdistributedtoextravascularspacesrapidly;afteradoseof400mganAUCof35mg·h/lisobserved.

Thesteady-statevolumeofdistribution(Vss)isapproximately2l/kg.Invitroandexvivoexperimentsshoweda

proteinbindingofapproximately40-42%independentoftheconcentrationofthedrug.Moxifloxacinismainlybound

toserumalbumin.

Thefollowingpeakconcentrations(geometricmean)wereobservedfollowingadministrationofasingleoraldoseof

Prevotellaspp.

“Other”micro-organisms

Chlamydophila(Chlamydia)pneumoniae*

Chlamydiatrachomatis*

Coxiellaburnetii

Legionellapneumophila

Mycoplasmagenitalium

Mycoplasmahominis

Mycoplasmapneumoniae*

Speciesforwhichacquiredresistancemaybeaproblem

AerobicGram-positivemicro-organisms

Staphylococcusaureus(methicillin-resistant) +

AerobicGram-negativemicro-organisms

Enterobactercloacae*

Escherichiacoli*

Klebsiellaoxytoca

Neisseriagonorrhoeae* +

Inherentlyresistantorganisms

AerobicGram-negativemicro-organisms

Pseudomonasaeruginosa

*Activityhasbeensatisfactorilydemonstratedinsusceptiblestrainsinclinicalstudiesintheapproved

clinicalindications.

ESBL-producingstrainsarecommonlyresistanttofluoroquinolones

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Metabolism

MoxifloxacinundergoesPhaseIIbiotransformationandisexcretedviarenalandbiliary/faecalpathwaysasunchanged

drugaswellasintheformofasulpho-compound(M1)andaglucuronide(M2).M1andM2aretheonlymetabolites

relevantinhumans,botharemicrobiologicallyinactive.

InclinicalPhaseIandinvitrostudiesnometabolicpharmacokineticinteractionswithotherdrugsundergoingPhaseI

biotransformationinvolvingcytochromeP450enzymeswereobserved.Thereisnoindicationofoxidativemetabolism.

Elimination

Moxifloxaciniseliminatedfromplasmawithameanterminalhalflifeofapproximately12hours.Themeanapparent

totalbodyclearancefollowinga400mgdoserangesfrom179to246ml/min.Renalclearanceamountedtoabout24-

53ml/minsuggestingpartialtubularreabsorptionofthedrugfromthekidneys.

Aftera400mgdose,recoveryfromurine(approximately19%forunchangeddrug,approximately2.5%forM1,and

approximately14%forM2)andfaeces(approximately25%ofunchangeddrug,approximately36%forM1,andno

recoveryforM2)totalledtoapproximately96%.

Concomitantadministrationofmoxifloxacinwithranitidineorprobeneciddidnotalterrenalclearanceoftheparent

drug.

Higherplasmaconcentrationsareobservedinhealthyvolunteerswithlowbodyweight(suchaswomen)andinelderly

volunteers.

Thepharmacokineticpropertiesofmoxifloxacinarenotsignificantlydifferentinpatientswithrenalimpairment

(includingcreatinineclearance>20ml/min/1.73m 2

).Asrenalfunctiondecreases,concentrationsoftheM2metabolite

(glucuronide)increasebyuptoafactorof2.5(withacreatinineclearanceof<30ml/min/1.73m 2

Onthebasisofthepharmacokineticstudiescarriedoutsofarinpatientswithliverfailure(ChildPughA,B),itisnot

possibletodeterminewhetherthereareanydifferencescomparedwithhealthyvolunteers.Impairedliverfunctionwas

associatedwithhigherexposuretoM1inplasma,whereasexposuretoparentdrugwascomparabletoexposurein

healthyvolunteers.Thereisinsufficientexperienceintheclinicaluseofmoxifloxacininpatientswithimpairedliver

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5.3Preclinicalsafetydata

Effectsonthehaematopoeticsystem(slightdecreasesinthenumberoferythrocytesandplatelets)wereseeninratsand

monkeys.Aswithotherquinolones,hepatotoxicity(elevatedliverenzymesandvacuolardegeneration)wasseenin

rats,monkeysanddogs.InmonkeysCNStoxicity(convulsions)occurred.Theseeffectswereseenonlyaftertreatment

withhighdosesofmoxifloxacinorafterprolongedtreatment.

Moxifloxacin,likeotherquinolones,wasgenotoxicininvitrotestsusingbacteriaormammaliancells.Sincethese

effectscanbeexplainedbyaninteractionwiththegyraseinbacteriaand-athigherconcentrations-byaninteraction

withthetopoisomeraseIIinmammaliancells,athresholdconcentrationforgenotoxicitycanbeassumed.Ininvivo

tests,noevidenceofgenotoxicitywasfounddespitethefactthatveryhighmoxifloxacindoseswereused.Thus,a

sufficientmarginofsafetytothetherapeuticdoseinmancanbeprovided.Moxifloxacinwasnon-carcinogenicinan

initiation-promotionstudyinrats.

Manyquinolonesarephotoreactiveandcaninducephototoxic,photomutagenicandphotocarcinogeniceffects.In

contrast,moxifloxacinwasproventobedevoidofphototoxicandphotogenotoxicpropertieswhentestedina

comprehensiveprogrammeofinvitroandinvivostudies.Underthesameconditionsotherquinolonesinducedeffects.

Athighconcentrations,moxifloxacinisaninhibitoroftherapidcomponentofthedelayedrectifierpotassiumcurrent

oftheheartandmaythuscauseprolongationsoftheQTinterval.Toxicologicalstudiesperformedindogsusingoral

dosesof ≥90mg/kgleadingtoplasmaconcentrations≥16mg/lcausedQTprolongations,butnoarrhythmias.Only

afterveryhighcumulativeintravenousadministrationofmorethan50foldthehumandose(>300mg/kg),leadingto

plasmaconcentrationsof ≥200mg/l(morethan40foldthetherapeuticlevel),reversible,non-fatalventricular

arrhythmiaswereseen.

Quinolonesareknowntocauselesionsinthecartilageofthemajordiarthrodialjointsinimmatureanimals.Thelowest

oraldoseofmoxifloxacincausingjointtoxicityinjuveniledogswasfourtimesthemaximumrecommended

therapeuticdoseof400mg(assuminga50kgbodyweight)onamg/kgbasis,withplasmaconcentrationstwotothree

timeshigherthanthoseatthemaximumtherapeuticdose.

Toxicitytestsinratsandmonkeys(repeateddosinguptosixmonths)revealednoindicationregardinganoculotoxic

risk.Indogs,highoraldoses( ≥60mg/kg)leadingtoplasmaconcentrations≥20mg/lcausedchangesinthe

electroretinogramandinisolatedcasesanatrophyoftheretina.

Reproductivestudiesperformedinrats,rabbitsandmonkeysindicatethatplacentaltransferofmoxifloxacinoccurs.

Studiesinrats(p.o.andi.v.)andmonkeys(p.o.)didnotshowevidenceofteratogenicityorimpairmentoffertility

followingadministrationofmoxifloxacin.Aslightlyincreasedincidenceofvertebralandribmalformationswas

observedinfoetusesofrabbitsbutonlyatadose(20mg/kgi.v.)whichwasassociatedwithseverematernaltoxicity.

Therewasanincreaseintheincidenceofabortionsinmonkeysandrabbitsathumantherapeuticplasma

concentrations.Inrats,decreasedfoetalweights,anincreasedprenatalloss,aslightlyincreaseddurationofpregnancy

andanincreasedspontaneousactivityofsomemaleandfemaleoffspringwasobservedatdoseswhichwere63times

themaximumrecommendeddoseonamg/kgbasiswithplasmaconcentrationsintherangeofthehumantherapeutic

dose.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Microcrystallinecellulose

Croscarmellosesodium

Lactosemonohydrate

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Filmcoat:

Hypromellose

Macrogol4000

Ferricoxide(E172)

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

Storeintheoriginalpackageinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

Over-labelledcartoncontainingover-labelledblisterstripof5tablets.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

B&SHealthcare,

Unit4,BradfieldRoad,

Ruislip,Middlesex,

HA40NU,UK

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1328/144/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:18 th

February2011

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