AVELOX 400 Milligram Film Coated Tablet

Ireland - English - HPRA (Health Products Regulatory Authority)

Buy It Now

Active ingredient:
MOXIFLOXACIN
Available from:
LTT Pharma Limited
INN (International Name):
MOXIFLOXACIN
Dosage:
400 Milligram
Pharmaceutical form:
Film Coated Tablet
Prescription type:
Product subject to prescription which may not be renewed (A)
Authorization status:
Withdrawn
Authorization number:
PPA1562/087/001
Authorization date:
2013-03-05

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Avelox400mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onefilm-coatedtabletcontains400mgmoxifloxacin(ashydrochloride).

Excipientwithknowneffect:Thefilm-coatedtabletcontainslactosemonohydrate(seesection4.4).

Forthefulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

ProductimportedfromtheUK:

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-coatedtabletsarenotrecommendedforuseinmonotherapyofmildtomoderatepelvic

inflammatorydiseasebutshouldbegivenincombinationwithanotherappropriateantibacterialagent(e.g.

acephalosporin)duetoincreasingmoxifloxacinresistanceofNeisseriagonorrhoeaeunlessmoxifloxacin-

resistantNeisseriagonorrhoeaecanbeexcluded(seesections4.4and5.1).

Avelox400mgfilm-coatedtabletsmayalsobeusedtocompleteacourseoftherapyinpatientswhohaveshown

improvementduringinitialtreatmentwithintravenousmoxifloxacinforthefollowingindications:

-Community-acquiredpneumonia

-Complicatedskinandskinstructureinfections

Avelox400mgfilm-coatedtabletsshouldnotbeusedtoinitiatetherapyforanytypeofskinandskinstructure

infectionorinseverecommunity-acquiredpneumonia.

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantibacterialagents.

4.2Posologyandmethodofadministration

Posology(adults)

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 27/09/2012 CRN 2118380 page number: 1

Renal/hepaticimpairment

Noadjustmentofdosageisrequiredinpatientswithmildtoseverelyimpairedrenalfunctionorinpatientsonchronic

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

Thereisinsufficientdatainpatientswithimpairedliverfunction(seesection4.3).

Otherspecialpopulations

Noadjustmentofdosageisrequiredintheelderlyandinpatientswithlowbodyweight.

Paediatricpopulation

Moxifloxaciniscontraindicatedinchildrenandadolescents(<18years).Efficacyandsafetyofmoxifloxacinin

childrenandadolescentshavenotbeenestablished(seesection4.3).

Methodofadministration

Thefilm-coatedtabletshouldbeswallowedwholewithsufficientliquidandmaybetakenindependentofmeals.

Durationofadministration

Avelox400mgfilm-coatedtabletsshouldbeusedforthefollowingtreatmentdurations:

Acuteexacerbationofchronicbronchitis 5-10days

Communityacquiredpneumonia 10days

Acutebacterialsinusitis 7days

Mildtomoderatepelvicinflammatorydisease14days

Avelox400mgfilm-coatedtabletshavebeenstudiedinclinicaltrialsforupto14daystreatment.

Sequential(intravenousfollowedbyoral)therapy

Inclinicalstudieswithsequentialtherapymostpatientsswitchedfromintravenoustooraltherapywithin4days

(community-acquiredpneumonia)or6days(complicatedskinandskinstructureinfections).Therecommendedtotal

durationofintravenousandoraltreatmentis7-14daysforcommunity-acquiredpneumoniaand7-21daysfor

complicatedskinandskinstructureinfections.

Therecommendeddose(400mgoncedaily)anddurationoftherapyfortheindicationbeingtreatedshouldnotbe

exceeded.

4.3Contraindications

Hypersensitivitytomoxifloxacin,otherquinolonesortoanyoftheexcipientslistedinsection6.1.

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

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 27/09/2012 CRN 2118380 page number: 2

4.4Specialwarningsandprecautionsforuse

Thebenefitofmoxifloxacintreatmentespeciallyininfectionswithalowdegreeofseverityshouldbebalancedwith

theinformationcontainedinthewarningsandprecautionssection.

ProlongationofQTcintervalandpotentiallyQTc-prolongation-relatedclinicalconditions

MoxifloxacinhasbeenshowntoprolongtheQTcintervalontheelectrocardiograminsomepatients.Intheanalysisof

ECGsobtainedintheclinicaltrialprogram,QTcprolongationwithmoxifloxacinwas6msec±26msec,1.4%

comparedtobaseline.AswomentendtohavealongerbaselineQTcintervalcomparedwithmen,theymaybemore

sensitivetoQTc-prolongingmedications.Elderlypatientsmayalsobemoresusceptibletodrug-associatedeffectson

theQTinterval.

Medicationthatcanreducepotassiumlevelsshouldbeusedwithcautioninpatientsreceivingmoxifloxacin(seealso

sections4.3and4.5).

Moxifloxacinshouldbeusedwithcautioninpatientswithongoingproarrhythmicconditions(especiallywomenand

elderlypatients),suchasacutemyocardialischaemiaorQTprolongationasthismayleadtoanincreasedriskfor

ventriculararrhythmias(incl.torsadedepointes)andcardiacarrest(seealsosection4.3).ThemagnitudeofQT

prolongationmayincreasewithincreasingconcentrationsofthedrug.Therefore,therecommendeddoseshouldnotbe

exceeded.

Ifsignsofcardiacarrhythmiaoccurduringtreatmentwithmoxifloxacin,treatmentshouldbestoppedandanECG

shouldbeperformed.

Hypersensitivity/allergicreactions

Hypersensitivityandallergicreactionshavebeenreportedforfluoroquinolonesincludingmoxifloxacinafterfirst

administration.Anaphylacticreactionscanprogresstoalife-threateningshock,evenafterthefirstadministration.In

thesecasesmoxifloxacinshouldbediscontinuedandsuitabletreatment(e.g.treatmentforshock)initiated.

Severeliverdisorders

Casesoffulminanthepatitispotentiallyleadingtoliverfailure(includingfatalcases)havebeenreportedwith

moxifloxacin(seesection4.8).Patientsshouldbeadvisedtocontacttheirdoctorpriortocontinuingtreatmentifsigns

andsymptomsoffulminanthepaticdiseasedevelopsuchasrapidlydevelopingastheniaassociatedwithjaundice,dark

urine,bleedingtendencyorhepaticencephalopathy.

Liverfunctiontests/investigationsshouldbeperformedincaseswhereindicationsofliverdysfunctionoccur.

Seriousbullousskinreactions

CasesofbullousskinreactionslikeStevens-Johnsonsyndromeortoxicepidermalnecrolysishavebeenreportedwith

moxifloxacin(seesection4.8).Patientsshouldbeadvisedtocontacttheirdoctorimmediatelypriortocontinuing

treatmentifskinand/ormucosalreactionsoccur.

Patientspredisposedtoseizures

Quinolonesareknowntotriggerseizures.UseshouldbewithcautioninpatientswithCNSdisordersorinthepresence

ofotherriskfactorswhichmaypredisposetoseizuresorlowertheseizurethreshold.Incaseofseizures,treatmentwith

moxifloxacinshouldbediscontinuedandappropriatemeasuresinstituted.

Peripheralneuropathy

Casesofsensoryorsensorimotorpolyneuropathyresultinginparaesthesias,hypoaesthesias,dysaesthesias,orweakness

havebeenreportedinpatientsreceivingquinolonesincludingmoxifloxacin.Patientsundertreatmentwith

moxifloxacinshouldbeadvisedtoinformtheirdoctorpriortocontinuingtreatmentifsymptomsofneuropathysuchas

pain,burning,tingling,numbness,orweaknessdevelop(seesection4.8).

Psychiatricreactions

Psychiatricreactionsmayoccurevenafterthefirstadministrationofquinolones,includingmoxifloxacin.Inveryrare

casesdepressionorpsychoticreactionshaveprogressedtosuicidalthoughtsandself-injuriousbehavioursuchas

suicideattempts(seesection4.8).Intheeventthatthepatientdevelopsthesereactions,moxifloxacinshouldbe

discontinuedandappropriatemeasuresinstituted.Cautionisrecommendedifmoxifloxacinistobeusedinpsychotic

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 27/09/2012 CRN 2118380 page number: 3

Antibiotic-associateddiarrhoeaincl.colitis

Antibiotic-associateddiarrhoea(AAD)andantibiotic-associatedcolitis(AAC),includingpseudomembranouscolitis

andClostridiumdifficile-associateddiarrhoea,hasbeenreportedinassociationwiththeuseofbroadspectrum

antibioticsincludingmoxifloxacinandmayrangeinseverityfrommilddiarrhoeatofatalcolitis.Thereforeitis

importanttoconsiderthisdiagnosisinpatientswhodevelopseriousdiarrhoeaduringoraftertheuseofmoxifloxacin.

IfAADorAACissuspectedorconfirmed,ongoingtreatmentwithantibacterialagents,includingmoxifloxacin,should

bediscontinuedandadequatetherapeuticmeasuresshouldbeinitiatedimmediately.Furthermore,appropriateinfection

controlmeasuresshouldbeundertakentoreducetheriskoftransmission.Drugsinhibitingperistalsisare

contraindicatedinpatientswhodevelopseriousdiarrhoea.

Patientswithmyastheniagravis

Moxifloxacinshouldbeusedwithcautioninpatientswithmyastheniagravisbecausethesymptomscanbe

exacerbated.

Tendoninflammation,tendonrupture

Tendoninflammationandrupture(especiallyAchillestendon),sometimesbilateral,mayoccurwithquinolonetherapy

includingmoxifloxacin,evenwithin48hoursofstartingtreatmentandhavebeenreporteduptoseveralmonthsafter

discontinuationoftherapy.Theriskoftendinitisandtendonruptureisincreasedinelderlypatientsandinthosetreated

concurrentlywithcorticosteroids.Atthefirstsignofpainorinflammation,patientsshoulddiscontinuetreatmentwith

moxifloxacin,resttheaffectedlimb(s)andconsulttheirdoctorimmediatelyinordertoinitiateappropriatetreatment

(e.g.immobilisation)fortheaffectedtendon(seesections4.3and4.8).

Patientswithrenalimpairment

Elderlypatientswithrenaldisordersshouldusemoxifloxacinwithcautioniftheyareunabletomaintainadequatefluid

intake,becausedehydrationmayincreasetheriskofrenalfailure.

Visiondisorders

Ifvisionbecomesimpairedoranyeffectsontheeyesareexperienced,aneyespecialistshouldbeconsulted

immediately(seesections4.7and4.8).

Preventionofphotosensitivityreactions

Quinoloneshavebeenshowntocausephotosensitivityreactionsinpatients.However,studieshaveshownthat

moxifloxacinhasalowerrisktoinducephotosensitivity.Neverthelesspatientsshouldbeadvisedtoavoidexposureto

eitherUVirradiationorextensiveand/orstrongsunlightduringtreatmentwithmoxifloxacin.

Patientswithglucose-6-phosphatedehydrogenasedeficiency

Patientswithafamilyhistoryoforactualglucose-6-phosphatedehydrogenasedeficiencyarepronetohaemolytic

reactionswhentreatedwithquinolones.Therefore,moxifloxacinshouldbeusedwithcautioninthesepatients.

Patientswithgalactoseintolerance,Lapplactasedeficiencyorglucose-galactosemalabsorption

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

Patientswithpelvicinflammatorydisease

Forpatientswithcomplicatedpelvicinflammatorydisease(e.g.associatedwithatubo-ovarianorpelvicabscess),for

whomanintravenoustreatmentisconsiderednecessary,treatmentwithAvelox400mgfilm-coatedtabletsisnot

recommended.

Pelvicinflammatorydiseasemaybecausedbyfluoroquinolone-resistantNeisseriagonorrhoeae.Thereforeinsuch

casesempiricalmoxifloxacinshouldbeco-administeredwithanotherappropriateantibiotic(e.g.acephalosporin)

unlessmoxifloxacin-resistantNeisseriagonorrhoeaecanbeexcluded.Ifclinicalimprovementisnotachievedafter

3daysoftreatment,thetherapyshouldbereconsidered.

PatientswithspecialcSSSI

Clinicalefficacyofintravenousmoxifloxacininthetreatmentofsevereburninfections,fasciitisanddiabeticfoot

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 27/09/2012 CRN 2118380 page number: 4

Interferencewithbiologicaltests

MoxifloxacintherapymayinterferewiththeMycobacteriumspp.culturetestbysuppressionofmycobacterialgrowth

causingfalsenegativeresultsinsamplestakenfrompatientscurrentlyreceivingmoxifloxacin.

PatientswithMRSAinfections

MoxifloxacinisnotrecommendedforthetreatmentofMRSAinfections.Incaseofasuspectedorconfirmedinfection

duetoMRSA,treatmentwithanappropriateantibacterialagentshouldbestarted(seesection5.1).

Paediatricpopulation

Duetoadverseeffectsonthecartilageinjuvenileanimals(seesection5.3)theuseofmoxifloxacininchildrenand

adolescents<18yearsiscontraindicated(seesection4.3).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Interactionswithmedicinalproducts

AnadditiveeffectonQTintervalprolongationofmoxifloxacinandothermedicinalproductsthatmayprolongtheQTc

intervalcannotbeexcluded.Thismightleadtoanincreasedriskofventriculararrhythmias,includingtorsadede

pointes.Therefore,co-administrationofmoxifloxacinwithanyofthefollowingmedicinalproductsiscontraindicated

(seealsosection4.3):

anti-arrhythmicsclassIA(e.g.quinidine,hydroquinidine,disopyramide)

anti-arrhythmicsclassIII(e.g.amiodarone,sotalol,dofetilide,ibutilide)

antipsychotics(e.g.phenothiazines,pimozide,sertindole,haloperidol,sultopride)

tricyclicantidepressiveagents

certainantimicrobialagents(saquinavir,sparfloxacin,erythromycinIV,pentamidine,antimalarialsparticularly

halofantrine)

certainantihistaminics(terfenadine,astemizole,mizolastine)

others(cisapride,vincamineIV,bepridil,diphemanil).

Moxifloxacinshouldbeusedwithcautioninpatientswhoaretakingmedicationthatcanreducepotassiumlevels(e.g.

loopandthiazide-typediuretics,laxativesandenemas[highdoses],corticosteroids,amphotericinB)ormedicationthat

isassociatedwithclinicallysignificantbradycardia.

Anintervalofabout6hoursshouldbeleftbetweenadministrationofagentscontainingbivalentortrivalentcations

(e.g.antacidscontainingmagnesiumoraluminium,didanosinetablets,sucralfateandagentscontainingironorzinc)

andadministrationofmoxifloxacin.

Concomitantadministrationofcharcoalwithanoraldoseof400mgmoxifloxacinledtoapronouncedpreventionof

drugabsorptionandareducedsystemicavailabilityofthedrugbymorethan80%.Therefore,theconcomitantuseof

thesetwodrugsisnotrecommended(exceptforoverdosecases,seealsosection4.9).

Afterrepeateddosinginhealthyvolunteers,moxifloxacinincreasedC

ofdigoxinbyapproximately30%without

affectingAUCortroughlevels.Noprecautionisrequiredforusewithdigoxin.

Instudiesconductedindiabeticvolunteers,concomitantadministrationoforalmoxifloxacinwithglibenclamide

resultedinadecreaseofapproximately21%inthepeakplasmaconcentrationsofglibenclamide.Thecombinationof

glibenclamideandmoxifloxacincouldtheoreticallyresultinamildandtransienthyperglycaemia.However,the

observedpharmacokineticchangesforglibenclamidedidnotresultinchangesofthepharmacodynamicparameters

(bloodglucose,insulin).Thereforenoclinicallyrelevantinteractionwasobservedbetweenmoxifloxacinand

glibenclamide.

ChangesinINR

Alargenumberofcasesshowinganincreaseinoralanticoagulantactivityhavebeenreportedinpatientsreceiving

antibacterialagents,especiallyfluoroquinolones,macrolides,tetracyclines,cotrimoxazoleandsomecephalosporins.

Theinfectiousandinflammatoryconditions,ageandgeneralstatusofthepatientappeartoberiskfactors.Underthese

circumstances,itisdifficulttoevaluatewhethertheinfectionorthetreatmentcausedtheINR(internationalnormalised

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 27/09/2012 CRN 2118380 page number: 5

Ifnecessary,theoralanticoagulantdosageshouldbeadjustedasappropriate.

Clinicalstudieshaveshownnointeractionsfollowingconcomitantadministrationofmoxifloxacinwith:ranitidine,

probenecid,oralcontraceptives,calciumsupplements,morphineadministeredparenterally,theophylline,cyclosporine

oritraconazole.

InvitrostudieswithhumancytochromeP450enzymessupportedthesefindings.Consideringtheseresultsametabolic

interactionviacytochromeP450enzymesisunlikely.

Interactionwithfood

Moxifloxacinhasnoclinicallyrelevantinteractionwithfoodincludingdairyproducts.

4.6Fertility,pregnancyandlactation

Pregnancy

Thesafetyofmoxifloxacininhumanpregnancyhasnotbeenevaluated.Animalstudieshaveshownreproductive

toxicity(seesection5.3).Thepotentialriskforhumansisunknown.Duetotheexperimentalriskofdamageby

fluoroquinolonestotheweight-bearingcartilageofimmatureanimalsandreversiblejointinjuriesdescribedinchildren

receivingsomefluoroquinolones,moxifloxacinmustnotbeusedinpregnantwomen(seesection4.3).

Breastfeeding

Thereisnodataavailableinlactatingornursingwomen.Preclinicaldataindicatethatsmallamountsofmoxifloxacin

aresecretedinmilk.Intheabsenceofhumandataandduetotheexperimentalriskofdamagebyfluoroquinolonesto

theweight-bearingcartilageofimmatureanimals,breast-feedingiscontraindicatedduringmoxifloxacintherapy(see

section4.3).

Fertility

Animalstudiesdonotindicateimpairmentoffertility(seesection5.3).

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%.

Withineachfrequencygrouping,undesirableeffectsarepresentedinorderofdecreasingseriousness.Frequenciesare

definedas:

common(1/100to<1/10)

uncommon(1/1,000to<1/100)

rare(1/10,000to<1/1,000)

veryrare(<1/10,000)

SystemOrgan

Class(MedDRA) Common Uncommon Rare VeryRare

Infectionsand

infestations Superinfectionsdue

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 27/09/2012 CRN 2118380 page number: 6

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

(seesection4.4)

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-

injurious

behaviour,suchas

suicidalideations/

thoughts,orsuicide

attempts,see

section4.4)

Depersonalization

Psychoticreactions

(potentially

culminatinginself-

injurious

behaviour,suchas

suicidalideations/

thoughts,orsuicide

attempts,see

section4.4)

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

Amnesia

Peripheral

neuropathyand

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 27/09/2012 CRN 2118380 page number: 7

Eyedisorders Visualdisturbances

incl.diplopiaand

blurredvision

(especiallyinthe

courseofCNS

reactions,see

section4.4) Transientlossof

vision(especially

inthecourseof

CNSreactions,see

sections4.4and

4.7)

Earandlabyrinth

disorders Tinnitus

Hearing

impairmentincl.

deafness(usually

reversible)

Cardiacdisorders QTprolongationin

patientswith

hypokalaemia(see

sections4.3and

4.4) QTprolongation

(seesection4.4)

Palpitations

Tachycardia

Atrialfibrillation

Anginapectoris Ventricular

tachyarrhythmias

Syncope(i.e.,acute

andshortlasting

lossof

consciousness) Unspecified

arrhythmias

TorsadedePointes

(seesection4.4)

Cardiacarrest(see

section4.4)

Vascular

disorders Vasodilatation Hypertension

Hypotension

Respiratory,

thoracicand

mediastinal

disorders Dyspnea(including

asthmatic

conditions)

Gastrointestinal

disorders Nausea

Vomiting

Gastrointestinaland

abdominalpains

Diarrhoea Decreasedappetite

andfoodintake

Constipation

Dyspepsia

Flatulence

Gastritis

Increasedamylase Dysphagia

Stomatitis

Antibiotic

associatedcolitis

(incl.pseudo-

membranous

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)

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 27/09/2012 CRN 2118380 page number: 8

Therehavebeenveryrarecasesofthefollowingsideeffectsreportedfollowingtreatmentwithotherfluoroquinolones,

whichmightpossiblyalsooccurduringtreatmentwithmoxifloxacin:hypernatraemia,hypercalcaemia,haemolytic

anaemia,rhabdomyolysis,photosensitivityreactions(seesection4.4).

4.9Overdose

Nospecificcountermeasuresafteraccidentaloverdosearerecommended.Intheeventofoverdose,symptomatic

treatmentshouldbeimplemented.ECGmonitoringshouldbeundertaken,becauseofthepossibilityofQTinterval

prolongation.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

andconnective

tissuedisorders Myalgia section4.4)

Musclecramp

Muscletwitching

Muscleweakness (seesection4.4)

Arthritis

Musclerigidity

Exacerbationof

symptomsof

myastheniagravis

(seesection4.4)

Renalandurinary

disorders Dehydration Renalimpairment

(incl.increasein

BUNand

creatinine)

Renalfailure(see

section4.4)

Generaldisorders

and

administrationsite

conditions Feelingunwell

(predominantly

astheniaorfatigue)

Painfulconditions

(incl.paininback,

chest,pelvicand

extremities)

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 27/09/2012 CRN 2118380 page number: 9

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

susceptibletomoxifloxacin.

Breakpoints

EUCASTclinicalMICanddiskdiffusionbreakpointsformoxifloxacin(01.01.2012):

MicrobiologicalSusceptibility

Theprevalenceofacquiredresistancemayvarygeographicallyandwithtimeforselectedspeciesandlocalinformation

ofresistanceisdesirable,particularlywhentreatingsevereinfections.Asnecessary,expertadviceshouldbesought

wherethelocalprevalenceofresistanceissuchthatutilityoftheagentinatleastsometypesofinfectionsis

Organism Susceptible Resistant

Staphylococcusspp. 0.5mg/l

24mm >1mg/l

<21mm

S.pneumoniae 0.5mg/l

22mm >0.5mg/l

<22mm

StreptococcusGroupsA,B,C,G 0.5mg/l

18mm >1mg/l

<15mm

H.influenzae 0.5mg/l

25mm >0.5mg/l

<25mm

M.catarrhalis 0.5mg/l

23mm >0.5mg/l

<23mm

Enterobacteriaceae 0.5mg/l

20mm >1mg/l

<17mm

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

*Non-speciesrelatedbreakpointshavebeendeterminedmainlyonthebasisof

pharmacokinetic/pharmacodynamicdataandareindependentofMICdistributionsof

specificspecies.Theyareforuseonlyforspeciesthathavenotbeengivenaspecies-

specificbreakpointandarenotforusewithspecieswhereinterpretativecriteriaremain

tobedetermined.

Commonlysusceptiblespecies

AerobicGram-positivemicro-organisms

Gardnerellavaginalis

Staphylococcusaureus*(methicillin-susceptible)

Streptococcusagalactiae(GroupB)

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

Streptococcuspneumoniae*

Streptococcuspyogenes*(GroupA)

Streptococcusviridansgroup(S.viridans,S.mutans,S.mitis,S.sanguinis,S.salivarius,

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 27/09/2012 CRN 2118380 page number: 10

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;afteradoseof400mganAUCof35m·gh/lisobserved.

Thesteady-statevolumeofdistribution(Vss)isapproximately2l/kg.Invitroandexvivoexperimentsshoweda

proteinbindingofapproximately40-42%independentoftheconcentrationofthedrug.Moxifloxacinismainlybound

AerobicGram-negativemicro-organisms

Acinetobacterbaumanii

Haemophilusinfluenzae*

Haemophilusparainfluenzae*

Legionellapneumophila

Moraxella(Branhamella)catarrhalis*

Anaerobicmicro-organisms

Fusobacteriumspp.

Prevotellaspp.

“Other”micro-organisms

Chlamydophila(Chlamydia)pneumoniae*

Chlamydiatrachomatis*

Coxiellaburnetii

Mycoplasmagenitalium

Mycoplasmahominis

Mycoplasmapneumoniae*

Speciesforwhichacquiredresistancemaybeaproblem

AerobicGram-positivemicro-organisms

Enterococcusfaecalis*

Enterococcusfaecium*

Staphylococcusaureus(methicillin-resistant) +

AerobicGram-negativemicro-organisms

Enterobactercloacae*

Escherichiacoli* #

Klebsiellapneumoniae* #

Klebsiellaoxytoca

Neisseriagonorrhoeae* +

Proteusmirabilis*

Anaerobicmicro-organisms

Bacteroidesfragilis*

Peptostreptococcusspp.*

Inherentlyresistantorganisms

AerobicGram-negativemicro-organisms

Pseudomonasaeruginosa

*Activityhasbeensatisfactorilydemonstratedinsusceptiblestrainsinclinicalstudiesintheapproved

clinicalindications.

ESBL-producingstrainsarecommonlyresistanttofluoroquinolones

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 27/09/2012 CRN 2118380 page number: 11

Thefollowingpeakconcentrations(geometricmean)wereobservedfollowingadministrationofasingleoraldoseof

400mgmoxifloxacin:

Biotransformation

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.

Elderlyandpatientswithlowbodyweight

Higherplasmaconcentrationsareobservedinhealthyvolunteerswithlowbodyweight(suchaswomen)andinelderly

volunteers.

Renalimpairment

Thepharmacokineticpropertiesofmoxifloxacinarenotsignificantlydifferentinpatientswithrenalimpairment

(includingcreatinineclearance>20ml/min/1.73m 2

).Asrenalfunctiondecreases,concentrationsoftheM2metabolite

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

Hepaticimpairment

Onthebasisofthepharmacokineticstudiescarriedoutsofarinpatientswithliverfailure(ChildPughA,B),itisnot

possibletodeterminewhetherthereareanydifferencescomparedwithhealthyvolunteers.Impairedliverfunctionwas

associatedwithhigherexposuretoM1inplasma,whereasexposuretoparentdrugwascomparabletoexposurein

healthyvolunteers.Thereisinsufficientexperienceintheclinicaluseofmoxifloxacininpatientswithimpairedliver

Tissue Concentration Site:Plasmaratio

Plasma 3.1mg/l -

Saliva 3.6mg/l 0.75-1.3

Blisterfluid

mg/l 1.7 1

Bronchialmucosa 5.4mg/kg 1.7-2.1

Alveolarmacrophages 56.7mg/kg 18.6-70.0

Epithelialliningfluid 20.7mg/l 5-7

Maxillarysinus 7.5mg/kg 2.0

Ethmoidsinus 8.2mg/kg 2.1

Nasalpolyps 9.1mg/kg 2.6

Interstitialfluid

mg/l 0.8-1.4 2,3

Femalegenitaltract*

10.2 4

mg/kg 1.72 4

*intravenousadministrationofasingle400mgdose

10hafteradministration

unboundconcentration

from3hupto36hpostdose

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 27/09/2012 CRN 2118380 page number: 12

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

Microcrystallinecellulose

Croscarmellosesodium

Lactosemonohydrate

Magnesiumstearate

Hypromellose

Macrogol4000

Ferricoxide(E172)

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 27/09/2012 CRN 2118380 page number: 13

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelflifeexpirydateforthisproductshallbethedateshownontheblisterandouterpackageoftheproductonthe

marketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

Storeintheoriginalpackageinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

Blisterstripcontaining5tabletsinanover-labelledcarton.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

LTTPharmaLimited

Unit18

OxleasowRoad

EastMoonsMoat

Redditch

Worcestershire

B980RE

UnitedKingdom

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1562/087/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:24thSeptember2012

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 27/09/2012 CRN 2118380 page number: 14

Similar products

Search alerts related to this product

View documents history

Share this information