CODALUX

Main information

  • Trade name:
  • CODALUX Eye Drops Solution 50/5
  • Dosage:
  • 50/5
  • Pharmaceutical form:
  • Eye Drops Solution
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CODALUX Eye Drops Solution 50/5
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0959/003/001
  • Authorization date:
  • 27-05-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Codalux50microgram/ml+5mg/mlEyeDrops,Solution

2QUALITATIVEANDQUANTITATIVECOMPOSITION

1mlsolutioncontainslatanoprost50microgramsandtimololmaleate6.83mgequivalentto5mgtimolol.

Itcontains0.412mg/mlofbenzalkoniumchloridesolution50%.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Eyedrops,solution

Thesolutionisaclearcolourlessliquid.pH5.5-6.5.

Osmolality260-320mOsm/kg.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Reductionofintraocularpressure(IOP)inpatientswithopenangleglaucomaandocularhypertensionwhoare

insufficientlyresponsivetotopicalbeta-blockersorprostaglandinanalogues.

4.2Posologyandmethodofadministration

Recommendeddosageforadults(includingtheelderly):

Recommendedtherapyisoneeyedropintheaffectedeye(s)oncedaily.

Ifonedoseismissed,treatmentshouldcontinuewiththenextdoseasplanned.Thedoseshouldnotexceedonedropin

theaffectedeye(s)daily.

Administration:

Contactlensesshouldberemovedbeforeinstillationoftheeyedropsandmaybereinsertedafter15minutes(see

section4.4).

Ifmorethanonetopicalophthalmicdrugisbeingused,thedrugsshouldbeadministeredatleastfiveminutesapart.

Whenusingnasolacrimalocclusionorclosingtheeyelidsfor2minutes,thesystemicabsorptionisreduced.Thismay

resultinadecreaseinsystemicsideeffectsandanincreaseinlocalactivity.

Useinchildrenandadolescents

Safetyandeffectivenessinchildrenandadolescentshasnotbeenestablished.

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Codaluxiscontraindicatedinpatientswith:

-Hypersensitivitytotheactivesubstancesortoanyoftheexcipients.

-Sinusbradycardia,sicksinussyndromesino-atrialblock,secondorthirddegreeatrioventricularblocknotcontrolled

withpace-maker.Overtcardiacfailure,cardiogenicshock.

-Reactiveairwaydiseaseincludingbronchialasthmaorahistoryofbronchialasthma,severechronicobstructive

pulmonarydisease.

4.4Specialwarningsandprecautionsforuse

Oculareffects

Latanoprostmaygraduallychangetheeyecolourbyincreasingtheamountofbrownpigmentintheiris.Similarto

experiencewithlatanoprosteyedrops,increasedirispigmentationwasseenin16-20%ofallpatientstreatedwith

latanoprostandtimololforuptooneyear(basedonphotographs).Thiseffecthaspredominantlybeenseeninpatients

withmixedcolouredirides,i.e.green-brown,yellow-brownorblue/grey-brown,andisduetoincreasedmelanin

contentinthestromalmelanocytesoftheiris.Typicallythebrownpigmentationaroundthepupilspreads

concentricallytowardstheperipheryinaffectedeyes,buttheentireirisorpartsofitmaybecomemorebrownish.In

patientswithhomogeneouslyblue,grey,greenorbrowneyes,thechangehasonlyrarelybeenseenduringtwoyearsof

treatmentinclinicaltrialswithlatanoprost.Thechangeiniriscolouroccursslowlyandmaynotbenoticeablefor

severalmonthstoyearsandithasnotbeenassociatedwithanysymptomorpathologicalchanges.

Nofurtherincreaseinbrownirispigmenthasbeenobservedafterdiscontinuationoftreatment,buttheresultantcolour

changemaybepermanent.

Neithernaevinorfrecklesoftheirishavebeenaffectedbytreatment.

Accumulationofpigmentinthetrabecularmeshworkorelsewhereintheanteriorchamberhasnotbeenobservedbut

patientsshouldbeexaminedregularlyand,dependingontheclinicalsituation,treatmentmaybestoppedifincreased

irispigmentationensues.

Beforetreatmentisinstitutedpatientsshouldbeinformedofthepossibilityofachangeineyecolour.Unilateral

treatmentcanresultinpermanentheterochromia.

Thereisnodocumentedexperiencewithlatanoprostininflammatory,neovascular,chronicangleclosureorcongenital

glaucoma,inopenangleglaucomaofpseudophakicpatientsandinpigmentaryglaucoma.Latanoprosthasnoorlittle

effectonthepupilbutthereisnodocumentedexperienceinacuteattacksofclosedangleglaucoma.Thereforeitis

recommendedthatCodaluxshouldbeusedwithcautionintheseconditionsuntilmoreexperienceisobtained.

Macularoedema,includingcystoidmacularoedema,hasbeenreportedduringtreatmentwithlatanoprost.These

reportshavemainlyoccurredinaphakicpatients,inpseudophakicpatientswithatornposteriorlenscapsule,orin

patientswithknownriskfactorsformacularoedema.Codaluxshouldbeusedwithcautioninthesepatients.

Cornealdiseases

Ophthalmic-blockersmayinducedrynessofeyes.Patientswithcornealdiseasesshouldbetreatedwithcaution.

Choroidaldetachment

Choroidaldetachmenthasbeenreportedwithadministrationofaqueoussuppressanttherapy(e.g.timolol,

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Systemiceffects

Likeothertopicallyappliedophthalmicagents,timololisabsorbedsystemically.Duetothebeta-adrenergic

componenttimolol,thesametypesofcardiovascular,pulmonaryandotheradversereactionsseenwithsystemicbeta-

adrenergicblockingagentsmayoccur.IncidenceofsystemicADRsaftertopicalophthalmicadministrationislower

thanforsystemicadministration.Toreducethesystemicabsorption,see4.2.

Anaphylacticreactions

Whiletakingbeta-blockers,patientswithahistoryofatopyorahistoryofsevereanaphylacticreactiontoavarietyof

allergensmaybemorereactivetorepeatedchallengewithsuchallergensandunresponsivetotheusualdosesof

adrenalineusedtotreatanaphylacticreactions.

Cardiacdisorders

Inpatientswithcardiovasculardiseases(e.g.coronaryheartdisease,Prinzmetal'sanginaandcardiacfailure)and

hypotensiontherapywithbeta-blockersshouldbecriticallyassessedandthetherapywithotheractivesubstances

shouldbeconsidered.Patientswithcardiovasculardiseasesshouldbewatchedforsignsofdeteriorationofthese

diseasesandofadversereactions.

Duetoitsnegativeeffectonconductiontime,beta-blockersshouldonlybegivenwithcautiontopatientswithfirst

degreeheartblock.

Vasculardisorders

Patientswithsevereperipheralcirculatorydisturbance/disorders(i.e.severeformsofRaynaud’sdiseaseorRaynaud’s

syndrome)shouldbetreatedwithcaution.

Respiratorydisorders

Respiratoryreactions,includingdeathduetobronchospasminpatientswithasthmahavebeenreportedfollowing

administrationofsomeophthalmicbeta-blockers.

Codaluxshouldbeusedwithcaution,inpatientswithmild/moderatechronicobstructivepulmonarydisease(COPD)

andonlyifthepotentialbenefitoutweighsthepotentialrisk.

Hypoglycaemia/diabetes

Beta-blockersshouldbeadministeredwithcautioninpatientssubjecttospontaneoushypoglycaemiaortopatientswith

labilediabetes,asbeta-blockersmaymaskthesignsandsymptomsofacutehypoglycaemia.

Hyperthyroidism

Beta-blockersmayalsomaskthesignsofhyperthyroidism

Surgicalanaesthesia

-blockingophthalmologicalpreparationsmayblocksystemic -agonisteffectse.g.ofadrenaline.The

anaesthesiologistshouldbeinformedwhenthepatientisreceiving<ACTIVEsubstance>.

Otherbeta-blockingagents

Theeffectonintra-ocularpressureortheknowneffectsofsystemicbeta-blockademaybepotientatedwhentimololis

giventothepatientsalreadyreceivingasystemicbeta-blockingagent.Theresponseofthesepatientsshouldbeclosely

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Timololmayinteractwithotherdrugs,seeSection4.5.

Useofcontactlenses

Codaluxcontainsbenzalkoniumchloride,whichiscommonlyusedasapreservativeinophthalmicproducts.

Benzalkoniumchloridehasbeenreportedtocausepunctatekeratopathyand/ortoxiculcerativekeratopathy,maycause

eyeirritationandisknowntodiscoloursoftcontactlenses.Closemonitoringisrequiredwithfrequentorprolongeduse

ofCodaluxindryeyepatients,orinconditionswherethecorneaiscompromised.Avoidcontactwithsoftcontact

lenses.ContactlensesmayabsorbbenzalkoniumchlorideandtheseshouldberemovedbeforeapplyingCodaluxbut

maybereinsertedafter15minutes(seesection4.2).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Nospecificdruginteractionstudieshavebeenperformedwithlatanoprostandtimolol.

Therehavebeenreportsofparadoxicalelevationsinintraocularpressurefollowingtheconcomitantophthalmic

administrationoftwoprostaglandinanalogues.Therefore,theuseoftwoormoreprostaglandins,prostaglandin

analogues,orprostaglandinderivativesisnotrecommended.

Mydriasisresultingfromconcomitantuseofophthalmicbeta-blockersandadrenaline(ephinephrine)hasbeenreported

occasionally.

Thereisapotentialforadditiveeffectsresultinginhypotensionand/ormarkedbradycardiawhenophthalmicbeta-

blockerssolutionisadministeredconcomitantlywithoralcalciumchannelblockers,betaadrenergicblockingagents,

antiarrhythmics(includingamiodarone),digitalisglycosides,parasympathomimetics,guanethidine.

Thehypertensivereactiontosuddenwithdrawalofclonidinecanbepotentiatedwhentakingbeta-blockers.

Potentiatedsystemicbeta-blockade(e.g.,decreasedheartrate,depression)hasbeenreportedduring

combinedtreatmentwithCYP2D6inhibitors(e.g.quinidine,fluoxetine,paroxetine)andtimolol.

4.6Fertility,pregnancyandlactation

PREGNANCY

Latanoprost:

Therearenoadequatedatafromtheuseoflatanoprostinpregnantwomen.Studiesinanimalshaveshownreproductive

toxicity(seeSection5.3).Thepotentialriskforhumansisunknown.

Timolol:

Therearenoadequatedatafortheuseoftimololinpregnantwomen.Timololshouldnotbeusedduringpregnancy

unlessclearlynecessary.

Toreducethesystemicabsorption,see4.2.

Epidemiologicalstudieshavenotrevealedmalformativeeffectsbutshowariskforintrauterinegrowthretardation

whenbeta-blockersareadministeredbytheoralroute.Inaddition,signsandsymptomsofbeta-blockade(e.g.

bradycardia,hypotension,respiratorydistressandhypoglycaemia)havebeenobservedintheneonatewhenbeta-

blockershavebeenadministereduntildelivery.IfCodaluxisadministereduntildelivery,theneonateshouldbe

carefullymonitoredduringthefirstdaysoflife.

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LACTATION

Beta-blockersareexcretedintobreastmilk.However,attherapeuticdosesoftimololineyedropsitisnotlikelythat

sufficientamountswouldbepresentinbreastmilktoproduceclinicalsymptomsofbeta-blockadeintheinfant.To

reducethesystemicabsorption,see4.2.

Latanoprostanditsmetabolitesmaypassintobreastmilk;Codaluxshouldthereforenotbeusedinwomenwhoare

breast-feeding.

4.7Effectsonabilitytodriveandusemachines

Instillationofeyedropsmaycausetransientblurringofvision.Untilthishasresolved,patientsshouldnotdriveoruse

machines.

4.8Undesirableeffects

Forlatanoprost,themajorityofadverseeventsrelatetotheocularsystem.Indatafromtheextensionphaseofthe

latanoprostandtimololpivotaltrials,16-20%ofpatientsdevelopedincreasedirispigmentation,whichmaybe

permanent.Inanopen5yearlatanoprostsafetystudy,33%ofpatientsdevelopedirispigmentation(seeSection4.4).

Otherocularadverseeventsaregenerallytransientandoccurondoseadministration.Fortimolol,themostserious

adverseeventsaresystemicinnature,includingbradycardia,arrhythmia,congestiveheartfailure,bronchospasmand

allergicreactions.

Treatmentrelatedadverseeventsseeninclinicaltrialswithlatanoprostandtimololarelistedbelow.

Adverseeventsarecategorizedbyfrequencyasfollows:verycommon(1/10),common(1/100to<1/10),uncommon

(1/1,000to<1/100),rare(1/10,000to<1/1,000)andveryrare(<1/10,000).

Additionaladverseeventshavebeenreportedspecifictotheuseoftheindividualcomponentsoflatanoprostand

timolol50microgram/ml+5mg/mlEyeDrops,Solutionineitherinclinicalstudies,spontaneousreportsorinthe

availableliterature.

Forlatanoprost,theseare:

Withineachfrequencygrouping,undesirableeffectsarepresentedinorderofdecreasingseriousness.

SYSTEM

ORGAN

CLASS Verycommon

(1/10) Common

(1/100to

<1/10) Uncommon

(1/1,000to

1/100) Rare

(1/10,000to

<1/1,000) Veryrare

(<1/10,000)

NervousSystem

Disorders Headache

EyeDisorders Increasediris

pigmentation Eyeirritation

(including

stinging,

burningand

itching),Eye

pain. Eye

hyperaemia,

Conjunctivitis,

Visionblurred,

Lacrimation

increased,

Blepharitis,

Corneal

disorders.

Skinand

Subcutaneous

Tissue

Disorders Skinrash,

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Dizziness.

EyeDisorders:

Eyelashandvellushairchanges(increasedlength,thickness,pigmentation,andnumber),Punctateepithelialerosions,

periorbitaloedema,iritis/uveitis,macularoedema(inaphakic,pseudophakicpatientswithtornposteriorlenscapsules

orinpatientswithknownriskfactorsformacularoedema),Dryeye,Keratitis,Cornealoedemaanderosions,

Misdirectedeyelashessometimesresultingineyeirritation.

CardiacDisorders:

Aggravationofanginainpatientswithpre-existingdisease,Palpitations.

Respiratory,ThoracicandMediastinalDisorders

Asthma,Asthmaaggravation,Dyspnoea.

SkinandSubcutaneousTissueDisorders:

Darkeningofpalpebralskin.

Musculoskeletal,ConnectiveTissueandBoneDisorders:

Jointpain,Musclepain.

GeneraldisordersandAdministrationSiteConditions:

Chestpain

Likeothertopicallyappliedophthalmicdrugs,timololisabsorbedintothesystemiccirculation.Thismaycausesimilar

undesirableeffectsasseenwithsystemicbeta-blockingagents.IncidenceofsystemicADRsaftertopicalophthalmic

administrationislowerthanforsystemicadministration.Listedadversereactionsincludereactionsseenwithinthe

classofophthalmicbeta-blockers.

Additionaladversereactionshavebeenseenwithophthalmicbeta-blockersandmaypotentiallyoccurwith.

Thereforefortimolol,theseare:

ImmuneSystemDisorders:

Systemicallergicreactionsincludingangioedema,urticaria,localizedandgeneralizedrash,pruritus,anaphylactic

reaction.

Metabolismandnutritiondisorders:

Hypoglycaemia.

PsychiatricDisorders:

Insomnia,depression,nightmares,memoryloss.

NervousSystemDisorders:

Syncope,cerebrovascularaccident,cerebralischemia,increasesinsignsandsymptomsofmyastheniagravis,dizziness,

paraesthesia,andheadache.

EyeDisorders:

Signsandsymptomsofocularirritation(e.g.burning,stinging,itching,tearing,redness),blepharitis,keratitis,blurred

visionandchoroidaldetachmentfollowingfiltrationsurgery(see4.4Specialwarningsandspecialprecautionsforuse).

Decreasedcornealsensitivity,dryeyes,cornealerosionptosis,diplopia.

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EarandLabyrinthDisorders:

Tinnitus

CardiacDisorders:

Bradycardia,chestpain,palpitations,oedema,arrhythmia,congestiveheartfailure,atrioventricularblock,cardiac

arrest,cardiacfailure.

VascularDisorders:

Hypotension,Raynaud'sphenomenon,coldhandsandfeet.

Respiratory,ThoracicandMediastinalDisorders:

Bronchospasm(predominantlyinpatientswithpre-existingbronchospasticdisease),dyspnoea,cough.

GastrointestinalDisorders:

Dysgeusia,nausea,dyspepsia,diarrhoea,drymouth,abdominalpain,vomiting.

SkinandSubcutaneousTissueDisorders:

Alopecia,psoriasiformrashorexacerbationofpsoriasis,skinrash.

Musculoskeletalandconnectivetissuedisorders:

Myalgia.

Reproductivesystemandbreastdisorders:

Sexualdysfunction,decreasedlibido.

GeneralDisordersandAdministrationSiteConditions:

Asthenia/fatigue.

4.9Overdose

Nodataareavailableinhumanswithregardtooverdosewithlatanoprostandtimolol.

Symptomsofsystemictimololoverdoseare:bradycardia,hypotension,bronchospasmandcardiacarrest.Ifsuch

symptomsoccurthetreatmentshouldbesymptomaticandsupportive.Studieshaveshownthattimololdoesnotdialyse

readily.

Apartfromocularirritationandconjunctivalhyperaemianootherocularorsystemicsideeffectsareknownif

latanoprostisoverdosed.

Iflatanoprostisaccidentallyingestedorallythefollowinginformationmaybeuseful:Treatment:Gastriclavageif

needed.Symptomatictreatment.Latanoprostisextensivelymetabolisedduringthefirstpassthroughtheliver.

Intravenousinfusionof3micrograms/kginhealthyvolunteersinducednosymptomsbutadoseof5.5-10

micrograms/kgcausednausea,abdominalpain,dizziness,fatigue,hotflushesandsweating.Theseeventsweremildto

moderateinseverityandresolvedwithouttreatment,within4hoursafterterminatingtheinfusion.

5PHARMACOLOGICALPROPERTIES

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Pharmacotherapeuticgroup:

Ophthalmological-betablockingagents-timolol,combinations

ATCcode:S01ED51

Mechanismofaction

Codalux consistsoftwocomponents:latanoprostandtimololmaleate.Thesetwocomponentsdecreaseelevated

intraocularpressure(IOP)bydifferentmechanismsofactionandthecombinedeffectresultsinadditionalIOP

reductioncomparedtoeithercompoundadministeredalone.

Latanoprost,aprostaglandinF

2alpha analogue,isaselectiveprostanoidFPreceptoragonistthatreducestheIOPby

increasingtheoutflowofaqueoushumour.Themainmechanismofactionisincreaseduveoscleraloutflow.

Additionally,someincreaseinoutflowfacility(decreaseintrabecularoutflowresistance)hasbeenreportedinman.

Latanoprosthasnosignificanteffectontheproductionofaqueoushumour,theblood-aqueousbarrierortheintraocular

bloodcirculation.Chronictreatmentwithlatanoprostinmonkeyeyes,whichhadundergoneextracapsularlens

extraction,didnotaffecttheretinalbloodvesselsasdeterminedbyfluoresceinangiography.Latanoprosthasnot

inducedfluoresceinleakageintheposteriorsegmentofpseudophakichumaneyesduringshort-termtreatment.

Timololisabeta-1andbeta-2(non-selective)adrenergicreceptorblockingagentthathasnosignificantintrinsic

sympathomimetic,directmyocardialdepressantormembrane-stabilisingactivity.TimolollowersIOPbydecreasing

theformationofaqueousintheciliaryepithelium.Theprecisemechanismofactionisnotclearlyestablished,but

inhibitionoftheincreasedcyclicAMPsynthesiscausedbyendogenousbeta-adrenergicstimulationisprobable.

Timololhasnotbeenfoundtosignificantlyaffectthepermeabilityoftheblood-aqueousbarriertoplasmaproteins.In

rabbits,timololwaswithouteffectontheregionalocularbloodflowafterchronictreatment.

Pharmacodynamiceffects

Clinicaleffects

Indosefindingstudies,latanoprostandtimololproducedsignificantlygreaterdecreasesinmeandiurnalIOPcompared

tolatanoprostandtimololadministeredoncedailyasmonotherapy.Intwowellcontrolled,doublemaskedsix-month

clinicalstudiestheIOPreducingeffectoflatanoprostandtimolol50microgram/ml+5mg/mleyedrops,solutionwas

comparedwithlatanoprostandtimololmonotherapyinpatientswithanIOPofatleast25mmHgorgreater.Following

a2-4weekrun-inwithtimolol(meandecreaseinIOPfromenrolmentof5mmHg),additionaldecreasesinmean

diurnalIOPof3.1,2.0and0.6mmHgwereobservedafter6monthsoftreatmentforlatanoprostandtimolol50

microgram/ml+5mg/mleyedrops,solution,latanoprostandtimolol(twicedaily),respectively.TheIOPlowering

effectoflatanoprostandtimololwasmaintainedin6monthopenlabelextensionsofthesestudies.

ExistingdatasuggestthateveningdosingmaybemoreeffectiveinIOPloweringthanmorningdosing.However,when

consideringarecommendationofeithermorningoreveningdosing,sufficientconsiderationshouldbegiventothe

lifestyleofthepatientandtheirlikelycompliance.

Itshouldbekeptinmindthatincaseofinsufficientefficacyofthefixedcombination,resultsfromstudiesindicatethat

theuseofunfixedadministrationofTimololbidandlatanoprostonceadaymightbestillefficient.

OnsetofactionofCodaluxiswithinonehourandmaximaleffectoccurswithinsixtoeighthours.AdequateIOP

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5.2Pharmacokineticproperties

Latanoprost

Latanoprostisanisopropylesterprodrug,whichperseisinactive,butafterhydrolysisbyesterasesinthecorneatothe

acidoflatanoprost,becomesbiologicallyactive.Theprodrugiswellabsorbedthroughthecorneaandalldrugthat

enterstheaqueoushumourishydrolysedduringthepassagethroughthecornea.Studiesinmanindicatethatthe

maximumconcentrationintheaqueoushumour,approximately15-30ng/ml,isreachedabout2hoursaftertopical

administrationoflatanoprostalone.Aftertopicalapplicationinmonkeyslatanoprostisdistributedprimarilyinthe

anteriorsegment,theconjunctivaandtheeyelids.

Theacidoflatanoprosthasaplasmaclearanceof0.40l/h/kgandasmallvolumeofdistribution,0.16l/kg,resultingin

arapidhalf-lifeinplasma,17minutes.Aftertopicalocularadministrationthesystemicbioavailabilityoftheacidof

latanoprostis45%.Theacidoflatanoprosthasaplasmaproteinbindingof87%.

Thereispracticallynometabolismoftheacidoflatanoprostintheeye.Themainmetabolismoccursintheliver.The

mainmetabolites,the1,2-dinorand1,2,3,4-tetranormetabolites,exertnooronlyweakbiologicalactivityinanimal

studiesandareexcretedprimarilyintheurine.

Timolol

Themaximumconcentrationoftimololintheaqueoushumourisreachedabout1houraftertopicaladministrationof

eyedrops.Partofthedoseisabsorbedsystemicallyandamaximumplasmaconcentrationof1ng/mlisreached10-20

minutesaftertopicaladministrationofoneeyedroptoeacheyeoncedaily(300micrograms/day).Thehalf-lifeof

timololinplasmaisabout6hours.Timololisextensivelymetabolisedintheliver.Themetabolitesareexcretedinthe

urinetogetherwithsomeunchangedtimolol.

Latanoprostandtimolol50microgram/ml+5mg/mleyedrops,solution

Nopharmacokineticinteractionsbetweenlatanoprostandtimololwereobservedalthoughtherewasanapproximate2-

foldincreasedconcentrationoftheacidoflatanoprostinaqueoushumour1-4hoursafteradministrationoflatanoprost

andtimolol50microgram/ml+5mg/mleyedrops,solutioncomparedtomonotherapy.

5.3Preclinicalsafetydata

Theocularandsystemicsafetyprofileoftheindividualcomponentsiswellestablished.Noadverseocularorsystemic

effectswereseeninrabbitstreatedtopicallywiththefixedcombinationorwithconcomitantlyadministeredlatanoprost

andtimololophthalmicsolutions.Safetypharmacology,genotoxicityandcarcinogenicitystudieswitheachofthe

componentsrevealednospecialhazardsforhumans.Latanoprostdidnotaffectcornealwoundhealingintherabbit

eye,whereastimololinhibitedtheprocessintherabbitandthemonkeyeyewhenadministeredmorefrequentlythan

onceaday.

Forlatanoprost,noeffectsonmaleandfemalefertilityinratsandnoteratogenicpotentialinratsandrabbitshavebeen

established.Noembryotoxicitywasobservedinratsafterintravenousdosesofupto250micrograms/kg/day.However

latanoprostcausedembryofetaltoxicity,characterisedbyincreasedincidenceoflateresorptionandabortionandby

reducedfoetalweight,inrabbitsatintravenousdosesof5micrograms/kg/day(approximately100timestheclinical

dose)andabove.Timololshowednoeffectsonmaleandfemalefertilityinratsorteratogenicpotentialinmice,rats

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Sodiumchloride

Sodiumdihydrogenphosphatemonohydrate

Disodiumphosphateanhydrous

Benzalkoniumchloride

HydrochloricAcid(forpHadjustment)

Sodiumhydroxide(forpHadjustment)

Waterforinjections

6.2Incompatibilities

Invitrostudieshaveshownthatprecipitationoccurswheneyedropscontainingthiomersalaremixedwithlatanoprost

50microgram/mleyedrops,solution.Ifsuchdrugsareusedconcomitantlywithlatanoprostandtimolol50

microgram/ml+5mg/mleyedrops,solution,theeyedropsshouldbeadministeredwithanintervalofatleastfive

minutes.

6.3Shelflife

Unopened:18months

Shelflifeafterthefirstopening:28days

Storageconditionsoftheproductafterthefirstopening:Seesection6.4

6.4Specialprecautionsforstorage

Storeinarefrigerator(2°C–8°C).

Keepbottleinoutercartoninordertoprotectfromlight.

Storageconditionsoftheproductafterthefirstopening:Donotstoreabove25°C.

Usewithin4weeks.

6.5Natureandcontentsofcontainer

LDPEbottles,withanLDPEdropperapplicatorandaPPtamperevidentcap

Eachbottlecontains2.5mleyedropsolution.

Packsizes:

1x2.5ml

3x2.5ml

6x2.5ml

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements

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7MARKETINGAUTHORISATIONHOLDER

AziendeChimicheRiuniteAngeliniFrancesco

VialeAmelia70,00181

Rome

Italy

8MARKETINGAUTHORISATIONNUMBER

PA959/3/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:27thMay2011

10DATEOFREVISIONOFTHETEXT

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