CLAROPT

Main information

  • Trade name:
  • CLAROPT Eye Drops Solution 20+5 Mg/ Ml
  • Dosage:
  • 20+ 5 Mg/ Ml
  • Pharmaceutical form:
  • Eye Drops Solution
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CLAROPT Eye Drops Solution 20+5 Mg/Ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0126/227/001
  • Authorization date:
  • 25-11-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Claropt20mg/ml+5mg/mleyedrops,solution

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachmlcontains20mgdorzolamide(asDorzolamidehydrochloride)and5mgtimolol(astimololmaleate).

Excipients:eachmlofeyedropssolutioncontains0.075mgbenzalkoniumchloride.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Eyedrops,solution.

Clear,slightlyviscous,colourlessaqueoussolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Claropt20mg/ml+5m/mleyedrops,solutionisindicated

inthetreatmentofelevatedintra-ocularpressure(IOP)inpatientswithopen-angleglaucomaorpseudo-exfoliative

glaucomawhentopicalbeta-blockermonotherapyisnotsufficient.

4.2Posologyandmethodofadministration

ThedoseisonedropofClaropt20mg/ml+5m/mleyedrops,solutioninthe(conjunctivalsacofthe)affectedeye(s)

twotimesdaily.

Ifanothertopicalophthalmicmedicinalproductisbeingused,theotheragentshouldbeadministeredatleastten

minutesapart.

Paediatricpopulation:

Efficacyinpaediatricpatientshasnotbeenestablished.

Safetyinpaediatricpatientsbelowtheageoftwoyearshasnotbeenestablished.(Forinformationregardingsafetyin

paediatricpatients 2and<6yearsofage,seesection5.1).

Patientsshouldbeinstructedtowashtheirhandsbeforeuseandavoidallowingthetipofthedispensingcontainerto

contacttheeyeorsurroundingstructures.

Inordertosecurecorrectdosage-thedroppertipshouldnotbeenlarged.

Patientsshouldalsobeinstructedthatocularsolutions,ifhandledimproperly,canbecomecontaminatedbycommon

bacteriaknowntocauseocularinfections.Seriousdamagetotheeyeandsubsequentlossofvisionmayresultfrom

usingcontaminatedsolutions.

PatientsshouldbeinformedofthecorrecthandlingoftheophthalmicClaropt20mg/ml+5m/mleyedrops,solution.

Usageinstructions:

1.Thetamper-proofsealonthebottleneckmustbeunbrokenbeforetheproductisbeingusedforthefirsttime.Agap

betweenthebottleandthecapisnormalforanunopenedbottle.

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3.Thepatient’sheadmustbetiltedbackandthelowereyelidmustbepulledgentlydowntoformasmallpocket

betweentheeyelidandtheeye.

4.Thebottleshouldbeinvertedandsqueezeduntilasingledropisdispensedintotheeye.THEEYEOREYELID

MUSTNOTBETOUCHEDWITHTHEDROPPERTIP.

5.Steps3&4shouldberepeatedwiththeothereyeifitisnecessary.

6.Thecapmustbeputbackonandthebottlemustbeclosedstraightafterithasbeenused.

4.3Contraindications

Claropt20mg/ml+5m/mleyedrops,solution

iscontra-indicatedinpatientswith:

reactiveairwaydisease,includingbronchialasthmaorahistoryofbronchialasthma,orseverechronic

obstructivepulmonarydisease

sinusbradycardia,second-orthird-degreeatrioventricularblock,overtcardiacfailure,cardiogenicshock

severerenalimpairment(creatinineclearance<30ml/min)orhyperchloraemicacidosis

hypersensitivitytooneorbothactivesubstancesortoanyoftheexcipients.

Theabovearebasedonthecomponentsandarenotuniquetothecombination.

4.4Specialwarningsandprecautionsforuse

Cardiovascular/respiratoryreactions

Aswithothertopically-appliedophthalmicagents,thisdrugmaybeabsorbedsystemically.Thetimololcomponentisa

beta-blocker.Therefore,thesametypesofadversereactionsfoundwithsystemicadministrationofbeta-blockersmay

occurwithtopicaladministration,includingworseningofPrinzmetal'sangina,worseningofsevereperipheraland

centralcirculatorydisorders,andhypotension.

Becauseofthetimololmaleatecomponent,cardiacfailureshouldbeadequatelycontrolledbeforebeginningtherapy

withClaropt20mg/ml+5m/mleyedrops,solution.Inpatientswithahistoryofseverecardiacdisease,signsofcardiac

failureshouldbewatchedforandpulseratesshouldbechecked.

Respiratoryreactionsandcardiacreactions,includingdeathduetobronchospasminpatientswithasthmaandrarely

deathinassociationwithcardiacfailure,havebeenreportedfollowingadministrationoftimololmaleate.

Hepaticimpairment

Dorzolamide/Timololeyedropssolutionhasnotbeenstudiedinpatientswithhepaticimpairmentandthereforeshould

beusedwithcautioninsuchpatients.

Immunologyandhypersensitivity

Aswithothertopically-appliedophthalmicagents,thisdrugmaybeabsorbedsystemically.Thedorzolamide

componentisasulphonamide.Thereforethesametypesofadversereactionsfoundwithsystemicadministrationof

sulphonamidesmayoccurwithtopicaladministration.Ifsignsofseriousreactionsorhypersensitivityoccur,

discontinueuseofthispreparation.

Localocularadverseeffects,similartothoseobservedwithdorzolamidehydrochlorideeyedrops,havebeenseenwith

Dorzolamide/Timololeyedropssolution.Ifsuchreactionsoccur,discontinuationofClaropt20mg/ml+5m/mleye

drops,solutionshouldbeconsidered.

Whiletaking-blockers,patientswithahistoryofatopyorahistoryofsevereanaphylacticreactiontoavarietyof

allergensmaybemorereactivetoaccidental,diagnostic,ortherapeuticrepeatedchallengewithsuchallergens.Such

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Concomitanttherapy

Thefollowingconcomitantmedicationisnotrecommended:

−dorzolamideandoralcarbonicanhydraseinhibitors

−topicalbeta-adrenergicblockingagents.

Withdrawaloftherapy

Aswithsystemicbeta-blockers,ifdiscontinuationofophthalmictimololisneededinpatientswithcoronaryheart

disease,therapyshouldbewithdrawngradually.

Additionaleffectsofbeta-blockade

Therapywithbeta-blockersmaymaskcertainsymptomsofhypoglycaemiainpatientswithdiabetesmellitusor

hypoglycaemia.

Therapywithbeta-blockersmaymaskcertainsymptomsofhyperthyroidism.Abruptwithdrawalofbeta-blocker

therapymayprecipitateaworseningofsymptoms.

Therapywithbeta-blockersmayaggravatesymptomsofmyastheniagravis.

Additionaleffectsofcarbonicanhydraseinhibition

Therapywithoralcarbonicanhydraseinhibitorshasbeenassociatedwithurolithiasisasaresultofacid-base

disturbances,especiallyinpatientswithapriorhistoryofrenalcalculi.Althoughnoacid-basedisturbanceshavebeen

observedwithDorzolamide/Timololeyedropssolution,urolithiasishasbeenreportedinfrequently.BecauseClaropt

20mg/ml+5m/mleyedrops,solutioncontainsatopicalcarbonicanhydraseinhibitorthatisabsorbedsystemically,

patientswithapriorhistoryofrenalcalculimaybeatincreasedriskofurolithiasiswhileusingClaropt20mg/ml+

5m/mleyedrops,solution.

Other

Themanagementofpatientswithacuteangle-closureglaucomarequirestherapeuticinterventionsinadditiontoocular

hypotensiveagents.Dorzolamide/Timololeyedropssolutionhasnotbeenstudiedinpatientswithacuteangle-closure

glaucoma.

Cornealoedemaandirreversiblecornealdecompensationhavebeenreportedinpatientswithpre-existingchronic

cornealdefectsand/orahistoryofintra-ocularsurgerywhileusingdorzolamide.Topicaldorzolamideshouldbeused

withcautioninsuchpatients.

Choroidaldetachmentconcomitantwithocularhypotonyhavebeenreportedafterfiltrationprocedureswith

administrationofaqueoussuppressanttherapies.

Aswiththeuseofotherantiglaucomadrugs,diminishedresponsivenesstoophthalmictimololmaleateafterprolonged

therapyhasbeenreportedinsomepatients.However,inclinicalstudiesinwhich164patientshavebeenfollowedfor

atleastthreeyears,nosignificantdifferenceinmeanintra-ocularpressurehasbeenobservedafterinitialstabilisation.

Contactlensuse

Claropt20mg/ml+5m/mleyedrops,solutioncontainsthepreservativebenzalkoniumchloride,whichmaycauseeye

irritation.Benzalkoniumchlorideisknowntodiscoloursoftcontactlenses.Removecontactlensespriortoapplication

andwaitatleast15minutesbeforereinsertion.

Paediatricuse

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

SpecificdruginteractionstudieshavenotbeenperformedwithDorzolamide/Timololeyedropssolution.

Inclinicalstudies,Dorzolamide/Timololeyedropssolutionwasusedconcomitantlywiththefollowingsystemic

medicationswithoutevidenceofadverseinteractions:ACE-inhibitors,calciumchannelblockers,diuretics,non-

steroidalanti-inflammatorydrugsincludingaspirin,andhormones(e.g.oestrogen,insulin,thyroxine).

However,thepotentialexistsforadditiveeffectsandproductionofhypotensionand/ormarkedbradycardiawhen

timololmaleateophthalmicsolutionisadministeredtogetherwithoralcalciumchannelblockers,catecholamine-

depletingdrugsorbeta-adrenergicblockingagents,antiarrhythmics(includingamiodarone),digitalisglycosides,

parasympathomimetics,narcotics,andmonoamineoxidase(MAO)inhibitors.

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

treatmentwithCYP2D6inhibitors(e.g.quinidine,SSRIs)andtimolol.

ThedorzolamidecomponentofClaropt20mg/ml+5mg/mleyedrops,solutionisacarbonicanhydraseinhibitorand

althoughadministeredtopically,isabsorbedsystemically.Inclinicalstudies,dorzolamidehydrochlorideophthalmic

solutionwasnotassociatedwithacid-basedisturbances.However,thesedisturbanceshavebeenreportedwithoral

carbonicanhydraseinhibitorsandhaveinsomeinstances,resultedindruginteractions(e.g.,toxicityassociatedwith

high-dosesalicylatetherapy).Therefore,thepotentialforsuchdruginteractionsshouldbeconsideredinpatients

receivingClaropt20mg/ml+5mg/mleyedrops,solution.

AlthoughClaropt20mg/ml+5mg/mleyedrops,solutionalonehaslittleornoeffectonpupilsize,mydriasisresulting

fromconcomitantuseofophthalmictimololmaleateandepinephrinehasbeenreportedoccasionally.

Beta-blockersmayincreasethehypoglycaemiceffectofantidiabeticagents.

Oralbeta-adrenergicblockingagentsmayexacerbatethereboundhypertensionwhichcanfollowthewithdrawalof

clonidine.

4.6Fertility,pregnancyandlactation

Pregnancy

Claropt20mg/ml+5mg/mleyedrops,solutionshouldnotbeusedduringpregnancy.

Dorzolamide

Noadequateclinicaldatainexposedpregnanciesareavailable.Inrabbits,dorzolamideproducedteratogeniceffectsat

maternotoxicdoses(seeSection5.3).

Timolol

Wellcontrolledepidemiologicalstudieswithsystemicbetablockersshowednoevidenceofteratogeniceffects,but

somepharmacologicaleffectssuchasbradycardiawereobservedinfetusesorneonates.IfClaropt20mg/ml+5mg/ml

eyedrops,solutionisadministereduntildelivery,theneonateshouldbecarefullymonitoredduringthefirstdaysof

life.

Lactation

Itisnotknownwhetherdorzolamideisexcretedinhumanmilk.Inlactatingratsreceivingdorzolamide,decreasesin

thebodyweightgainofoffspringwereobserved.Timololdoesappearinhumanmilk.Claropt20mg/ml+5mg/mleye

drops,solutionshouldnotbeusedduringlactation.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.Possiblesideeffectssuch

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4.8Undesirableeffects

InclinicalstudiesnoadverseexperiencesspecifictoDorzolamide/Timololhavebeenobserved;adverseexperiences

havebeenlimitedtothosethatwerereportedpreviouslywithdorzolamidehydrochlorideand/ortimololmaleate.In

general,commonadverseexperiencesweremildanddidnotcausediscontinuation.

Duringclinicalstudies,1,035patientsweretreatedwithDorzolamide/Timololeyedropssolution.Approximately2.4%

ofallpatientsdiscontinuedtherapywithDorzolamide/Timololeyedropssolutionbecauseoflocalocularadverse

reactions,approximately1.2%ofallpatientsdiscontinuedbecauseoflocaladversereactionssuggestiveofallergyor

hypersensitivity(suchaslidinflammationandconjunctivitis).

ThefollowingadversereactionshavebeenreportedwithDorzolamide/Timololeyedropssolutionoroneofits

componentseitherduringclinicaltrialsorduringpost-marketingexperience:

[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)andNotknown(cannotbeestimatedfromtheavailabledata)].

NervoussystemandPsychiatricdisorders:

Dorzolamidehydrochlorideophthalmicsolution:

Common:headache*

Rare:dizziness*,paresthesia*

Timololmaleateophthalmicsolution:

Common:headache*

Uncommon:dizziness*,depression*

Rare:insomnia*,nightmares*,memoryloss,paraesthesia*,increaseinsignsandsymptomsofmyastheniagravis,

decreasedlibido*,cerebrovascularaccident*

Eyedisorders:

Dorzolamide/Timololophthalmicsolution:

VeryCommon:burningandstinging

Common:conjunctivalinjection,blurredvision,cornealerosion,ocularitching,tearing

Dorzolamidehydrochlorideophthalmicsolution:

Common:eyelidinflammation*,eyelidirritation*

Uncommon:iridocyclitis*

Rare:irritationincludingredness*,pain*,eyelidcrusting*,transientmyopia(whichresolvedupondiscontinuationof

therapy),cornealoedema*,ocularhypotony*,choroidaldetachment(followingfiltrationsurgery)*

Timololmaleateophthalmicsolution:

Common:signsandsymptomsofocularirritationincludingblepharitis*,keratitis*,decreasedcornealsensitivity,and

dryeyes*

Uncommon:visualdisturbancesincludingrefractivechanges(duetowithdrawalofmiotictherapyinsomecases)*

Rare:ptosis,diplopia,choroidaldetachment(followingfiltrationsurgery)*

Earandlabyrinthdisorders:

Timololmaleateophthalmicsolution:

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CardiacandVasculardisorders:

Timololmaleateophthalmicsolution:

Uncommon:bradycardia*,syncope*

Rare:hypotension*,chestpain*,palpitation*,oedema*,arrhythmia*,congestiveheartfailure*,heartblock*,cardiac

arrest*,cerebralischaemia,claudication,Raynaud'sphenomenon*,coldhandsandfeet*

Respiratory,thoracic,andmediastinaldisorders:

Dorzolamide/Timololophthalmicsolution:

Common:sinusitis

Rare:shortnessofbreath,respiratoryfailure,rhinitis

Dorzolamidehydrochlorideophthalmicsolution:

Rare:epistaxis*

Timololmaleateophthalmicsolution:

Uncommon:dyspnoea*

Rare:bronchospasm(predominantlyinpatientswithpre-existingbronchospasticdisease)*,cough*

Gastro-intestinaldisorders:

Dorzolamide/Timololophthalmicsolution:

VeryCommon:tasteperversion

Dorzolamidehydrochlorideophthalmicsolution:

Common:nausea*

Rare:throatirritation,drymouth*

Timololmaleateophthalmicsolution:

Uncommon:nausea*,dyspepsia*

Rare:diarrhoea,drymouth*

Skinandsubcutaneoustissuedisorders:

Dorzolamide/Timololophthalmicsolution:

Rare:contactdermatitis

Dorzolamidehydrochlorideophthalmicsolution:

Rare:rash*

Timololmaleateophthalmicsolution:

Rare:alopecia*,psoriasiformrashorexacerbationofpsoriasis*

Musculoskeletalandconnectivetissuedisorders:

Timololmaleateophthalmicsolution:

Rare:systemiclupuserythematosus

RenalandUrinarydisorders:

Dorzolamide/Timololophthalmicsolution:

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Reproductivesystemandbreastdisorders:

Timololmaleateophthalmicsolution:

Rare:Peyronie'sdisease*

Generaldisordersandadministrationsitedisorders:

Dorzolamide/Timololophthalmicsolution:

Rare:signsandsymptomsofsystemicallergicreactions,includingangioedema,urticaria,pruritus,rash,anaphylaxis,

rarelybronchospasm

Dorzolamidehydrochlorideophthalmicsolution:

Common:asthenia/fatigue*

Timololmaleateophthalmicsolution:

Uncommon:asthenia/fatigue*

*TheseadversereactionswerealsoobservedwithDorzolamide/Timololophthalmicsolutionduringpost-marketing

experience.

Laboratoryfindings

Dorzolamide/Timololeyedropssolutionwasnotassociatedwithclinicallymeaningfulelectrolytedisturbancesin

clinicalstudies.

4.9Overdose

NodataareavailableinhumansinregardtooverdosagebyaccidentalordeliberateingestionofDorzolamide/Timolol

eyedropssolution.

Therehavebeenreportsofinadvertentoverdosagewithtimololmaleateophthalmicsolutionresultinginsystemic

effectssimilartothoseseenwithsystemicbeta-adrenergicblockingagentssuchasdizziness,headache,shortnessof

breath,bradycardia,bronchospasm,andcardiacarrest.Themostcommonsignsandsymptomstobeexpectedwith

overdosageofdorzolamideareelectrolyteimbalance,developmentofanacidoticstate,andpossiblycentralnervous

systemeffects.

Onlylimitedinformationisavailablewithregardtohumanoverdosagebyaccidentalordeliberateingestionof

dorzolamidehydrochloride.Withoralingestion,somnolencehasbeenreported.Withtopicalapplicationthefollowing

havebeenreported:nausea,dizziness,headache,fatigue,abnormaldreams,anddysphagia.

Treatmentshouldbesymptomaticandsupportive.Serumelectrolytelevels(particularlypotassium)andbloodpH

levelsshouldbemonitored.Studieshaveshownthattimololdoesnotdialysereadily.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antiglaucomapreparationsandmiotics,Beta-BlockingAgents,Timolol,Combinations.

ATCcode:S01ED51

Mechanismofaction

Dorzolamide/Timololeyedropssolutioniscomprisedoftwocomponents:dorzolamidehydrochlorideandtimolol

maleate.Eachofthesetwocomponentsdecreaseselevatedintra-ocularpressurebyreducingaqueoushumorsecretion,

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DorzolamidehydrochlorideisapotentinhibitorofhumancarbonicanhydraseII.Inhibitionofcarbonicanhydrasein

theciliaryprocessesoftheeyedecreasesaqueoushumorsecretion,presumablybyslowingtheformationof

bicarbonateionswithsubsequentreductioninsodiumandfluidtransport.Timololmaleateisanon-selectivebeta-

adrenergicreceptorblockingagent.Theprecisemechanismofactionoftimololmaleateinloweringintra-ocular

pressureisnotclearlyestablishedatthistime,althoughafluoresceinstudyandtonographystudiesindicatethatthe

predominantactionmayberelatedtoreducedaqueousformation.However,insomestudiesaslightincreaseinoutflow

facilitywasalsoobserved.Thecombinedeffectofthesetwoagentsresultsinadditionalintra-ocularpressurereduction

comparedtoeithercomponentadministeredalone.

Followingtopicaladministration,Dorzolamide/Timololeyedropssolutionreduceselevatedintra-ocularpressure,

whetherornotassociatedwithglaucoma.Elevatedintra-ocularpressureisamajorriskfactorinthepathogenesisof

opticnervedamageandglaucomatousvisualfieldloss.

Dorzolamide/Timololeyedropssolutionreducesintra-ocularpressurewithoutthecommonsideeffectsofmioticssuch

asnightblindness,accommodativespasmandpupillaryconstriction.

Pharmacodynamiceffects

Clinicaleffects:

AdultPatients

Clinicalstudiesofupto15monthsdurationwereconductedtocomparetheIOP-loweringeffectof

Dorzolamide/Timololeyedropssolutionb.i.d.(dosedmorningandbedtime)toindividually-andconcomitantly-

administered0.5%timololand2.0%dorzolamideinpatientswithglaucomaorocularhypertensionforwhom

concomitanttherapywasconsideredappropriateinthetrials.Thisincludedbothuntreatedpatientsandpatients

inadequatelycontrolledwithtimololmonotherapy.Themajorityofpatientsweretreatedwithtopicalbeta-blocker

monotherapypriortostudyenrollment.Inananalysisofthecombinedstudies,theIOP-loweringeffectof

Dorzolamide/Timololeyedropssolutionb.i.d.wasgreaterthanthatofmonotherapywitheither2%dorzolamidet.i.d.

or0.5%timololb.i.d.TheIOP-loweringeffectofDorzolamide/Timololeyedropssolutionb.i.d.wasequivalenttothat

ofconcomitanttherapywithdorzolamideb.i.d.andtimololb.i.d.TheIOP-loweringeffectofDorzolamide/Timololeye

dropssolutionb.i.d.wasdemonstratedwhenmeasuredatvarioustimepointsthroughoutthedayandthiseffectwas

maintainedduringlong-termadministration.

PaediatricPopulation

Athreemonthcontrolledstudy,withtheprimaryobjectiveofdocumentingthesafetyof2%dorzolamide

hydrochlorideophthalmicsolutioninchildrenundertheageof6yearshasbeenconducted.Inthisstudy,30patients

undersixandgreaterthanorequaltotwoyearsofagewhoseIOPwasnotadequatelycontrolledwithmonotherapyby

dorzolamideortimololreceivedDorzolamide/Timololeyedropssolutioninanopenlabelphase.Efficacyinthose

patientshasnotbeenestablished.Inthissmallgroupofpatients,twicedailyadministrationofDorzolamide/Timolol

eyedropssolutionwasgenerallywelltoleratedwith19patientscompletingthetreatmentperiodand11patients

discontinuingforsurgery,achangeinmedication,orotherreasons.

5.2Pharmacokineticproperties

Dorzolamidehydrochloride:

Unlikeoralcarbonicanhydraseinhibitors,topicaladministrationofdorzolamidehydrochlorideallowsforthedrugto

exertitseffectsdirectlyintheeyeatsubstantiallylowerdosesandthereforewithlesssystemicexposure.Inclinical

trials,thisresultedinareductioninIOPwithouttheacid-basedisturbancesoralterationsinelectrolytescharacteristic

oforalcarbonicanhydraseinhibitors.

Whentopicallyapplied,dorzolamidereachesthesystemiccirculation.Toassessthepotentialforsystemiccarbonic

anhydraseinhibitionfollowingtopicaladministration,drugandmetaboliteconcentrationsinredbloodcells(RBCs)

andplasmaandcarbonicanhydraseinhibitioninRBCsweremeasured.DorzolamideaccumulatesinRBCsduring

chronicdosingasaresultofselectivebindingtoCA-IIwhileextremelylowconcentrationsoffreedruginplasmaare

maintained.TheparentdrugformsasingleN-desethylmetabolitethatinhibitsCA-IIlesspotentlythantheparentdrug

butalsoinhibitsalessactiveisoenzyme(CA-I).ThemetabolitealsoaccumulatesinRBCswhereitbindsprimarilyto

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Dorzolamideisprimarilyexcretedunchangedintheurine;themetaboliteisalsoexcretedinurine.Afterdosingends,

dorzolamidewashesoutofRBCsnon-linearly,resultinginarapiddeclineofdrugconcentrationinitially,followedbya

slowereliminationphasewithahalf-lifeofaboutfourmonths.

Whendorzolamidewasgivenorallytosimulatethemaximumsystemicexposureafterlongtermtopicalocular

administration,steadystatewasreachedwithin13weeks.Atsteadystate,therewasvirtuallynofreedrugormetabolite

inplasma;CAinhibitioninRBCswaslessthanthatanticipatedtobenecessaryforapharmacologicaleffectonrenal

functionorrespiration.Similarpharmacokineticresultswereobservedafterchronic,topicaladministrationof

dorzolamidehydrochloride.However,someelderlypatientswithrenalimpairment(estimatedcreatinineclearance30-

60millilitre/min)hadhighermetaboliteconcentrationsinRBCs,butnomeaningfuldifferencesincarbonicanhydrase

inhibitionandnoclinicallysignificantsystemicsideeffectsweredirectlyattributabletothisfinding.

Timololmaleate:

Inastudyofplasmadrugconcentrationinsixsubjects,thesystemicexposuretotimololwasdeterminedfollowing

twicedailytopicaladministrationoftimololmaleateophthalmicsolution0.5%.Themeanpeakplasmaconcentration

followingmorningdosingwas0.46ng/millilitreandfollowingafternoondosingwas0.35ng/millilitre.

5.3Preclinicalsafetydata

Theocularandsystemicsafetyprofileoftheindividualcomponentsiswellestablished.

Dorzolamide

Inrabbitsgivenmaternotoxicdosesofdorzolamideassociatedwithmetabolicacidosis,malformationsofthevertebral

bodieswereobserved.

Timolol

Animalstudieshavenotshownateratogeniceffect.

Furthermore,noadverseoculareffectswereseeninanimalstreatedtopicallywithdorzolamidehydrochlorideand

timololmaleateophthalmicsolutionorwithconcomitantly-administereddorzolamidehydrochlorideandtimolol

maleate.Invitroandinvivostudieswitheachofthecomponentsdidnotrevealamutagenicpotential.Therefore,no

significantriskforhumansafetyisexpectedwiththerapeuticdosesofDorzolamide/Timololeyedropssolution.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Mannitol(E421)

HydroxyethylCellulose

SodiumCitrate(E331)

SodiumHydroxide(E524)(forpHadjustment)

Benzalkoniumchloride

Waterforinjections

6.2Incompatibilities

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6.3Shelflife

2years

Afterfirstopening:28days

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialtemperaturestorageconditions.

6.5Natureandcontentsofcontainer

WhiteopaquemediumdensitypolyethylenebottleophthalmicdispenserwithasealedLDPEdroppertipandaHDPE

screwcapwithtamperproofsealinacardboardbox.

Packsize:1,3or6bottlesof5mleach

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

ClonmelHealthcareLimited

WaterfordRoad

Clonmel

Co.Tipperary

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA126/227/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:25thNovember2011

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