COSOPT

Main information

  • Trade name:
  • COSOPT Eye Drops Solution 20/ 5 Base mg/ ml
  • Dosage:
  • 20/ 5 Base mg/ ml
  • Pharmaceutical form:
  • Eye Drops Solution
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • COSOPT Eye Drops Solution 20/5 Base mg/ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1447/040/001
  • Authorization date:
  • 31-03-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

COSOPT20mg/ml+5mg/mleyedrops,solution.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachmlcontains22.26mgofdorzolamidehydrochloridecorrespondingto20mgdorzolamideand6.83mgof

timololmaleatecorrespondingto5mgtimolol.

Excipients:Benzalkoniumchloride

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Eyedrops,Solution

ProductimportedfromItaly:

Clear,colourlesstonearlycolourless,slightlyviscoussolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Indicatedinthetreatmentofelevatedintraocularpressure(IOP)inpatientswithopen-angleglaucomaor

pseudoexfoliativeglaucomawhentopicalbeta-blockermonotherapyisnotsufficient.

4.2Posologyandmethodofadministration

ThedoseisonedropofCOSOPTinthe(conjunctivalsacofthe)affectedeye(s)twotimesdaily.

Ifanothertopicalophthalmicagentisbeingused,COSOPTandtheotheragentshouldbeadministeredatleast

tenminutesapart.

Patientsshouldbeinstructedtowashtheirhandsbeforeuseandavoidallowingthetipofthecontainertocome

intocontactwiththeeyeorsurroundingstructures.

Patientsshouldalsobeinstructedthatocularsolutions,ifhandledimproperly,canbecomecontaminatedby

commonbacteriaknowntocauseocularinfections.Seriousdamagetotheeyeandsubsequentlossofvision

mayresultfromusingcontaminatedsolutions.

PatientsshouldbeinformedofthecorrecthandlingoftheOCUMETERPLUSbottles.

UsageInstructions

1.Beforeusingthemedicationforthefirsttime,besuretheSafetyStriponthefrontofthebottleisunbroken.Agap

betweenthebottleandthecapisnormalforanunopenedbottle.

2.TearofftheSafetyStriptobreaktheseal.

3.Toopenthebottle,unscrewthecapbyturningasindicatedbythearrowsonthetopofthecap.Donotpullthecap

directlyupandawayfromthebottle.Pullingthecapdirectlyupwillpreventyourdispenserfromoperating

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4.Tiltyourheadbackandpullyourlowereyeliddownslightlytoformapocketbetweenyoureyelidandyoureye.

5.Invertthebottle,andpresslightlywiththethumborindexfingeroverthe“FingerPushArea”untilasingledropis

dispensedintotheeyeasdirectedbyyourdoctor.DONOTTOUCHYOUREYEOREYELIDWITHTHE

DROPPERTIP.

6.Ifdropdispensingisdifficultafteropeningforthefirsttime,replacethecaponthebottleandtighten(Donot

overtighten)andthenremovebyturningthecapintheoppositedirectionsasindicatedbythearrowsonthetopof

thecap.

7.Repeatsteps4&5withtheothereyeifinstructedtodosobyyourdoctor.

8.Replacethecapbyturninguntilitisfirmlytouchingthebottle.Thearrowontheleftsideofthecapmustbealigned

withthearrowontheleftsideofthebottlelabelforproperclosure.Donotovertightenoryoumaydamagethe

bottleandcap.

9.Thedispensertipisdesignedtoprovideasingledrop;therefore,doNOTenlargetheholeofthedispensertip.

10.Afteryouhaveusedalldoses,therewillbesomeCOSOPTleftinthebottle.Youshouldnotbeconcernedsincean

extraamountofCOSOPThasbeenaddedandyouwillgetthefullamountofCOSOPTthatyourdoctorprescribed.

Donotattempttoremovetheexcessmedicinefromthebottle.

PaediatricUse

Efficacyinpaediatricpatientshasnotbeenestablished.

Safetyinpaediatricpatientsbelowtheageof2yearshasnotbeenestablished.(Forinformationregarding

safetyinpaediatricpatients2and<6yearsofage,seesection5.1)

4.3Contraindications

‘Cosopt’iscontra-indicatedinpatientswith:

reactiveairwaydisease,includingbronchialasthmaorahistoryofbronchialasthma,orseverechronicobstructive

pulmonarydisease

sinusbradycardia,second-orthird-degreeatrioventricularblock,overtcardiacfailure,cardiogenicshock

severerenalimpairment(CrCl<30ml/min)orhyperchloraemicacidosis

hypersensitivitytooneorbothactivesubstancesortoanyoftheexcipients.

Theabovearebasedonthecomponentsandarenotuniquetothecombination.

4.4Specialwarningsandprecautionsforuse

Cardiovascular/RespiratoryReactions

Aswithothertopically-appliedophthalmicagents,thisdrugmaybeabsorbedsystemically.Thetimololcomponentis

abeta-blocker.Therefore,thesametypesofadversereactionsfoundwithsystemicadministrationofbeta-blockers

mayoccurwithtopicaladministration,includingworseningofPrinzmetalangina,worseningofsevereperipheraland

centralcirculatorydisorders,andhypotension.

Becauseofthetimololmaleatecomponent,cardiacfailureshouldbeadequatelycontrolledbeforebeginningtherapy

withCOSOPT.Inpatientswithahistoryofseverecardiacdisease,signsofcardiacfailureshouldbewatchedforand

pulseratesshouldbechecked.

Respiratoryreactionsandcardiacreactions,includingdeathduetobronchospasminpatientswithasthmaandrarely

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HepaticImpairment

COSOPThasnotbeenstudiedinpatientswithhepaticimpairmentandthereforeshouldbeusedwithcautioninsuch

patient.

ImmunologyandHypersensitivity

Aswithothertopically-appliedophthalmicagents,thisdrugmaybeabsorbedsystemically.Thedorzolamide

componentisasulfonamide.Thereforethesametypesofadversereactionsfoundwithsystemicadministrationof

sulfonamidesmayoccurwithtopicaladministration.Ifsignsofseriousreactionsorhypersensitivityoccur,discontinue

useofthispreparation.

Localocularadverseeffects,similartothoseobservedwithdorzolamidehydrochlorideeyedrops,havebeenseenwith

COSOPT.Ifsuchreactionsoccur,discontinuationofCOSOPTshouldbeconsidered.

Whiletaking-blockers,patientswithahistoryofatopyorahistoryofsevereanaphylacticreactiontoavarietyof

allergensmaybemorereactivetoaccidental,diagnostic,ortherapeuticrepeatedchallengewithsuchallergens.Such

patientsmaybeunresponsivetotheusualdosesofepinephrineusedtotreatanaphylacticreactions.

ConcomitantTherapy

Thefollowingconcomitantmedicationisnotrecommended:

dorzolamideandoralcarbonicanhydraseinhibitors

topicalbeta-adrenergicblockingagents

WithdrawalofTherapy

Aswithsystemicbeta-blockers,ifdiscontinuationofophthalmictimololisneededinpatientswithcoronaryheart

disease,therapyshouldbewithdrawngradually.

AdditionalEffectsofBeta-Blockade

Therapywithbeta-blockersmaymaskcertainsymptomsofhypoglycemiainpatientswithdiabetesmellitusor

hypoglycemia.

Therapywithbeta-blockersmaymaskcertainsymptomsofhyperthyroidism.Abruptwithdrawalofbeta-blocker

therapymayprecipitateaworseningofsymptoms.

Therapywithbeta-blockersmayaggravatesymptomsofmyastheniagravis.

AdditionalEffectsofCarbonicAnhydraseInhibition

Therapywithoralcarbonicanhydraseinhibitorshasbeenassociatedwithurolithiasisasaresultofacid-base

disturbances,especiallyinpatientswithapriorhistoryofrenalcalculi.Althoughnoacid-basedisturbanceshavebeen

observedwithCOSOPT,urolithiasishasbeenreportedinfrequently.BecauseCOSOPTcontainsatopicalcarbonic

anhydraseinhibitorthatisabsorbedsystemically,patientswithapriorhistoryofrenalcalculimaybeatincreasedrisk

ofurolithiasiswhileusingCOSOPT.

Other

Themanagementofpatientswithacuteangle-closureglaucomarequirestherapeuticinterventionsinadditiontoocular

hypotensiveagents.COSOPThasnotbeenstudiedinpatientswithacuteangle-closureglaucoma.

Cornealoedemaandirreversiblecornealdecompensationhavebeenreportedinpatientswithpre-existingchronic

cornealdefectsand/orahistoryofintraocularsurgerywhileusingdorzolamide.Topicaldorzolamideshouldbeused

withcautioninsuchpatients.

Choroidaldetachmentconcomitantwithocularhypotonyhavebeenreportedafterfiltrationprocedureswith

administrationofaqueoussuppressanttherapies.

Aswiththeuseofotherantiglaucomadrugs,diminishedresponsivenesstoophthalmictimololmaleateafterprolonged

therapyhasbeenreportedinsomepatients.However,inclinicalstudiesinwhich164patientshavebeenfollowedfor

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ContactLensUse

COSOPTcontainsthepreservativebenzalkoniumchloride,whichmaycauseeyeirritation.Removecontactlenses

priortoapplicationandwaitatleast15minutesbeforereinsertion.Benzalkoniumchlorideisknowntodiscoloursoft

contactlenses.

PaediatricUse

Seesection5.1.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

SpecificdruginteractionstudieshavenotbeenperformedwithCOSOPT.

Inclinicalstudies,COSOPTwasusedconcomitantlywiththefollowingsystemicmedicationswithoutevidenceof

adverseinteractions:ACE-inhibitors,calciumchannelblockers,diuretics,non-steroidalanti-inflammatorydrugs

includingaspirin,andhormones(e.g.,estrogen,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.

AlthoughCOSOPTalonehaslittleornoeffectonpupilsize,mydriasisresultingfromconcomitantuseofophthalmic

timololmaleateandepinephrine(adrenaline)hasbeenreportedoccasionally.

Beta-blockersmayincreasethehypoglycemiceffectofantidiabeticagents.

Oralbeta-adrenergicblockingagentsmayexacerbatethereboundhypertensionwhichcanfollowthewithdrawalof

clonidine.

4.6Fertility,pregnancyandlactation

UseDuringPregnancy

COSOPTshouldnotbeusedduringpregnancy.

Dorzolamide

Noadequateclinicaldatainexposedpregnanciesareavailable.Inrabbits,dorzolamideproducedteratogeniceffectat

maternotoxicdoses(seeSection5.3).

Timolol

Wellcontrolledepidemiologicalstudieswithsystemicbeta-blockersshowednoevidenceofteratogeniceffects,but

somepharmacologicaleffectssuchasbradycardiawereobservedinfoetusesorneonates.IfCOSOPTisadministered

untildelivery,theneonateshouldbecarefullymonitoredduringthefirstdaysoflife.

UseDuringLactation

Itisnotknownwhetherdorzolamideisexcretedinhumanmilk.Inlactatingratsreceivingdorzolamide,decreasesin

thebodyweightgainofoffspringwereobserved.Timololdoesappearinhumanmilk.

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4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.Possiblesideeffectssuchas

blurredvisionmayaffectsomepatients’abilitytodriveand/oroperatemachinery.

4.8Undesirableeffects

InclinicalstudiesnoadverseexperiencesspecifictoCOSOPThavebeenobserved;adversereactionshavebeen

limitedtothosethatwerereportedpreviouslywithdorzolamidehydrochlorideand/ortimololmaleate.

Duringclinicalstudies,1035patientsweretreatedwithCOSOPT.Approximately2.4%ofallpatients

discontinuedtherapywithCOSOPTbecauseoflocalocularadversereactions,approximately1.2%ofall

patientsdiscontinuedbecauseoflocaladversereactionssuggestiveofallergyorhypersensitivity(suchaslid

inflammationandconjunctivitis).

ThefollowingadversereactionshavebeenreportedwithCOSOPToroneofitscomponentseitherduring

clinicaltrialsorduringpost-marketingexperience:

[VeryCommon:(1/10),Common:(1/100to<1/10),Uncommon:(1/1000to<1/100),andRare:(1/10,000

to<1/1000)]

Musculoskeletalandconnectivetissuedisorders:

Timololmaleateeyedrops,solution:

Rare: systemiclupuserythematosus

Nervoussystemdisorders:

Dorzolamidehydrochlorideeyedrops,solution:

Common: headache*

Rare: dizziness*,paresthesia*

Timololmaleateeyedrops,solution:

Common: headache*

Uncommon: dizziness*,depression*

Rare: insomnia*,nightmares*,memoryloss,paresthesia*,increaseinsignsandsymptomsof

myastheniagravis,decreasedlibido*,cerebrovascularaccident*

Eyedisorders:

COSOPT:

VeryCommon: burningandstinging

Common: conjunctivalinjection,blurredvision,cornealerosion,ocularitching,tearing

Dorzolamidehydrochlorideeyedrops,solution:

Common: eyelidinflammation*,eyelidirritation*

Uncommon: iridocyclitis*

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

discontinuationoftherapy),cornealoedema*,ocularhypotony*,choroidaldetachment

(followingfiltrationsurgery)*

Timololmaleateeyedrops,solution:

Common: signsandsymptomsofocularirritationincludingblepharitis*,keratitis*,decreasedcorneal

sensitivity,anddryeyes*

Uncommon: visualdisturbancesincludingrefractivechanges(duetowithdrawalofmiotictherapyinsome

cases)*

Rare: ptosis,diplopia,choroidaldetachment(followingfiltrationsurgery)*

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Timololmaleateeyedrops,solution:

Rare: tinnitus*

Cardiacandvasculardisorders:

Timololmaleateeyedrops,solution:

Uncommon: bradycardia*,syncope*

Rare: hypotension*,chestpain*,palpitation*,edema*,arrhythmia*,congestiveheartfailure*,heart

block*,cardiacarrest*,cerebralischemia,claudication,Raynaud’sphenomenon*,coldhands

andfeet*

Respiratory,thoracic,andmediastinaldisorders:

COSOPT:

Common: sinusitis

Rare: shortnessofbreath,respiratoryfailure,rhinitis

Dorzolamidehydrochlorideeyedrops,solution:

Rare: epistaxis*

Timololmaleateeyedrops,solution:

Uncommon: dyspnea*

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

Gastrointestinaldisorders:

COSOPT:

VeryCommon: tasteperversion

Dorzolamidehydrochlorideeyedrops,solution:

Common: nausea*

Rare: throatirritation,drymouth*

Timololmaleateeyedrops,solution:

Uncommon: nausea*,dyspepsia*

Rare: diarrhea,drymouth*

Skinandsubcutaneoustissuedisorders:

COSOPT:

Rare: contactdermatitis

Dorzolamidehydrochlorideeyedrops,solution:

Rare: rash*

Timololmaleateeyedrops,solution:

Rare: alopecia*,psoriasiformrashorexacerbationofpsoriasis*

Renalandurinarydisorders:

COSOPT:

Uncommon: urolithiasis

Reproductivesystemandbreastdisorders:

Timololmaleateeyedrops,solution:

Rare: Peyronie’sdisease*

Generaldisordersandadministrationsiteconditions:

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Rare: signsandsymptomsofsystemicallergicreactions,includingangioedema,urticaria,pruritus,

rash,anaphylaxis,rarelybronchospasm

Dorzolamidehydrochlorideeyedrops,solution:

Common: asthenia/fatigue*

Timololmaleateeyedrops,solution:

Uncommon: asthenia/fatigue*

*TheseadversereactionswerealsoobservedwithCOSOPTduringpost-marketingexperience.

LaboratoryFindings

COSOPTwasnotassociatedwithclinicallymeaningfulelectrolytedisturbancesinclinicalstudies.

4.9Overdose

NodataareavailableinhumansinregardtooverdosebyaccidentalordeliberateingestionofCOSOPT.

Symptoms

Therehavebeenreportsofinadvertentoverdoseswithtimololmaleateophthalmicsolutionresultinginsystemic

effectssimilartothoseseenwithsystemicbeta-adrenergicblockingagentssuchasdizziness,headache,

shortnessofbreath,bradycardia,bronchospasm,andcardiacarrest.Themostcommonsignsandsymptomsto

beexpectedwithoverdosesofdorzolamideareelectrolyteimbalance,developmentofanacidoticstate,and

possiblycentralnervoussystemeffects.

Onlylimitedinformationisavailablewithregardtohumanoverdosebyaccidentalordeliberateingestionof

dorzolamidehydrochloride.Withoralingestion,somnolencehasbeenreported.Withtopicalapplicationthe

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

Treatment

Treatmentshouldbesymptomaticandsupportive.Serumelectrolytelevels(particularlypotassium)andblood

pHlevelsshouldbemonitored.Studieshaveshownthattimololdoesnotdialyzereadily.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antiglaucomapreparationsandmiotics,Betablockingagents,Timolol,

combinations,ATCcode:S01ED51

MechanismofAction

COSOPTiscomprisedoftwocomponents:dorzolamidehydrochlorideandtimololmaleate.Eachofthesetwo

componentsdecreaseselevatedintraocularpressurebyreducingaqueoushumorsecretion,butdoessobya

differentmechanismofaction.

DorzolamidehydrochlorideisapotentinhibitorofhumancarbonicanhydraseII.Inhibitionofcarbonic

anhydraseintheciliaryprocessesoftheeyedecreasesaqueoushumorsecretion,presumablybyslowingthe

formationofbicarbonateionswithsubsequentreductioninsodiumandfluidtransport.Timololmaleateisa

nonselectivebeta-adrenergicreceptorblockingagent.Theprecisemechanismofactionoftimololmaleatein

loweringintraocularpressureisnotclearlyestablishedatthistime,althoughafluoresceinstudyandtonography

studiesindicatethatthepredominantactionmayberelatedtoreducedaqueousformation.However,insome

studiesaslightincreaseinoutflowfacilitywasalsoobserved.

Thecombinedeffectofthesetwoagentsresultsinadditionalintraocularpressurereduction(IOP)comparedto

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Followingtopicaladministration,COSOPTreduceselevatedintraocularpressure,whetherornotassociated

withglaucoma.Elevatedintraocularpressureisamajorriskfactorinthepathogenesisofopticnervedamage

andglaucomatousvisualfieldloss.COSOPTreducesintraocularpressurewithoutthecommonsideeffectsof

mioticssuchasnightblindness,accommodativespasmandpupillaryconstriction.

Pharmacodynamiceffects

ClinicalEffects

Clinicalstudiesofupto15monthsdurationwereconductedtocomparetheIOP-loweringeffectofCOSOPT

b.i.d.(dosedmorningandbedtime)toindividually-andconcomitantly-administered0.5%timololand2.0%

dorzolamideinpatientswithglaucomaorocularhypertensionforwhomconcomitanttherapywasconsidered

appropriateinthetrials.Thisincludedbothuntreatedpatientsandpatientsinadequatelycontrolledwithtimolol

monotherapy.Themajorityofpatientsweretreatedwithtopicalbeta-blockermonotherapypriortostudy

enrollment.Inananalysisofthecombinedstudies,theIOP-loweringeffectofCOSOPTb.i.d.wasgreaterthan

thatofmonotherapywitheither2%dorzolamidet.i.d.or0.5%timololb.i.d.TheIOP-loweringeffectof

COSOPTb.i.d.wasequivalenttothatofconcomitanttherapywithdorzolamideb.i.d.andtimololb.i.d.The

IOP-loweringeffectofCOSOPTb.i.d.wasdemonstratedwhenmeasuredatvarioustimepointsthroughoutthe

dayandthiseffectwasmaintainedduringlong-termadministration.

Paediatricuse

A3monthcontrolledstudy,withtheprimaryobjectiveofdocumentingthesafetyof2%dorzolamide

hydrochlorideophthalmicsolutioninchildrenundertheageof6yearshasbeenconducted.Inthisstudy,30

patientsunder6andgreaterthanorequalto2yearsofagewhoseIOPwasnotadequatelycontrolledwith

monotherapybydorzolamideortimololreceivedCOSOPTinanopenlabelphase.Efficacyinthosepatients

hasnotbeenestablished.Inthissmallgroupofpatients,twicedailyadministrationofCOSOPTwasgenerally

welltoleratedwith19patientscompletingthetreatmentperiodand11patientsdiscontinuingforsurgery,a

changeinmedication,orotherreasons.

5.2Pharmacokineticproperties

DorzolamideHydrochloride

Unlikeoralcarbonicanhydraseinhibitors,topicaladministrationofdorzolamidehydrochlorideallowsforthe

activesubstancetoexertitseffectsdirectlyintheeyeatsubstantiallylowerdosesandthereforewithless

systemicexposure.Inclinicaltrials,thisresultedinareductioninIOPwithouttheacid-basedisturbancesor

alterationsinelectrolytescharacteristicoforalcarbonicanhydraseinhibitors.

Whentopicallyapplied,dorzolamidereachesthesystemiccirculation.Toassessthepotentialforsystemic

carbonicanhydraseinhibitionfollowingtopicaladministration,activesubstanceandmetaboliteconcentrations

inredbloodcells(RBCs)andplasmaandcarbonicanhydraseinhibitioninRBCsweremeasured.Dorzolamide

accumulatesinRBCsduringchronicdosingasaresultofselectivebindingtoCA-IIwhileextremelylow

concentrationsoffreeactivesubstanceinplasmaaremaintained.TheparentactivesubstanceformsasingleN-

desethylmetabolitethatinhibitsCA-IIlesspotentlythantheparentactivesubstancebutalsoinhibitsaless

activeisoenzyme(CA-I).ThemetabolitealsoaccumulatesinRBCswhereitbindsprimarilytoCA-I.

Dorzolamidebindsmoderatelytoplasmaproteins(approximately33%).Dorzolamideisprimarilyexcreted

unchangedintheurine;themetaboliteisalsoexcretedinurine.Afterdosingends,dorzolamidewashesoutof

RBCsnonlinearly,resultinginarapiddeclineofactivesubstanceconcentrationinitially,followedbyaslower

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Whendorzolamidewasgivenorallytosimulatethemaximumsystemicexposureafterlongtermtopicalocular

administration,steadystatewasreachedwithin13weeks.Atsteadystate,therewasvirtuallynofreeactive

substanceormetaboliteinplasma;CAinhibitioninRBCswaslessthanthatanticipatedtobenecessaryfora

pharmacologicaleffectonrenalfunctionorrespiration.Similarpharmacokineticresultswereobservedafter

chronic,topicaladministrationofdorzolamidehydrochloride.However,someelderlypatientswithrenal

impairment(estimatedCrCl30-60ml/min)hadhighermetaboliteconcentrationsinRBCs,butnomeaningful

differencesincarbonicanhydraseinhibitionandnoclinicallysignificantsystemicsideeffectsweredirectly

attributabletothisfinding.

TimololMaleate

Inastudyofplasmaactivesubstanceconcentrationinsixsubjects,thesystemicexposuretotimololwas

determinedfollowingtwicedailytopicaladministrationoftimololmaleateophthalmicsolution0.5%.The

meanpeakplasmaconcentrationfollowingmorningdosingwas0.46ng/mlandfollowingafternoondosingwas

0.35ng/ml.

5.3Preclinicalsafetydata

Theocularandsystemicsafetyprofileoftheindividualcomponentsiswellestablished.

Dorzolamide

Inrabbitsgivenmaternotoxicdosesofdorzolamideassociatedwithmetabolicacidosis,malformationsofthevertebral

bodieswereobserved.

Timolol

Animalstudieshavenotshownteratogeniceffect.

Furthermore,noadverseoculareffectswereseeninanimalstreatedtopicallywithdorzolamidehydrochlorideand

timololmaleateophthalmicsolutionorwithconcomitantly-administereddorzolamidehydrochlorideandtimolol

maleate.Invitroandinvivostudieswitheachofthecomponentsdidnotrevealamutagenicpotential.Therefore,no

significantriskforhumansafetyisexpectedwiththerapeuticdosesofCOSOPT.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Hyetellose

Mannitol

Sodiumcitrate

Sodiumhydroxide

Benzalkoniumchloride

Waterforinjections

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

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6.4Specialprecautionsforstorage

Keepthebottleintheoutercarton,inordertoprotectfromlight.

6.5Natureandcontentsofcontainer

Tamper-evidentbottlewithdropper.

1x5mlbottleinanoverlabelledoutercarton.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

G&ALicensingLtd

Ballymurray

Co.Roscommon

Ireland

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1447/40/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:31stMarch2010

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