1. Comprehensive Glaucoma Management with COSOPT™
COSOPT (dorzolamide HCI-timolol maleate ophthalmic solution) is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
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2. Evolution of the Definition of Primary Open-Angle Glaucoma
Former definition
A disorder characterized by increased IOP that may cause impaired vision, ranging from slight loss to absolute blindness
Current definition
Primary open-angle glaucoma is a multifactorial optic neuropathy in which there is a characteristic acquired loss of retinal ganglion cells and atrophy of the optic nerve
Traditional definitions of glaucoma have largely focused on increased intraocular pressure (IOP).1 Despite the association between elevated IOP and progressive eye damage in glaucoma,2 however, some patients with IOP over 21 mmHg have no damage to the optic nerve (ocular hypertension), and some patients with IOP 11 to 21 mmHg have visual loss characteristic of glaucoma (normal- or low-tension glaucoma).3 Current research also supports the concept of glaucoma as a neuropathic disorder encompassing pathogenetic mechanisms beyond IOP.4,5 Newer definitions, for example, from the American Academy of Ophthalmology (AAO) guidelines, therefore refer to glaucoma as a multifactorial optic neuropathy in which there is a characteristic acquired loss of retinal ganglion cells and atrophy of the optic nerve.5 However, with these definitions, IOP still remains a major risk factor for glaucoma.
IOP=intraocular pressure
Adapted from Berkow R, Fetcher AJ, eds. The Merck Manual of Diagnosis and Therapy, 15th ed, 1987; Preferred Practice Pattern™. American Academy of Ophthalmology, 2000.
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3. Risk Factors for Glaucomatous Optic Nerve Damage
Established
Elevated IOP
Age
Race
Family history
Potential
Cold hands/feet
Diabetes mellitus
Systemic hypertension
Nocturnal hypotension
Migraines
Peripheral vasospasm
Atherosclerosis
Myopia
Optic disc hemorrhages
Peripapillary atrophy
Diastolic and/or perfusion pressure
Almost all glaucoma specialists would agree that IOP, although it is not the only risk factor for glaucoma, is certainly the most important.3,6 However, most glaucoma specialists also would indicate that there are additional risk factors associated with damage concerning the IOP. The risk factors are not precisely understood. Age, race, family history, high myopia, and history of vascular disease are often thought to be most important.2,3,6
There are often potential risk factors associated with the vascular disease that have been indicated in some studies including: cold hands and feet, migraines, peripheral vasospasm, and optic disc hemorrhage.2,7-9 In addition, variations in the optic disc anatomy such as peripapillary atrophy may be associated with progression to glaucoma.10-11
Adapted from Flammer J Glaucoma, 2001; Drance S et al Am J Ophthalmol 2001;131: ; Bonomi L et al Ophthalmology 2000;107: ; Hoyng PF et al Int Ophthalmol 1992;16:65-73; Raitta C, Sarmela T Acta Ophthalmol 1970;48: ; Hayakawa T et al J Glaucoma 1998;7:
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4. Mean change in visual-field defect score
AGIS Demonstrated that Low IOP Is Associated with Reduced Progression of Visual-Field Defect* 4
<50% of visits IOP <18 mmHg (mean 20.2)
50–75% of visits IOP <18 mm Hg (mean 16.9)
75–100% of visits IOP <18 mm Hg (mean 14.7)
100% of visits IOP <18 mmHg (mean 12.3) 3 2
Mean change in visual-field defect score 1
The Advanced Glaucoma Intervention Study (AGIS) is a prospective trial that provides support for the important role of elevated IOP in visual-field loss.12 Patients with primary open-angle glaucoma (POAG) inadequately controlled by medication were randomly assigned to one of two sequences of glaucoma surgery (argon laser trabeculoplasty-trabeculectomy-trabeculectomy or trabeculectomy-argon laser trabeculoplasty-trabeculectomy). The relationship between IOP and progression of visual-field damage was then evaluated over six years following surgery.
In an associative analysis of the data, 586 eyes were categorized into four groups based on the percentage of six-month visits over the six years when IOP was below 18 mmHg: <50% of visits, 50–75% of visits, 75–100% of visits, or 100% of visits.12
As the slide shows, visual-field loss was lowest in patients with IOP below 18 mmHg at 100% of visits (mean IOP 12.3 mmHg).12 In contrast, patients with the highest IOP levels, that is, below 18 mmHg in <50% of visits (mean 20.2 mmHg), had the greatest visual losses.12,* However, at seven years 14.4% of patients in the group with IOP below 18 mmHg at 100% of visits had a worsening of four or more units of the visual field.
*Conclusive results from randomized clinical trials needed. –1
(N=586 eyes) –2 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Follow-Up (months)
*Conclusive results from randomized clinical trials needed
Adapted from the AGIS Investigators Am J Ophthalmol 2000;130:
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5. As Did OHTS... 22.5 9.5 4.4 4.0 % IOP reduction (from baseline)
25%
25%
Treated (n=817)
Observation (n=819)
22.5
20%
20%
15%
15%
53.7% differential
10%
10%
9.5 5%
The Ocular Hypertension Treatment Study (OHTS), led by Michael Kass, was designed in the early 1990s to answer the question if treatment of ocular hypertension in general reduced the incidence of progression to POAG.13 The trial had 1636 patients randomized in a 1:1 ratio to either treatment with a topical ocular hypotensive medication to achieve a 20% reduction in IOP or no treatment. The inclusion IOPs were between 24 and 32 mmHg in one eye and between 21 and 32 mmHg in the other eye. The patients were followed for at least five years. The results of this study showed patients who received treatment (average of 22.5% IOP reduction) had a cumulative probability of progressing to POAG in 4.4% of cases, while untreated patients had a probability of progressing in 9.5% of cases. There was no difference in tolerability between the treatment and nontreatment groups.
In summary, the OHTS trial tells us that treatment for ocular hypertension (OHT) patients is useful. It does not tell us exactly who or at what level they should be treated or what the exact risk factors for progression are. 5%
4.0
4.4 0% 0%
% IOP reduction (from baseline)
Cumulative probability of developing POAG*
*At month 60 OHTS=Ocular Hypertension Treatment Study; POAG=primary open-angle glaucoma
Adapted from Kass M et al Arch Ophthalmol 2002;120:
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6. COSOPT™ Maintained IOP Reduction up to 9 mmHg over 15 Months28
COSOPT (n=112)
dorzolamide 2% (n=109)
timolol 0.5% (n=110) 26 24 22
IOP 2 hours after administration (mmHg) 20
–9 mmHg (p<0.05 vs. baseline) 18 17
While OHTS indicated that reduction of IOP in OHT is important, the exact amount that the IOP should be reduced is still not certain. In POAG, studies have shown that a reduction to 18 mmHg or below may be the most protective against progression, and some investigators would conclude that IOPs of <14 mmHg are the most beneficial.12
The dorzolamide/timolol fixed combination in COSOPT™ suppresses aqueous production and can reduce the IOP up to 34% from untreated baseline given twice daily. This reduction goes well beyond the reduction seen in OHTS as well as provides an ability to bring the majority of patients to IOPs of 18 mmHg or below when treating POAG.
COSOPT was studied in two three-month multicenter, randomized, parallel-group trials of identical designs in patients with open-angle glaucoma or OHT.14 In one of these studies, 108 patients who had received COSOPT during the double-blind portion, received an additional 12 months of COSOPT twice daily in an open-label extension.14,15
Over the year-long extension, COSOPT maintained reductions in peak IOP (hour 2) of up to 9 mmHg (p<0.05 vs. baseline at all time points).15 16
Double blind
Open extension
–34%
Week 2 1 2 3 6 9 12 15
Month
p<0.05 for all mean IOP values vs. baseline
Adapted from Boyle JE et al Ophthalmology 1998;105(10):
COSOPT (dorzolamide HCI-timolol maleate ophthalmic solution) is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
Calcs:
Baseline=month 3 value
(26.9 mmHg)
26.932.6%=8.8 mmHg (month 6)
26.9 33%=8.9 mmHg (month 9)
26.9 34.3%=9.2 mmHg (month 12)
26.9 32.4%=8.8 mmHg (month 15)
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COSOPT (dorzolamide HCI-timolol maleate ophthalmic solution) is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.

7. In a Clinical Study COSOPT™ Provided Powerful IOP Reduction
Equivalent Efficacy* of COSOPT vs. Latanoprost 0.005%
COSOPT (n=138)
Latanoprost (n=143) –1 –2 –3 –4
Mean change in diurnal IOP from baseline (mmHg) –5 –6
–27.1%
–28.6%
–29.0%
In a randomized, observer-blind, parallel-group, multicenter study, the IOP-lowering effects of COSOPT™ and latanoprost were compared in patients with OHT. After an approximately three-week washout, during which ocular hypertensive medications were discontinued, patients were randomly assigned to three months of treatment with either COSOPT twice daily (n=145) or latanoprost 0.005% once daily (n=143). On day 1 and at months 1, 2, and 3, diurnal IOP (average of the values at hours 0, 2, 6, and 8 [8 AM, 10 AM, 2 PM, and 4 PM]) was analyzed.15
By month 1, both treatments had considerably reduced mean diurnal IOP, and these reductions were sustained for three months. By study end, mean diurnal IOP was 30.5% lower in the group receiving COSOPT and 29.0% lower in the latanoprost group compared with baseline. The IOP-lowering effects of COSOPT and latanoprost 0.005% were similar in statistical analysis of the data.15
– 7 –8
–29.3%
–30.6%
–30.5% –9
Baseline = patients with up to a three-week
washout period
Month 1
Month 2
Month 3
*Differences were not statistically significant.
Randomized, observer-blind, parallel-group, three-month, multicenter study
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8. COSOPT™ Provided Powerful 24-Hour IOP Control18
COSOPT (n=33)
Latanoprost (n=33) 17 16 15
Mean IOP (mmHg) 14 13 12 11 10
A randomized, single-blind, crossover study was conducted to compare COSOPT™ with the prostaglandin F2 analog latanoprost in patients with POAG or OHT.16
Patients who qualified for study participation at the screening visit were randomized to receive six weeks of either COSOPT twice daily or latanoprost 0.005% once daily. If required, a three-week washout period ensued. Patients then crossed over to the alternate regimen.16
At 10 PM, COSOPT provided significantly better IOP control (14.6 mmHg) than latanoprost (16.6 mmHg) (p=0.006). At all other timepoints, similar IOP reductions were achieved in both groups.16
6:00 AM
10:00 AM
2:00 PM
6:00 PM
10:00 PM*
2:00 AM
COSOPT provided significantly better IOP control than latanoprost at 10 PM (p=0.006)
At all other time points, similar IOP reductions were achieved in both groups
*p=0.006 vs. latanoprost
Adapted from Konstas AGP et al Ophthalmology 2003 (in press).
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9. Efficacy of COSOPT™ vs. Travoprost and Bimatoprost in Product Label Information
COSOPT a,b can provide an IOP reduction of 7.7–9.0 mmHg1
IOP lowering with travoprost and bimatoprost 4,5
travoprostc
bimatoprostd
COSOPT™ is indicated for the treatment of elevated IOP in patients with OHT, open-angle glaucoma, pseudoexfoliative glaucoma, or other secondary open-angle glaucomas when concomitant therapy is appropriate.
Bimatoprost and travoprost are available for lowering elevated IOP in patients with open-angle glaucoma and OHT who are intolerant of other IOP-lowering medications or who do not achieve sufficient IOP reduction with other therapies.18,19 Comparisons of respective product labels show the following:18,19
• IOP reductions of 6.6 to 8.0 mmHg have been seen with travoprost • IOP reductions of 6.9 to 8.7 mmHg have been seen with bimatoprost
Travoprost and bimatoprost IOP lowering as reflected in respective product labels
aFixed combination
bIn a three-month trial of patients with IOP 24 mmHg, patients were randomized to receive either COSOPT twice daily (n=114) vs. monotherapy with timolol 0.5% twice daily (n=112) or dorzolamide 2.0% three times daily (n=109). IOP values shown are trough and peak at day 90.
cIn patients with baseline IOP 24–36 mmHg treated with travoprost 0.004% once daily.
dIn patients with mean baseline IOP 22–34 mmHg treated with bimatoprost 0.03% once daily.
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10. COSOPT™: Proven IOP Control
Powerful IOP Control
Reduced IOP 33% from untreated baseline
Reduced IOP up to 34% in 12-month extension
Comparable efficacy vs. prostaglandins
3-month comparative trial vs. latanoprost
Consistent 24-hour diurnal control vs. latanoprost
Comparable efficacy vs. bimatoprost and travoprost
Proven safety profile
Generally well tolerated
Prescribed in over 23.6 million patient-months
In summary, COSOPT™ delivers powerful IOP-lowering efficacy which has been proven in long-term clinical trials conducted before and after launch in ,15 Additionally, it has been demonstrated that COSOPT provides comparable IOP-lowering efficacy versus latanoprost on a three-month mean diurnal basis and across a 24-hour diurnal period.15,16 The safety profile of COSOPT has been proven; adverse effects are limited to those previously reported with the dorzolamide or timolol components.
COSOPT has been prescribed in over 23.6 million patient-months.15
Adapted from Boyle JE et al Ophthalmology 1998;105(10): ; Konstas AGP et al Ophthalmology 2003 (in press).
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11. Moving Beyond IOP Control
The progression of glaucoma appears to be multifactorial
Up to 30% of newly diagnosed POAG patients may have “normal”* IOP
Lowering IOP alone does not always prevent progression of visual-field damage
Vascular factors, without elevated IOP, may lead to tissue ischemia and glaucomatous damage
Several findings have prompted a reassessment of the factors involved in glaucoma and resulting visual-field loss. One epidemiologic study suggests that up to 40% of patients with glaucoma have little or no elevation in IOP (i.e., 21 mmHg) at diagnosis.2,3,20 And although elevated IOP has long been postulated as a primary cause of glaucoma, reducing IOP alone does not always prevent progression of visual-field damage.21 Finally, while elevated IOP may lead to glaucomatous damage in the form of disc cupping and visual-field loss,4 these abnormalities may be caused by vascular factors that promote tissue ischemia.22 Therefore, the progression of glaucoma appears to be a multifactorial process.
*21 mmHg
Adapted from Flammer J Glaucoma. Bern: Verlag Hans Huber, 2001; Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy. 17th ed. Whitehouse Station, NJ: Merck Research Laboratories, 1999; Broadway DC, Drance SM Br J Ophthalmol 1998;82: ; Drance SM et al Am J Ophthalmol 1998;125(5): ; Dielemans I et al Ophthalmology 1994;101:
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12. Definition of CO•REGULATION™
The simultaneous and active alteration of two control systems within the eye in glaucoma
Mechanical: Decreased IOP
Vascular: Increased OBF
OBF
IOP
CO•REGULATION™ in glaucoma refers to the simultaneous and active alteration of two control systems within the eye. IOP can be regulated through reduction of aqueous humor production, while ocular blood flow (OBF) can be regulated through enhancement of blood supply to ocular tissues.23,24
CO•REGULATION is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
IOP=intraocular pressure
OBF=ocular blood flow
CO•REGULATION and the symbol for CO•REGULATION are trademarks of Merck & Co., Inc., Whitehouse Station, NJ, USA.
Adapted from Alward WLM Glaucoma: The Requisites in Ophthalmology. St. Louis: Mosby, 2000.
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13. The Role of Ischemia in Glaucoma
Inadequate blood perfusion of the tissues deprives tissues of nutrients and oxygen, and may lead to cell death
Ocular ischemia may be central to retinal ganglion cell death
Normal blood vessels in the eye perfuse and nourish ocular tissues. When ischemia—inadequate blood perfusion—deprives ocular cells of both nutrients and oxygen, the result may be cell death.2
Ocular ischemia may be central to retinal ganglion cell death in glaucoma.25 Recognition of ischemia in the pathogenesis and progression of this disease has led to investigations of the effect of glaucoma medications on OBF.26
Adapted from Flammer J Glaucoma. Bern: Verlag Hans Huber, 2001; Harris A et al Prog Retin Eye Res 1999;18(5): ; Harris A et al Curr Opin Ophthalmol 2001;12:
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14. The IOP-Ocular Perfusion-Apoptosis Relationship
Glaucomatous damage is due primarily to the death of retinal nerve (ganglion) cells and their axons.2 This death is believed to occur mainly through apoptosis, a noninflammatory process in which cells produce self-digesting enzymes. Increased IOP, besides mechanically damaging the optic disc, can trigger apoptosis by blocking axoplasmic flow and thereby severing the connection between the nerve cells and their axons. Reduced ocular perfusion can lead indirectly to apoptosis by diminishing the supply of oxygen. Although this decrease does not itself cause cell death, the subsequent renewal of oxygen concentrations produces free oxygen radicals, which is thought to promote toxic glutamate concentrations that may kill ganglion cells. Moreover, increased IOP can also decrease ocular perfusion. Therefore, the process of glaucomatous damage may represent a complex interaction between IOP and ocular perfusion, which could lead to apoptosis of retinal ganglion cells.2,27
Apoptosis
Adapted from Harris A Ophthalmol Times 1997;(Suppl 2):S1-S23.
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15. Measuring Ocular Blood Flow
No single technique can accurately assess all relevant vascular beds in glaucoma
Multiple techniques should be used to measure all relevant vascular beds in glaucoma
Several noninvasive techniques provide relevant information
OBF may be measured by a number of techniques; however, no gold standard yet exists. Further, it is impossible to isolate and measure the vascular beds of utmost interest in glaucoma, the retinal ganglion cell layer and deep layers of the optic nerve head. Ideally, multiple techniques should be used to measure all relevant vascular beds in glaucoma. Several noninvasive techniques provide relevant information.28
Adapted from Harris A et al Surv Ophthalmol 1998;42(6):
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16. OBF Measurement Techniques
Technique Parameter Location Pros Cons
Color Doppler Blood velocity, Retrobulbar vessels User specified vessels Expensive
Imaging (CDI) Calculated vascular and location and complex resistance
Scanning Laser Filling times, AVP, Retinal, choroid Highly sensitive to Invasive, Ophthalmoscope (SLO) capillary circulation time change expensive,
angiography velocities time-consuming
Heidelberg Retinal Unitless flow, Retinal capillary beds, Volumetric blood flow Unitless, Flowmetry (HRF) blood velocity Ocular nerve head expensive, difficult to interpret
Pulsatile Ocular Blood IOP Unknown, presume Inexpensive and easy Measure IOP, Flow (POBF) to be choroidal to use non-site specific
Color Doppler imaging (CDI) can measure blood velocities in the vessels that feed the eye.28 These velocity measurements are used to calculate Pourcelot’s resistivity index, which is an indication of resistance within the vascular beds of the eye. CDI has the advantage of being vessel selective, allowing individual vessels to be interrogated for velocity. It is, however, difficult to perform and very expensive. Further, it measures feeding vessels, not the areas of greatest interest—the ganglion cell layer and the optic nerve head.
Scanning laser ophthalmoscope (SLO) angiography can provide ocular perfusion dynamic information from the retina with fluorescein, and from the choroid with indocyanine green (ICG) angiography.25,28 Arteriovenous passage (AVP) times describe the amount of time between the first appearance of fluorescein in a retinal artery and first appearance in the adjacent vein. Similar parameters may be obtained from choroidal angiograms. This technique is highly sensitive to changes in ocular perfusion dynamics, but acquisition of the data is invasive and time-consuming.
The Heidelberg retinal flowmeter (HRF) provides a direct measurement of blood flow within the capillary beds of the retina.28 It provides volumetric flow measurements; however, the flow measurements are in arbitrary units, and HRF data are very difficult to interpret.25
The pulsatile ocular blood flow (POBF) device measures IOP in real time.28 As IOP pulsates with the cardiac cycle, the unit proposes to calculate changes in ocular volume using the changing IOP. It is assumed that the majority of this volume change occurs within the vasculature of the choroid. The device is inexpensive and easy to use,25 but it measures IOP and makes many assumptions to arrive at a calculation of the pulsatile portion of OBF. The diastolic or steady portion of flow is missed, and its contribution to total flow is unknown. Other devices described in the literature include blue field entopic simulation, laser speckle, laser Doppler velocimetry, and laser Doppler flowmetry.28
AVP=arteriovenous passage
Adapted from Harris A et al Prog Retin Eye Res 1999;18(5): ; Harris A et al Surv Ophthalmol 1998;42(6):
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17. Can any medications improve OBF independent of IOP?
In summary, Co•Regulation is the reduction of IOP accompanied by an increase in ocular perfusion.23,26 Of course, the ability of a medication to favorably alter ocular perfusion is dependent upon its ability to reach the vasculature of the retina and optic nerve.26 It is possible to measure ocular perfusion through a number of techniques, each one providing a piece of the story, but no single technique completely describing the hemodynamic status of the eye.28 With this in mind, what do we know about the hemodynamic effect of existing glaucoma medications?
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18. Glaucoma Medications and OBF
Drug Class Parameter Effect
Topical CAIs AVP Times Decrease
Retinal capillary velocity Increase
Selective beta blockers End diastolic velocity Increase
Alpha agonists End diastolic velocity Neutral
Prostaglandins End diastolic velocity Neutral
POBF Increase (IOP dependent)
Topical (and systemic for that matter) carbonic anhydrase inhibitors (CAIs) have been found to improve ocular hemodynamics using both CDI and fluorescein angiography While the implications of the CDI findings on the ganglion cell layer and the CDI findings themselves remain controversial, the improvements in AVP times demonstrate that the circulation time of blood through the vessels feeding the ganglion cell layer is improved. This finding is supported by capillary velocity data.
Selective beta blockers have been shown to increase velocities within the vessels that feed the eye.32 Interpretation of CDI data is difficult. Improvement of velocities does not necessarily mean increased flow. Further, the meaning of retrobulbar velocities as it applies to blood flow within the retinal ganglion cell layer and optic disc is unclear.
Alpha agonists have been studied by CDI; they appear to have no observable effect on OBF.33
Studies of the effects of topical prostaglandins on OBF in the vasculature that feeds the eye have shown conflicting results.17
CAIs = carbonic anhydrase inhibitors
Adapted from Nicolela MT et al Am J Ophthalmol 1996;122(6): ; Harris A et al J Ocul Pharmacol Ther 1999;15(3): ; Harris A et al Ophthalmology 2000;107(3): ; Harris A et al Acta Ophthalmol Scand 1996;74: ; Harris A et al Am J Ophthalmol 1995;120: ; Lachkar Y et al Arch Ophthalmol 1998;116:
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19. Topical CAIs: Inhibition of Carbonic Anhydrase
Dorzolamide
CO2
HCO3
The blockage of carbonic anhydrase is thought to result in a vasodilation as mediated by pH level, as well as a reduction in IOP.26
More
carbon dioxide vasodilation
Less
bicarbonate
Adapted from Harris A, Jonescu-Cuypers CP Curr Opin Ophthalmol 2001;12:
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20. Dorzolamide and Ocular Hemodynamics
Hastened AVP and capillary velocity in individuals with healthy eyes
Improved AVP and contrast sensitivity in NTG
Compared to betaxolol, dorzolamide improved inferotemporal retinal AVP in NTG
Topical CAIs have been studied in a number of groups, including individuals with normal eye examinations and normal-tension glaucoma (NTG) patients. Results demonstrated improved AVP in healthy volunteers and patients with NTG.29-31,34
NTG = normal-tension glaucoma
Adapted from Harris A et al J Ocul Pharmacol Ther 1999;15: ; Harris A et al Ophthalmology 2000;107; ; Harris A et al Acta Ophthalmol Scand 1996;74: ; Harris A et al Eur J Ophthalmol 2003;13:24-31.
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21. Results of Recent Clinical Studies Suggest Dorzolamide Improves AVP Times
Baseline
4 weeks of treatment 20
2.8
(n=9)
(n=9)
2.7
2.7 17 17 15
2.6 14 14
2.5
IOP (mmHg)
AVP Times* (sec) 10
2.4
Objective: To determine the impact of a selective beta blocker (betaxolol) and a topical CAI (dorzolamide) on the retinal and retrobulbar circulation.30
Design: Counterbalanced crossover, with open-label use of medications.
Participants: Nine persons with NTG, that is, visual-field loss and optic nerve head damage with IOP <21 mmHg.
Intervention: After a three-week drug washout, NTG patients were studied after one month of treatment with either 2% dorzolamide three times daily or 0.5% betaxolol twice daily, with determinations of IOP and retinal and retrobulbar hemodynamics.30
Main outcome measures: At baseline and after treatment with each drug, retinal AVP time was determined by SLO after fluorescein dye injection, and flow velocities in the central retinal and ophthalmic arteries were measured with color Doppler ultrasonography imaging.30
Results: Betaxolol and dorzolamide each lowered IOP significantly, with these changes apparent and maximal after two weeks (each p<0.05 vs. baseline). In contrast, dorzolamide (but not betaxolol) accelerated AVP of fluorescein dye in the inferior temporal quadrant of the retina (p<0.05 vs. baseline). Neither drug affected AVP in the superotemporal retina or any aspect of central retinal or ophthalmic artery flow velocity after either two or four weeks.30
Conclusions: Although both dorzolamide and betaxolol are effective ocular hypotensive agents and their topical instillation leaves retrobulbar hemodynamics unaltered, dorzolamide alone accelerates inferotemporal retinal dye transit.30 5
2.2
2.2
2.0
Dorzolamide
Betaxolol
Dorzolamide
Betaxolol
*In the temporal inferior artery
Adapted from Harris A et al Am J Ophthalmol 2000;107(3):
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22. Dorzolamide Enhances OBF in Patients with High-Tension Glaucoma
No significant effect on systemic blood pressure or heart rate following addition of dorzolamide to timolol
COSOPT™ significantly accelerated retinal arteriovenous passage time in superior temporal quadrant (p<0.01)
No effect on choroidal or retrobulbar circulation in either group
Experimentally, it has been demonstrated that topical CAIs alone30 and in combination with beta blockers35 accelerate retinal AVP times with no effect on the retrobulbar vasculature.
Adapted from Harris A et al Am J Ophthalmol 2000;107(3):
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23. No effects on systemic blood pressure or heart rate with dorzolamide
Results of Recent Clinical Studies Suggest Dorzolamide and Dorzolamide-Timolol Combination Improved OBF
No effects on systemic blood pressure or heart rate with dorzolamide
Accelerated AVP time in NTG and POAG
Improved OPA and POBF in POAG
In summary, it can be stated that studies on dorzolamide as monotherapy or in a fixed combination with timolol have shown an improvement in various OBF variables. These improvements can be seen in the retinal, choroidal, and retrobulbar regions.29,30,35,36
OPD=ocular perfusion dynamics; AVP=arteriovenous passage time; NTG=normal-tension glaucoma; POAG=primary open-angle glaucoma; OPA=ocular pulse amplitude; POBF=pulsatile ocular blood flow
Adapted from Harris A et al J Ocul Pharmacol Ther 1999;15(3): ; Harris A et al Ophthalmology 2000;107(3): ; Harris A et al Am J Ophthalmol 2001;132: ; Schmidt K-G et al Br J Ophthalmol 1998;82(7):
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24. Summary of CO•REGULATION™
The simultaneous and active alteration of two control systems within the eye in glaucoma
Mechanical: Decreased IOP
Vascular: Increased OBF
OBF
IOP
In closing, CO•REGULATION™ in glaucoma refers to the simultaneous and active alteration of two control systems within the eye. IOP can be regulated through reduction of aqueous humor production, while OBF can be regulated through enhancement of blood supply to ocular tissues.23,24
Adapted from Alward WLM Glaucoma: The Requisites in Ophthalmology. St. Louis: Mosby, 2000.
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25. COSOPT™: Pharmacology
Dorzolamide 2%
Inhibition of CAII activity (critical to aqueous humor production)
Decrease in aqueous humor production and consequent lowering of IOP
Timolol 0.5%
Decrease in aqueous humor production by blockade of ciliary beta-adrenergic receptors
Dorzolamide reduces aqueous humor production by inhibiting the activity of CAII, which catalyzes the reversible hydration of carbon dioxide (CO2) and the dehydration of carbonic acid (H2CO3).37,38
The inhibition of CAII by dorzolamide slows the secretion of bicarbonate ions from the ciliary process into the posterior chamber of the eye, thereby reducing the transport of sodium and fluid.37,38 The result is a decrease in aqueous humor production and the consequent lowering of IOP with dorzolamide.
Timolol is thought to decrease aqueous humor production by blockade of beta-adrenergic receptors in the ciliary processes.39 Although the precise mechanism of timolol’s ocular hypotensive effect has not been established, a decrease in cyclic adenosine monophosphate level and a resulting reduction in aqueous humor formation have been postulated.39
CA=carbonic anhydrase
Adapted from Sharir M. In Textbook of Ocular Pharmacology. 1997: ; Shields MB Textbook of Glaucoma
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26. COSOPT™: Indications
COSOPT is indicated in the treatment of elevated IOP in patients with
Ocular hypertension
Open-angle glaucoma
Pseudoexfoliative glaucoma or other secondary open-angle glaucomas
When concomitant therapy is appropriate
COSOPT™ is indicated in the treatment of elevated IOP in patients with ocular hypertension, open-angle glaucoma, and pseudoexfoliative glaucoma or other secondary open-angle glaucomas when concomitant therapy is appropriate.
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27. COSOPT™: Contraindications
Bronchial asthma or a history of bronchial asthma, or severe chronic obstructive pulmonary disease
Sinus bradycardia, second- or third-degree atrioventricular block, overt cardiac failure, or cardiogenic shock
Hypersensitivity to any component of COSOPT
Source C
(WPC),
p 1, §IV
COSOPT™ is contraindicated in patients with bronchial asthma or a history of bronchial asthma, or severe chronic obstructive pulmonary disease. In addition, patients with sinus bradycardia, second- or third-degree atrioventricular block, overt cardiac failure, or cardiogenic shock should not receive COSOPT, nor should patients with hypersensitivity to any component of the product. All of these contraindications are based on the components of COSOPT and are not unique to the combination.
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28. Adverse Experiences with COSOPT™
In clinical trials
None specific to COSOPT
The same adverse experiences as the individual components
Most mild and did not cause discontinuation
Most frequent drug-related: ocular burning/stinging, taste perversion, corneal erosion, conjunctival injection, blurred vision, tearing, ocular itching
Rare: urolithiasis
Low discontinuation rates in clinical trials
In postmarketing experience
Dyspnea, respiratory failure, contact dermatitis
In clinical studies, no adverse experiences specific to COSOPT™ have been observed; adverse experiences have been limited to those reported previously with dorzolamide hydrochloride and/or timolol maleate. In general, common adverse experiences were mild and did not cause discontinuation. The most frequently reported drug-related adverse effects were ocular burning/stinging, taste perversion, corneal erosion, conjunctival injection, blurred vision, tearing, and ocular itching. Urolithiasis was reported rarely.
In postmarketing experience with COSOPT, dyspnea, respiratory failure, and contact dermatitis have been reported.
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29. Precautions with COSOPT™
Adequately control cardiac failure before initiation of therapy
Monitor patients with a history of severe cardiac disease for signs of cardiac failure
Avoid use in patients with severe renal impairment and patients receiving oral CAIs
Use with caution in patients with hepatic impairment and a history of atopy or of severe anaphylactic reactions
Consider discontinuation if local adverse effects are observed during therapy
Monitor for additive effects on IOP or on known systemic effects of beta blockade in patients receiving systemic beta blockers
Several precautions should be observed with the use of COSOPT™. Cardiac failure should be adequately controlled before therapy is initiated; patients with a history of severe cardiac disease should be watched for signs of cardiac failure, and pulse rates should be monitored. COSOPT is not recommended in patients with severe renal impairment (creatinine clearance <30 ml/min) or in those receiving oral CAIs, and should be used with caution in patients with hepatic impairment. If local adverse effects are observed, discontinuation of therapy with COSOPT should be considered. During beta-blocker therapy, patients with a history of atopy or of severe anaphylactic reactions may be unresponsive to the usual doses of epinephrine used to manage anaphylactic reactions. Patients receiving systemic beta blockers should be observed for potential additive effects on IOP or on the known systemic effects of beta blockade.
COSOPT has not been studied in patients with acute angle-closure glaucoma, who require interventions in addition to ocular hypotensive agents. Choroidal detachment has been reported with the administration of aqueous suppressant therapy (including dorzolamide and timolol) after filtration procedures. COSOPT should not be administered during soft contact lens use, and contact lenses should not be inserted earlier than 15 minutes after administration.
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30. Dosage and Administration/ How Supplied
One drop of COSOPT™ in the affected eye(s) twice daily
How Supplied
Supplied in 5 ml OCUMETER™ PLUS dispensers
The recommended dosing for COSOPT™ is 1 drop in the affected eye(s) twice daily. COSOPT is available in a 5 ml and a 10 ml OCUMETER™ PLUS dispenser.
OCUMETERTM PLUS ophthalmic dispenser is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
OCUMETERTM PLUS ophthalmic dispenser is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
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31. COSOPT™ in the Patient-Friendly OCUMETER™ PLUS Dispenser
Large cap Is easy to open and close
Color-coded cap Makes it easy to identify medication
The specially designed OCUMETER™ PLUS Dispenser makes COSOPT™ patient friendly and helps ensure that every drop of medication gets into the eye. The new, larger bottle is easy to hold and squeeze and allows improved handling and control. The new, larger cap can be readily taken off and replaced. A color-coded cap makes the medication instantly identifiable, and a transparent bottle allows patients to see the level of medication and anticipate the need for refills.15
COSOPT is available in 5 ml and 10 ml bottles. In either presentation, the bottle, while it may not appear full, does contain the stated amount of solution, and therefore patients will get the full amount of COSOPT prescribed.
Large bottle Is easy to hold, squeeze, and control
Transparent bottle Makes medication level visible so patient knows when to refill
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32. Clinical Experience with COSOPT™
In clinical practice
Available in 55 countries
Available for 5 years
Proven therapy—more than 23.6 million patient-months of treatment with COSOPT
COSOPT™ has been well tolerated in both clinical practice and clinical studies. Worldwide, COSOPT has been prescribed for more than 23.6 million patient-months (i.e., almost 2 million patient-years).15 In clinical studies involving over 1000 patients, adverse experiences generally were mild and did not cause discontinuation of therapy. Approximately 2.4% of all patients discontinued therapy with COSOPT because of local ocular adverse effects and approximately 1.2% because of local adverse effects suggestive of allergy or hypersensitivity.
Data on file, MSD.
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33. Conclusions
“Attention to IOP reduction remains important, but does not address all mechanisms present within many POAG patients… medication(s) must also increase perfusion to the eye.” K.-G. Schmidt*
“In summary, the main finding in the present study was that dorzolamide induces changes in ocular and periocular hemodynamics, improving blood perfusion of the eye.” A. Martinez**
In conclusion, epidemiologic evidence suggests that we should consider more than IOP alone in the management of glaucoma.40 Vascular risk factors point to the possible contribution of ischemia to disease progression in glaucoma.40
*Schmidt K-G. Br J Ophthalmol 1998; 82(7): **Martinez A. Invest Ophthalmol Vis Sci 1999;40(6):
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34. References Please refer to note page. References
1. Berkow R, Fletcher AJ, eds. The Merck Manual of Diagnosis and Therapy. 15th ed. Rahway, NJ: Merck Sharp & Dohme Research Laboratories, 1987.
2. Flammer J. Glaucoma. Bern: Verlag Hans Huber, 2001.
3. Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy. 17th ed. Whitehouse Station, NJ: Merck Research Laboratories, 1999.
4. Horton JC. Disorders of the eye. In: Braunwald E et al, eds. Harrison’s Principles of Internal Medicine. Vol th ed. New York: McGraw-Hill, 2001:
5. American Academy of Ophthalmology. Preferred Practice Pattern™. Primary open-angle glaucoma. San Francisco, CA: American Academy of Ophthalmology, 2000.
6. Wilson MR, Martone JF. Epidemiology of chronic open-angle glaucoma. In The Glaucomas. 2nd ed. St. Louis: Mosby, 1996:
7. Drance S, Anderson DR, Schulzer M for the Collaborative Normal-Tension Glaucoma Study Group. Risk factors for progression of visual field abnormalities in normal-tension glaucoma. Am J Ophthalmol 2001;131:
8. Bonomi L, Marchini G, Marraffa M et al. Vascular risk factors for primary open angle glaucoma. Ophthalmology 2000;107:
9. Hoyng PF, de Jong N, Oosting H et al. Platelet aggregation, disc haemorrhage and progressive loss of visual fields in glaucoma. A seven year follow-up study on glaucoma. Int Ophthalmol 1992; 16:65-73.
10. Raitta C, Sarmela T. Fluorescein angiography of the optic disc and the peripapillary area in chronic glaucoma. Acta Ophthalmol 1970;48:
11. Hayakawa T, Sugiyama K, Tomita G et al. Correlation of the peripapillary atrophy area with optic disc cupping and disc hemorrhage. J Glaucoma 1998;7:
12. The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol 2000;130:
13. Kass MA, Heuer DK, Higginbotham EJ et al. The Ocular Hypertension Treatment Study. A randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol 2002;120:
14. Boyle JE, Ghosh K, Gieser DK et al for the Dorzolamide–Timolol Study Group. A randomized trial comparing the dorzolamide–timolol combination given twice daily to monotherapy with timolol and dorzolamide. Ophthalmology 1998;105(10):
15. Data on file, MSD __________________.
16. Konstas AGP, Papapanos P, Tersis I et al. 24-Hour diurnal curve comparison of commercially available latanoprost 0.005% versus timolol/dorzolamide fixed combination. Ophthalmology 2003 (in press).
17. Nicolela MT, Buckley AR, Walman BE et al. A comparative study of the effects of timolol and latanoprost on blood flow velocity of the retrobulbar vessels. Am J Ophthalmol 1996;122(6):
18. Travoprost European label. Available at www. eudra.org/humandocs/humans/EPAR/travatan. Accessed February 5, 2003.
19. Bimatoprost European label. Available at Accessed February 5, 2003.
20. Dielemans I, Vingerling JR, Wolfs RC et al. The prevalence of open-angle glaucoma in a population-based study in the Netherlands. The Rotterdam Study. Ophthalmology 1994;101:
Please refer to note page.
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35. References (cont’d) Please refer to note page. References (cont’d)
21. Broadway DC, Drance SM. Glaucoma and vasospasm. Br J Ophthalmol 1998;82: Available at: Accessed June 30, 2001.
22. Drance SM, Crichton A, Mills RP. Comparison of the effect of latanoprost 0.005% and timolol 0.5% on the calculated ocular perfusion pressure in patients with normal-tension glaucoma. Am J Ophthalmol 1998;125(5):
23. Alward WLM. Glaucoma: The Requisites in Ophthalmology. St. Louis: Mosby, 2000.
24. Harris A, Jonescu-Cuypers C, Martin B et al. Simultaneous management of blood flow and IOP in glaucoma. Acta Ophthalmol Scand 2001;79:
25. Harris A, Chung HS, Ciulla TA et al. Progress in measurement of ocular blood flow and relevance to our understanding of glaucoma and age-related macular degeneration. Prog Retin Eye Res 1999;18(5):
26. Harris A, Jonescu-Cuypers CP. The impact of glaucoma medication on parameters of ocular perfusion. Curr Opin Ophthalmol 2001;12:
27. Harris A. Glaucoma management: Beyond intraoccular pressure. Ophthalmol Times 1997; (suppl 2):S1-S23.
28. Harris A, Kagemann L, Cioffi GA. Assessment of human ocular hemodynamics. Surv Ophthalmol 1998;42(6):
29. Harris A, Arend O, Kagemann L et al. Dorzolamide, visual function and ocular hemodynamics in normal-tension glaucoma. J Ocul Pharmacol Ther 1999;15(3):
30. Harris A, Arend O, Chung HS et al. A comparative study of betaxolol and dorzolamide effect on ocular circulation in normal-tension glaucoma patients. Ophthalmology 2000;107(3):
31. Harris A, Arend O, Arend S et al. Effects of topical dorzolamide on retinal and retrobulbar hemodynamics. Acta Ophthalmol Scand 1996;74:
32. Harris A, Spaeth GL, Sergott RC et al. Retrobulbar arterial hemodynamic effects of betaxolol and timolol in normal-tension glaucoma. Am J Ophthalmol 1995;120:
33. Lachkar Y, Migdal C, Dhanjil S. Effect of brimonidine tartrate on ocular hemodynamic measurements. Arch Ophthalmol 1998;116:
34. Harris A, Migliardi R, Cole CN et al. Comparative analysis of the effects of dorzolamide and latanoprost on ocular hemodynamics in normal tension glaucoma. Eur J Ophthalmol 2003;13:24-31.
Harris A, Jonescu-Cuypers CP, Kagemann L et al. Effect of dorzolamide timolol combination versus timolol 0.5% on ocular bloodflow in patients with primary open-angle glaucoma. Am J Ophthalmol 2001;132:
36. Schmidt K-G, Rückman A, Pillunat LE. Topical carbonic anhydrase inhibition increases ocular pulse amplitude in high tension open angle glaucoma. Br J Ophthalmol 1998;82(7):
37. Sharir M. Topical carbonic anhydrase inhibitors. In: Zimmerman TJ, Kooner KS, Fechtner RD et al, eds. Textbook of Ocular Pharmacology. Philadelphia: Lippincott-Raven, 1997:
38. Sugrue MF, Harris A, Adamsons I. Dorzolamide hydrochloride: A topically active, carbonic anhydrase inhibitor for the treatment of glaucoma. Drugs Today 1997;33(5):
39. Shields MB, ed. Textbook of Glaucoma. 4th ed. Baltimore: Williams & Wilkins, 1998.
40. Martinez A, Gonzalez F, Capeans C et al. Dorzolamide effect on ocular blood flow. Invest Ophthalmol Vis Sci 1999;40(6):
Please refer to note page.
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36. Comprehensive Glaucoma Management with COSOPT™
Copyright © 2003 Merck & Co., Inc., Whitehouse Station, NJ, USA.
All rights reserved CST 2003-W-6191-SS Printed in USA
VISIT US ON THE WORLD WIDE WEB AT
Copyright © 2003 Merck & Co., Inc., Whitehouse Station, NJ, USA.
All rights reserved CST 2003-W-6191-SS Printed in USA
VISIT US ON THE WORLD WIDE WEB AT
CST 2003-W-6191-SS