slide 1 comprehensive glaucoma management with cosopt ™ cosopt (dorzolamide hci-timolol maleate...

Comprehensive Glaucoma Management with COSOPT™

COSOPT (dorzolamide HCI-timolol maleate ophthalmic solution) is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.

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

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.

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

Adapted from Flammer J Glaucoma, 2001; Drance S et al Am J Ophthalmol 2001;131:699-708; Bonomi L et al Ophthalmology 2000;107:1287-1293; Hoyng PF et al Int Ophthalmol 1992;16:65-73; Raitta C, Sarmela T Acta Ophthalmol 1970;48:303-308; Hayakawa T et al J Glaucoma 1998;7:306-311.

AGIS Demonstrated that Low IOP Is Associated with Reduced Progression of Visual-Field Defect*

*Conclusive results from randomized clinical trials needed

Adapted from the AGIS Investigators Am J Ophthalmol 2000;130:429-440.

–2

–1

0

1

2

3

4

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

Follow-Up (months)

Me

an

ch

an

ge

inv

isu

al-

fie

ld d

efe

ct

sc

ore

<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)

(N=586 eyes)

As Did OHTS...

*At month 60OHTS=Ocular Hypertension Treatment Study; POAG=primary open-angle glaucoma

Adapted from Kass M et al Arch Ophthalmol 2002;120:701-713.

0%

5%

10%

15%

20%

25%Treated (n=817)Observation (n=819)

% IOP reduction(from baseline)

Cumulative probability ofdeveloping POAG*

4.0

22.5

9.5

4.4

53.7% differential

0%

5%

10%

15%

20%

25%

COSOPT™ Maintained IOP Reduction up to 9 mmHg over 15 Months

p<0.05 for all mean IOP values vs. baselineAdapted from Boyle JE et al Ophthalmology 1998;105(10):1945-1951.

0

16

17

18

20

26

28

Week 2

3 6

Month

IOP

2 h

ou

rs a

fter

adm

inis

trat

ion

(m

mH

g)

COSOPT (n=112)dorzolamide 2% (n=109)timolol 0.5% (n=110)

–9 mmHg (p<0.05

vs.baseline)

9 12 15

24

22

Double blind Open extension

21

–34%COSOPT (dorzolamide HCI-timolol maleate ophthalmic solution) is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.

In a Clinical Study

COSOPT™ Provided Powerful IOP ReductionEquivalent Efficacy* of COSOPT vs. Latanoprost 0.005%

*Differences were not statistically significant.

Randomized, observer-blind, parallel-group, three-month, multicenter study

–9

–8

– 7

–6

–5

–4

–3

–2

–1

0

Month 1 Month 2 Month 3

Mea

n c

han

ge

in d

iurn

al IO

P f

rom

bas

elin

e (m

mH

g)

COSOPT (n=138)Latanoprost (n=143)

Baseline = patients withup to a three-week

washout period

–27.1% –28.6% –29.0%

–29.3% –30.6% –30.5%

COSOPT™ Provided Powerful 24-Hour IOP Control

• 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. latanoprostAdapted from Konstas AGP et al Ophthalmology 2003 (in press).

0

10

11

12

13

16

18

6:00 AM

Mea

n IO

P (

mm

Hg

)

COSOPT (n=33)Latanoprost (n=33)

15

14

17

10:00 AM 2:00 PM 6:00 PM 10:00 PM* 2:00 AM

aFixed combinationbIn 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.

Efficacy of COSOPT™ vs. Travoprost and Bimatoprost in Product Label Information

• Travoprost and bimatoprost IOP loweringas reflected in respective product labels

• COSOPT a,b can providean IOP reductionof 7.7–9.0 mmHg1

• IOP lowering with travoprostand bimatoprost 4,5

travoprostc bimatoprostd

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

Adapted from Boyle JE et al Ophthalmology 1998;105(10):1945-1951; Konstas AGP et al Ophthalmology 2003 (in press).

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

*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;82:862-870; Drance SM et al Am J Ophthalmol 1998;125(5):585-592; Dielemans I et al Ophthalmology 1994;101:1851-1855.

Definition of CO•REGULATION™

The simultaneous and active alteration of two control systems within the eye in glaucoma

• Mechanical: Decreased IOP

• Vascular: Increased OBF

IOP=intraocular pressureOBF=ocular blood flowCO•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.

OBFIOP

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

Adapted from Flammer J Glaucoma. Bern: Verlag Hans Huber, 2001; Harris A et al Prog Retin Eye Res 1999;18(5):669-687; Harris A et al Curr Opin Ophthalmol 2001;12:131-137.

The IOP-Ocular Perfusion-Apoptosis Relationship

IOP

Apoptosis

Ocularperfusion

Adapted from Harris A Ophthalmol Times 1997;(Suppl 2):S1-S23.

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

Adapted from Harris A et al Surv Ophthalmol 1998;42(6):509-533.

OBF Measurement Techniques

MeasurementTechnique 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

AVP=arteriovenous passage

Adapted from Harris A et al Prog Retin Eye Res 1999;18(5):669-687; Harris A et al Surv Ophthalmol 1998;42(6):509-533.

Can any medications improve OBF independent of IOP?

Glaucoma Medications and OBF

Drug Class Parameter Effect

Topical CAIs AVP Times DecreaseRetinal capillary velocity Increase

Selective beta blockers End diastolic velocity Increase

Alpha agonists End diastolic velocity Neutral

Prostaglandins End diastolic velocity NeutralPOBF Increase (IOP dependent)

CAIs = carbonic anhydrase inhibitorsAdapted from Nicolela MT et al Am J Ophthalmol 1996;122(6):784-789; Harris A et al J Ocul Pharmacol Ther 1999;15(3):189-197;Harris A et al Ophthalmology 2000;107(3):430-434; Harris A et al Acta Ophthalmol Scand 1996;74:569-572; Harris A et al Am J Ophthalmol1995;120:168-175; Lachkar Y et al Arch Ophthalmol 1998;116:1591-1594.

Topical CAIs:Inhibition of Carbonic Anhydrase

Dorzolamide

More carbon dioxide

vasodilation

Lessbicarbonate

CO2

HCO3

Adapted from Harris A, Jonescu-Cuypers CP Curr Opin Ophthalmol 2001;12:131-137.

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

NTG = normal-tension glaucoma

Adapted from Harris A et al J Ocul Pharmacol Ther 1999;15:189-197; Harris A et al Ophthalmology 2000;107;430-434; Harris A et al Acta Ophthalmol Scand 1996;74:569-572; Harris A et al Eur J Ophthalmol 2003;13:24-31.

Results of Recent Clinical Studies Suggest

Dorzolamide Improves AVP Times

*In the temporal inferior artery

Adapted from Harris A et al Am J Ophthalmol 2000;107(3):430-434.

0

5

10

15

20

IOP

(m

mH

g)

Dorzolamide

14

17

Betaxolol

2.0

2.2

2.4

2.6

2.8

AV

P T

imes

* (s

ec)

Dorzolamide

2.2

2.7

2.5

2.7

Betaxolol

14

17

(n=9)

Baseline

4 weeks of treatment

(n=9)

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

Adapted from Harris A et al Am J Ophthalmol 2000;107(3):430-434.

Results of Recent Clinical Studies Suggest

Dorzolamide and Dorzolamide-TimololCombination 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

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):189-197; Harris A et al Ophthalmology 2000;107(3):430-434; Harris A et al Am J Ophthalmol 2001;132:490-495; Schmidt K-G et al Br J Ophthalmol 1998;82(7):758-762.

Summary of CO•REGULATION™

The simultaneous and active alteration of two control systems within the eye in glaucoma

• Mechanical: Decreased IOP

• Vascular: Increased OBF

Adapted from Alward WLM Glaucoma: The Requisites in Ophthalmology. St. Louis: Mosby, 2000.

OBFIOP

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

CA=carbonic anhydrase

Adapted from Sharir M. In Textbook of Ocular Pharmacology. 1997:287-290; Shields MB Textbook of Glaucoma. 1998.

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™: 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

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

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

Dosage and Administration/How Supplied

Dosage and Administration

• One drop of COSOPT™ in the affected eye(s) twice daily

How Supplied

• Supplied in 5 ml OCUMETER™ PLUS dispensers

OCUMETERTM PLUS ophthalmic dispenser is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.

COSOPT™ in the Patient-Friendly OCUMETER™ PLUS Dispenser

Large capIs easy to openand close

Large bottleIs easy to hold,squeeze, and control

Color-coded capMakes it easy to identify medication

Transparent bottleMakes medicationlevel visible so patientknows when to refill

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

Data on file, MSD.

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**

*Schmidt K-G. Br J Ophthalmol 1998; 82(7):758-762.**Martinez A. Invest Ophthalmol Vis Sci 1999;40(6):1270-1275.

References

Please refer to note page.

References (cont’d)

Please refer to note page.

Comprehensive Glaucoma Management with COSOPT™

Copyright © 2003 Merck & Co., Inc., Whitehouse Station, NJ, USA.

All rights reserved. 5-04 CST 2003-W-6191-SS Printed in USA

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slide 1 comprehensive glaucoma management with cosopt ™ cosopt (dorzolamide hci-timolol maleate...

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