Transcript No Slide Title

Comprehensive Glaucoma
™
Management with COSOPT
COSOPT (dorzolamide HCI-timolol maleate ophthalmic solution) is a trademark
of Merck & Co., Inc., Whitehouse Station, NJ, USA.
Slide 1
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.
Slide 2
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
–
–
–
–
Myopia
Optic disc hemorrhages
Peripapillary atrophy
Diastolic and/or
perfusion pressure
• Atherosclerosis
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.
Slide 3
AGIS Demonstrated that Low IOP Is
Associated with Reduced Progression
of Visual-Field Defect*
Mean change in
visual-field defect score
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
1
0
–1
(N=586 eyes)
–2
0
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;130:429-440.
Slide 4
As Did OHTS...
25%
20%
25%
Treated (n=817)
Observation (n=819)
22.5
20%
15%
15%
53.7% differential
10%
10%
9.5
5%
5%
4.0
4.4
0%
% IOP reduction
(from baseline)
Cumulative probability of
developing POAG*
0%
*At month 60
OHTS=Ocular Hypertension Treatment Study; POAG=primary open-angle glaucoma
Adapted from Kass M et al Arch Ophthalmol 2002;120:701-713.
Slide 5
COSOPT™ Maintained IOP Reduction
up to 9 mmHg over 15 Months
IOP 2 hours after
administration (mmHg)
28
COSOPT (n=112)
dorzolamide 2% (n=109)
timolol 0.5% (n=110)
26
24
22
–9 mmHg
20
(p<0.05
vs.
baseline)
18
17
16
Open extension
Double blind
0
Week 1
2
2
3
6
Month
p<0.05 for all mean IOP values vs. baseline
Adapted from Boyle JE et al Ophthalmology 1998;105(10):1945-1951.
9
12
15
–34%
COSOPT (dorzolamide HCI-timolol maleate ophthalmic solution) is
a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.
Slide 6
In a Clinical Study
COSOPT™ Provided Powerful IOP Reduction
Mean change in diurnal IOP from
baseline (mmHg)
Equivalent Efficacy* of COSOPT vs. Latanoprost 0.005%
0
COSOPT (n=138)
Latanoprost (n=143)
–1
–2
–3
–4
–5
–6
–27.1%
–28.6%
–29.0%
–29.3%
–30.6%
–30.5%
Month 1
Month 2
Month 3
–7
–8
–9
Baseline = patients with
up to a three-week
washout period
*Differences were not statistically significant.
Randomized, observer-blind, parallel-group, three-month, multicenter study
Slide 7
COSOPT™ Provided Powerful
24-Hour IOP Control
18
COSOPT (n=33)
Latanoprost (n=33)
Mean IOP (mmHg)
17
16
15
14
13
12
11
10
0
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).
Slide 8
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
• Travoprost and bimatoprost IOP lowering
as reflected in respective product labels
aFixed
combination
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.
bIn
Slide 9
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).
Slide 10
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.
Slide 11
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
OBF
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.
Slide 12
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.
Slide 13
The IOP-Ocular Perfusion-Apoptosis
Relationship
Ocular
perfusion
IOP
Apoptosis
Adapted from Harris A Ophthalmol Times 1997;(Suppl 2):S1-S23.
Slide 14
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.
Slide 15
OBF Measurement Techniques
Technique
Measurement
Parameter
Location
Pros
Cons
Color Doppler
Imaging (CDI)
Blood velocity,
Calculated vascular
resistance
Retrobulbar vessels
User specified vessels
and location
Expensive
and complex
Scanning Laser
Ophthalmoscope (SLO)
angiography
Filling times, AVP,
capillary
velocities
Retinal, choroid
Highly sensitive to
circulation time change
Invasive,
expensive,
time-consuming
Heidelberg Retinal
Flowmetry (HRF)
Unitless flow,
blood velocity
Retinal capillary beds, Volumetric blood flow
Ocular nerve head
Unitless,
expensive,
difficult to
interpret
Pulsatile Ocular Blood
Flow (POBF)
IOP
Unknown, presume
to be choroidal
Measure IOP,
non-site specific
Inexpensive and easy
to use
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.
Slide 16
Can any medications improve
OBF independent of IOP?
Slide 17
Glaucoma Medications and OBF
Drug Class
Parameter
Effect
Topical CAIs
AVP Times
Retinal capillary velocity
Decrease
Increase
Selective beta blockers
End diastolic velocity
Increase
Alpha agonists
End diastolic velocity
Neutral
Prostaglandins
End diastolic velocity
POBF
Neutral
Increase (IOP dependent)
CAIs = carbonic anhydrase inhibitors
Adapted 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 Ophthalmol
1995;120:168-175; Lachkar Y et al Arch Ophthalmol 1998;116:1591-1594.
Slide 18
Topical CAIs:
Inhibition of Carbonic Anhydrase
Dorzolamide
CO2
More
carbon dioxide
vasodilation
HCO3
Less
bicarbonate
Adapted from Harris A, Jonescu-Cuypers CP Curr Opin Ophthalmol 2001;12:131-137.
Slide 19
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.
Slide 20
Results of Recent Clinical Studies Suggest
Dorzolamide Improves AVP Times
Baseline
4 weeks of treatment
2.8
20
(n=9)
17
17
14
14
10
5
AVP Times* (sec)
IOP (mmHg)
15
(n=9)
2.6
2.7
2.7
2.5
2.4
2.2
2.2
2.0
0
Dorzolamide
Betaxolol
Dorzolamide
Betaxolol
*In the temporal inferior artery
Adapted from Harris A et al Am J Ophthalmol 2000;107(3):430-434.
Slide 21
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.
Slide 22
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
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.
Slide 23
Summary of CO•REGULATION™
The simultaneous and active alteration of two control
systems within the eye in glaucoma
• Mechanical: Decreased IOP
• Vascular: Increased OBF
IOP
OBF
Adapted from Alward WLM Glaucoma: The Requisites in Ophthalmology. St. Louis: Mosby, 2000.
Slide 24
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.
Slide 25
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
Slide 26
COSOPT™: Contraindications
• Bronchial asthma or a history of bronchial asthma,
or severe chronic obstructive pulmonary disease
Source C
(WPC),
p 1, §IV
• Sinus bradycardia, second- or third-degree
atrioventricular block, overt cardiac failure,
or cardiogenic shock
• Hypersensitivity to any component of COSOPT
Slide 27
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
Slide 28
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
Slide 29
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.
Slide 30
COSOPT™ in the Patient-Friendly
OCUMETER™ PLUS Dispenser
Large cap
Is easy to open
and close
Large bottle
Is easy to hold,
squeeze, and
control
Color-coded cap
Makes it easy to
identify medication
Transparent bottle
Makes medication
level visible so patient
knows when to refill
Slide 31
Clinical Experience with COSOPT™
• In clinical practice
– Available in 55 countries
– Available for 5 years
– Proven therapy—more than 23.6 million patientmonths of treatment with COSOPT
Data on file, MSD.
Slide 32
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.
Slide 33
References
Please refer to note page.
Slide 34
References (cont’d)
Please refer to note page.
Slide 35
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
VISIT US ON THE WORLD WIDE WEB AT http://www.merck.com
Slide 36