Medical Treatment For Glaucoma

MEDICAL TREATMENT
Medical treatment
I.
II.
III.
IV.
V.
VI.
Optimising medical treatment

Medical treatment algorithm
Various drug classes
Clinical trials
Preservatives
Key points
Medical treatment of glaucoma
Effective for the majority of patients

Generally acceptable therapeutic index
Mostly acceptable to patients
Widely available
SEAGIG. Asia Pacific Glaucoma Guidelines. 20032004.
Optimising medical treatment

Choose the most appropriate medication
Most likely to reach IOP target

Best safety profile
Minimal inconvenience
Affordable
Start with monotherapy wherever possible

Begin low and slow
Minimise concentration and frequency
Optimising medical treatment:

one-eyed therapeutic trial*
Start treatment in the worse eye

Check the IOP response after 24 weeks
Assess side-effects
If treatment is acceptable and effective, treat
both eyes
* Where appropriate

inadequate response
If the response to a one-eyed therapeutic trial
is inadequate, switch before adding
Perform another one-eyed therapeutic trial
Use more than one agent only if each has

demonstrated efficacy but is insufficient to
reach the IOP target
This principle also applies to fixed combinations

maximise adherence
Strategies to maximise adherence
Establish a therapeutic alliance with the
patient and family
Emphasise patient and family education
Aim to simplify therapy
Use the least complex regimen
Use a regimen that will minimise disruption of
the patients lifestyle

drop instillation
Teach the technique of drop instillation
Demonstrate the double DOT technique
Digital Occlusion Technique, Dont Open Technique
Punctal occlusion and eyelid closure for at least
3 minutes
Ensure the patient can perform the technique

If two or more drops are instilled, wait at least
5 minutes between drops
Provide educational material
Instilling drops at the same time each day

may improve adherence
Medical treatment algorithm (1)

Ineffective
Discard
Drug 2
No
Maximise adherence
Partial effectiveness/
side-effects
Drug 1
Stop hold in reserve
Maximise adherence
Reaches target?
No or tolerable
side-effects?
Reaches target?
No or tolerable side-effects?
Yes
Continue and
monitor treatment
Yes
No
Drug 3 or more
(if appropriate)
Maximise adherence
Medical treatment algorithm (2)

Ineffective
Discard
Combine any partially

effective and
tolerated drugs
No
Drug 3 or more
(if appropriate)
Partial effectiveness/
side-effects
Maximise adherence
Reaches target?
No or tolerable
side-effects?
Maximise adherence
Stop hold in reserve
Reaches target?
No or tolerable side-effects?
Yes
Yes
Continue and
monitor treatment
No
Laser or surgery
Mechanism of action of
various drug classes (1)
Mechanism
of action
Drug class
Preparations
Adrenergic agonists
Brimonidine, apraclonidine
Adrenergic agents
Epinephrine, phenylephrine
Non-selective
Beta-blockers
Reduction of
aqueous inflow
Timolol, levobunolol, carteolol

Beta-1 selective
Betaxolol
Systemic
Acetazolamide, methazolamide,
Carbonic anhydrase inhibitors dichlorphenamide
(CAIs)
Topical
Dorzolamide, brinzolamide
Mechanism of action of
Mechanism
of action
Increase in
aqueous outflow
Drug class
Preparations
Adrenergic agonists
Brimonidine
Cholinergics
Increase trabecular outflow
Pilocarpine
Carbachol
Prostaglandins and other

lipid receptor agonists
Increase uveoscleral outflow
Latanoprost
Travoprost
Bimatoprost
Unoprostone
Efficacy, safety and dosing

frequency of various drug classes
Drug class
Daily dosage
Efficacy
Adrenergic agonists
23
Beta-blockers
Side-effects
Local
Systemic
++ to +++
++
+ to ++
1 2
+++
+ to +++
CAIs
Topical
Systemic
23
24
++
++++
++
0
0 to ++
++ to ++++
Cholinergics
34
+++
++++
0 to ++
Stat dose(s)
+++++
++ to +++++
++++
+ to ++
2
1
2
2
+++ to ++++
++
+ to ++
++++
+ to +++
+ to +++
+ to +++
Hyperosmotic agents
Prostaglandins and other lipid
receptor agonists*
Proprietary fixed combinations
Beta-blockers + CAI
Beta-blockers + prostaglandins
Beta-blockers + pilocarpine
Beta-blockers + alpha agonists
*Excludes unoprostone
++++ to +++++
++++
Contraindications for
Adrenergic agonists
Monoamine oxidase inhibitor therapy

Age < 2 years
Beta-blockers
(non-selective)
Absolutely contraindicated in bronchial

asthma, chronic obstructive pulmonary
disease (COPD), bradycardia, heart
block
Use cautiously in cardiac failure
Beta-blockers
(selective)
Relatively contraindicated in bronchial

asthma, COPD, pulmonary disease,
bradycardia, heart block, cardiac failure
CAIs
(topical)
CAIs
(systemic)
Cholinergics
Relatively contraindicated with

compromised corneal endothelium,
sulphonamide allergy
Sulphonamide allergy, kidney stones or
failure, respiratory or metabolic acidosis,
hypokalaemia
Uveitic, neovascular and lens-induced
glaucomas
Post-drainage surgery
Aqueous misdirection syndrome
Hyperosmotic agents
Heart failure, pulmonary oedema, renal

failure
Caution with hypertension
Prostaglandins and
other lipid receptor
agonists
Relatively contraindicated in the

presence of active inflammatory ocular
conditions, cystoid macular oedema
Caution following complicated
intraocular surgery
Proprietary fixed
combinations
As for individual components
Clinical trials
Pivotal phase III trials for US Food and Drug
Administration (FDA) drug approval
All new IOP-lowering drugs must be compared
with timolol in at least two independent studies
These are large, multicentre, randomised,
double-masked trials sponsored by
pharmaceutical companies and designed
in conjunction with the FDA
High-quality evidence
Pivotal trial results:

timolol versus CAIs14
Timolol consistently demonstrates
greater efficacy than topical CAIs
(mean 0.8 mmHg)
Dorzolamide and brinzolamide are less
effective than timolol at both peak and
trough effect
1. Heijl A et al. Ophthalmology 1997; 104: 13741; 2. March WF et al. Am J Ophthalmol 2000; 129: 13643;
3. Silver LH. Am J Ophthalmol 1998; 126: 400408; 4. Strahlman E et al. Arch Ophthalmol 1995: 113: 100916.
Pivotal trial results:

fixed combination versus timolol15
Fixed-combination timolol/dorzolamide
produces a greater IOP reduction than
timolol alone
The magnitude of the difference in IOP
reduction ranged from 0.5 to 1.3 mmHg
across four trials
1. Boyle JE et al. Ophthalmology 1998; 105: 194551; 2. Clineschmidt CM et al. Ophthalmology 1998: 105: 19529;
3. Data in FDA summary basis of drug approval; 4. Hutzelmann J et al. Br J Ophthalmol 1998; 82: 124953;
5. Strohmaier K et al. Ophthalmology 1998: 105: 193644.
Pivotal trial results: prostaglandin

analogues versus timolol
Prostaglandin analogues
Bimatoprost, latanoprost and travoprost
Once-daily administration
Each reduces IOP more than timolol1
Unoprostone
Twice-daily administration
Less effective than timolol in reducing IOP2
1. Data in FDA summary basis of drug approval;

2. Nordmann JP et al. Am J Ophthalmol 2002; 133: 110.
.
Currently approved medications with

greater IOP-lowering efficacy than timolol (1)
Difference in mean IOP

(latanoprosttimolol; mmHg)
Latanoprost trials
0
-1
-2
-3
Data in FDA summary basis of drug approval.


(bimatoprosttimolol; mmHg)
Bimatoprost trials
0
-1
-2
-3

Travoprost trials
(travoprosttimolol; mmHg)
-1
-2
-3


(timolol/dorzolamidetimolol; mmHg)
Timolol/dorzolamide trials
0
-1
-2
-3
Brimonidine/timolol trial
IOP-lowering efficacy of fixed-combination
brimonidine/timolol versus each drug as monotherapy
Mean decrease from

baseline IOP
Fixed-combination 4.97.6 mmHg
brimonidine/timolol
Brimonidine
3.15.5 mmHg
Timolol
4.36.2 mmHg
Craven ER et al. J Ocul Pharmacol Ther 2005: 21: 33748.
Interaction between systemic medication

and topical glaucoma therapy
Timolol 0.5%
mmHg
Peak
Brimonidine 0.2%
Trough
-1
-1
-2
-2
-3
-3
-4
-4
-5
-6
Peak
Trough
-5
-6
-7
-7
-8
-8
No systemic beta-blockers
Systemic beta-blockers
*In the timolol-treated group, patients concurrently on systemic beta-blockers

had significantly less IOP lowering than those on timolol alone (p < 0.001).
Schuman JS. Ophthalmology 2000; 107: 11717.
Superiority of prostaglandin
analogues to other drug classes
The most effective IOP-lowering monotherapy
is a once-daily prostaglandin analogue
Bimatoprost, latanoprost, or travoprost
What is the evidence that one is more

effective than the others?
Six prospective, randomised, investigator-masked
trials directly comparing these agents have been
published
Trials varied in duration, patient characteristics,
and methods of data analysis
Latanoprost versus travoprost

Two reported clinical comparison
studies in patients with elevated IOP
1-year study1
Netland PA et al., 2001 (Alcon)
LAT n = 200, TRAV n = 196
12-week study2
Parrish RK et al., 2003 (Pharmacia)
BIM n = 136, LAT n = 136, TRAV n = 138
BIM, bimatoprost; LAT, latanoprost; TRAV, travoprost
1. Netland PA et al. Am J Ophthalmol 2001; 132: 47284;
2. Parrish RK et al. Am J Ophthalmol 2003; 135: 688703.
Latanoprost versus travoprost:

evidence of similar efficacy1,2
In both studies, neither latanoprost nor travoprost
provided consistently greater IOP lowering than the
comparator drug
No significant differences between drugs after week 2
Mean IOP reduction

SEM
Time at week 12
-4.5
8 AM
12 PM
4 PM
8 PM
-5.5
-6.5
-7.5
-8.5
-9.5
Travoprost
Latanoprost
1. Netland PA et al. Am J Ophthalmol 2001; 132: 47284;
2. Parrish RK et al. Am J Ophthalmol 2003; 135: 688703.
Bimatoprost versus latanoprost

Four reported comparative trials in patients with elevated IOP
1-month study1
DuBiner H et al., 2001 (Allergan)
BIM n = 21, LAT n = 22, vehicle n = 21
Results from other two treatment arms not reported
3-month study2
Gandolfi S et al., 2001 (Allergan)
BIM n = 119, LAT n = 113
12-week study3
BIM n = 136, LAT n = 136, TRAV n = 138
6-month study4
Noecker RS et al., 2003 (Allergan)
BIM n = 133, LAT n = 136
1. DuBiner H et al. Surv Ophthalmol 2001; 45: S35360; 2. Gandolfi S et al. Adv Ther 2001; 18: 11021;
3. Parrish RK et al. Am J Ophthalmol 2003; 135: 688703. 4. Noecker RS et al. Am J Ophthalmol 2003; 135: 5563.
Bimatoprost versus latanoprost:

1-month study
Baseline
mean IOP
(mmHg)
Day 29
mean reduction
in IOP (mmHg)
Day 29
mean IOP
reduction (%)
BIM
LAT
BIM
LAT
BIM
LAT
8 AM
25.6
25.2
8.0
7.6
30.9%
30.0%
12 PM
24.8
22.9
7.5
5.5
30.1%
23.1%
4 PM
24.1
22.0
6.5
4.4
26.3%
19.8%
8 PM
22.7
21.4
5.9
4.5
25.4%
19.8%
Baseline differences complicate interpretation of results

Consistently larger IOP reductions with bimatoprost
Results not statistically significant (low power)
DuBiner H et al. Surv Ophthalmol 2001; 45: S35360.

3-month study
26
Mean IOP
24
Latanoprost baseline
22
Bimatoprost baseline
Latanoprost month 3
20
Bimatoprost month 3
18
16
8 AM
12 PM
4 PM
*P .040 vs latanoprost
8 PM
Time
Baseline differences not statistically significant

Mean IOP significantly lower with bimatoprost than latanoprost,
by up to 1.0 mmHg at 12 PM and 4 PM
Gandolfi S et al. Adv Ther 2001; 18: 11021.

12-week study
Mean IOP reduction
+ SEM
Time at week 12
-4.5
8 AM
12 PM
4 PM
8 PM
-5.5
-6.5
-7.5
-8.5
-9.5
Latanoprost
Bimatoprost
Study population: previously treated patients (approximately

50% on latanoprost at screening)
Between-group differences not statistically significant;
consistently lower mean IOP with bimatoprost
Parrish RK et al. Am J Ophthalmol 2003; 135: 688703.

6-month study
0
Week 1
Month 1
Month 3
Month 6
8 AM 12 PM 4 PM
8 AM 12 PM 4 PM
8 AM 12 PM 4 PM
8 AM 12 PM 4 PM
Mean change from

baseline IOP + SEM
-1
-2
-3
-4
-5
-6
-7
-8
-9
*
*
*
Bimatoprost
* p 0.025 versus latanoprost
Latanoprost
Differences between groups ranged from 0.9 to 2.2 mmHg

All differences statistically significant in favour of bimatoprost
Noecker RS et al. Am J Ophthalmol 2003; 135: 5563.
Bimatoprost lowers IOP at least

as effectively as latanoprost
Four published head-to-head trials14;
IOP reported at 30 follow-up
measurements
Two studies (Gandolfi S et al. and
Noecker RS et al.) show superiority of
bimatoprost to latanoprost2,3
One review (Cantor) shows superiority
of bimatoprost over latanoprost5
1. DuBiner H et al. Surv Ophthalmol 2001; 45: S35360; 2. Gandolfi S et al. Adv Ther 2001; 18: 11021;
3. Noecker RS et al. Am J Ophthalmol 2003; 135: 55 63; 4. Parrish RK et al. Am J Ophthalmol 2003; 135: 688703;
5. Cantor LB. Expert Opin Pharmacother 2002; 3: 175362.
Bimatoprost and latanoprost:

safety and tolerability
Bimatoprost and latanoprost were safe and well
tolerated in all of the trials
Similar adverse event profile
Common adverse events: iris and blepharal pigmentation,
eyelash growth, conjunctival hyperaemia
Conjunctival hyperaemia may be more marked with

bimatoprost and travoprost than latanoprost
Not associated with inflammation or sequelae
Low rates of patient discontinuations for adverse

events with each drug
Higginbotham EJ et al. Arch Ophthalmol 2002; 120: 128693.
Bimatoprost versus travoprost

Four comparative studies in patients with elevated IOP
12-week study1
BIM n = 136, LAT n = 136, TRAV n = 138
6-month pilot study2

Cantor LB et al., 2004 (Allergan)
BIM n = 14, TRAV n = 12
6-month confirmatory study3

Cantor LB et al., 2006
BIM n = 76, TRAV n = 81
3-month study in black patient population4

Noecker RJ et al., 2003 (Allergan)
BIM n = 16, TRAV n = 15
1. Parrish RK et al. Am J Ophthalmol 2003; 135: 688703; 2. Cantor LB et al. Surv Ophthalmol 2004; 49 (Suppl 1): S128;
3. Cantor LB et al. Br J Ophthalmol 2006; 90: 13703; 4. Noecker RJ et al. Adv Ther 2003; 20: 1218.
Bimatoprost versus travoprost:

12-week study
Bimatoprost provided larger mean IOP reductions and
lower mean IOP than travoprost
Mean IOP reduction at week 12
Mean IOP reduction +
SEM
Time at Week 12
-4.5
8 AM
12 PM
4 PM
8 PM
-5.5
-6.5
-7.5
-8.5
Travoprost (n = 138)
-9.5
Bimatoprost (n =137)
Parrish RK et al. Am J Ophthalmol 2003; 135: 688703.

6-month pilot study
Baseline mean IOP was comparable between treatment groups
Bimatoprost provided larger mean IOP reductions at each timepoint
Differences not statistically significant, probably due to small sample size
Mean change over 6 months
Mean IOP change from

baseline (mmHg)
Week 1 Month 1 Month 3 Month 3
0
-1
9 AM
9 AM
9 AM
1 PM
Month 3 Month 6 Month 6 Month 6
4 PM
9 AM
1 PM
4 PM
-2
-3
-4
-5
-6
-7
-8
-9
-10
-4.5
-4.6
-4.9
-6.0
-7.6
-8.8
-6.9
-7.1
-8.4
-7.3
-6.9
-7.2
-7.4
-7.7
-8.8
-8.9
Bimatoprost (n = 14)
Travoprost (n = 12)
Cantor LB et al. Surv Ophthalmol 2004; 49 (Suppl 1): S128.

6-month confirmatory study
Baseline mean IOP was comparable between treatment groups
Bimatoprost provided larger mean IOP reductions at 6 months
Statistically significant difference at 9 AM
Mean change at 6 months

9 AM
1 PM
4 PM
Mean IOP change from

baseline (mm Hg)
0
-1
-2
-3
-4
-4.5
-5
-6
-5.7
-7
-8
-5.2
-5.3
-5.9
-7.1
* p = 0.014 versus travoprost
Travoprost (n = 81)
Cantor LB et al. Br J Ophthalmol 2006; 90: 13703.

3-month pilot study in black patients
Baseline mean IOP was 1 mmHg higher in the
travoprost group than in the bimatoprost
group (26.5 versus 25.5 mmHg)
Mean IOP reduction from baseline at month 3:
8.4 mmHg (33.7%) with bimatoprost
7.9 mmHg (30.0%) with travoprost
At final study visit, mean IOP reduction was

larger with bimatoprost, despite the 1.0 mmHg
lower baseline IOP
Noecker RJ et al. Adv Ther 2003; 20: 1218.

3-month pilot study in black patients
Neither study drug consistently provided
larger mean IOP reductions in a 3-month pilot
study in black patients
These preliminary results suggest that
bimatoprost is at least as effective as
travoprost in black patients; further study
is needed
Sample sizes too small for statistical
significance
Noecker RJ et al. Adv Ther 2003; 20: 1218.

evidence suggests greater IOP reductions
with bimatoprost
Bimatoprost consistently provided larger mean
IOP reductions than travoprost
In the 12-week study1, the difference between drugs
was 0.93 mmHg
Statistically significant in favour of bimatoprost in the
per-protocol population
In the 6-month pilot study2, differences favoured

bimatoprost at all follow-up measurements
In the 6-month confirmatory study3, the differences
ranged from 0.8 to 1.4 mmHg in favour of bimatoprost
at month 6
Statistically significant in favour of bimatoprost at 9 AM
1. Parrish RK et al. Am J Ophthalmol 2003; 135: 688703; 2. Cantor LB et al. Surv Ophthalmol 2004; 49 (Suppl 1): S128;
3. Cantor LB et al. Br J Ophthalmol 2006; 90: 13703.
Bimatoprost versus fixed-combination

timolol/dorzolamide
Bimatoprost provided significantly greater diurnal IOP control
than fixed-combination timolol/dorzolamide
Difference between groups up to 1.5 mmHg at month 3
Significantly higher percentages of bimatoprost patients

achieved low target IOPs than timolol/dorzolamide patients
Diurnal mean IOP at month 3
*p 0.038
20
19
Timolol/dorzolamide
18 *
17
Bimatoprost
16
Percentage of patients
Bimatoprost
Timolol/dorzolamide (n = 87)
21
Mean IOP (mm Hg)
Target pressure
80
51%
50%
40
**
**
17%
**
41%
39%
**
31%
64%
61%
**p < 0.008
60
20
76%
Timolol/dorzolamide
29%
24%
14%
8%
9%
0%
2%
0
8 AM
12 PM
4 PM
Time of day at month 3
8 PM
13
14
15
16
17
18
19
20
Target IOP (mmHg)
Coleman AL et al. Ophthalmology 2003; 110: 23628.
Weight of the evidence:

efficacy of bimatoprost18
Bimatoprost has consistently lowered IOP
more effectively than comparator drugs
41 study visits, over 90 timepoints,
nearly 3000 patients
On a population basis, over multiple studies,
bimatoprost has shown IOP-lowering efficacy
equal or superior to latanoprost, travoprost,
and fixed-combination timolol/dorzolamide
1. DuBiner H et al. Surv Ophthalmol 2001; 45 (Suppl 4): S35360; 2. Gandolfi S et al. Adv Ther 2001; 18: 11021;
3. Noecker RS et al. Am J Ophthalmol 2003; 135: 5563; 4. Parrish RK et al. Am J Ophthalmol 2003; 135: 688703;
5. Cantor LB et al. Surv Ophthalmol 2004; 49 (Suppl 1): S128; 6. Cantor LB et al. Br J Ophthalmol 2006; 90: 13703;
7. Noecker RJ et al. Adv Ther 2003; 20: 121 8; 8. Coleman AL et al. Ophthalmology 2003; 110: 23628.
Efficacy of bimatoprost: comparison of

studies mean percentage IOP reduction
40%
35%
30%
30%
32%
33%
34%
34%
35%
Reduction in
mean IOP (%)
30%
25%
20%
15%
10%
5%
0%
Noecker, 2003Higginbotham, 2002Gandolfi, 2001 Sherwood, 2001 Parrish, 2003
(n = 133)
(n = 474)
(n = 119)
(n = 474)
(n = 136)
DuBiner, 2001
(n = 21)
Brandt, 2001
(n = 234)
ec
r,
ki,
ke
zu
20
01
03
20
(n
=1
=1
(n
24
)
25%
36
)
Au
ng
,2
00
1(
n=
Su
56
sa
)
nn
a,
20
01
(n
Ga
=5
4)
nd
olf
i, 2
00
1(
n=
Du
11
3)
Bi
ne
r,
20
01
(n
=2
Ja
2)
mp
el,
20
02
He
(n
=8
dm
4)
an
,2
00
0(
n=
Pa
46
rri
0)
sh
,2
00
3(
n
=1
36
)
No
Su
Reduction in mean IOP (%)
Efficacy of latanoprost: comparison of

studies mean percentage IOP reduction
40%
35%
30%
27%
23%
28%
30%
30%
31%
32%
34%
24%
20%
15%
10%
5%
0%
IOP
(mean + SEM, mmHg)
Circadian IOP on day 2829

Timolol maleate
Timoptic
XE
Latanoprost
Xalatan
Lumigan
Bimatoprost
20
18
*
*
16
14
12
*
8 AM
12
*
PM
*
PM
Day 28
PM
12
AM
AM
AM
Day 29
Time
* p < 0.037 versus timolol maleate
In the overall analysis, bimatoprost patients had significantly lower IOP

than patients on timolol maleate gel-forming solution (up to 2.9 mmHg)
or latanoprost (up to 1.4 mmHg) (p = 0.003)
Walters TR et al. Surv Ophthalmol 2004; 49 (Suppl 1): S2635.
0%
Latanoprost
Bimatoprost
Travoprost
DuBiner, 2004 (n=16)
Parrish, 2003 (n=138)
Goldberg, 2001 (n=190)
Noecker, 2003b (n=15)
Cantor, 2004 (n=12)
Netland, 2001 (n=197)
Netland, 2003 (n=787)
36%
34%34%
32%32%
30%30%31%
Fellman, 2002 (n=197)
39%
Walters, 2004 (n=38)
Cantor, 2004 (n=14)
Noecker, 2003b (n=16)
Parrish, 2003 (n=136)
Sherwood, 2001 (n=474)
Gandolfi, 2001 (n=119)
Noecker, 2003a (n=133)
33%34%
35%
32%32%
30%30%30%31%
28%28%
30%
27%27%
24%
25% 23%
Coleman, 2003 (n=90)
40%
Dubiner, 2004 (n=18)
Parrish, 2003 (n=136)
Kontas, 2004 (n=51)
Walters, 2004 (n=38)
Hedman, 2000 (n=460)
Jampel, 2002 (n=84)
Stewart, 2001 (n=33)
Gandolfi, 2001 (n=113)
Netland, 2001 (n=193)
Susanna, 2001 (n=54)
Aung, 2001 (n=56)
Mishima, 1996 (n=89)
Noecker, 2003a (n=136)
Suzuki, 2001 (n=124)
% IOP reduction
Efficacy of prostaglandin analogues: mean

percentage IOP reduction across studies
45%
39%
36%
30%31%31%
28%29%
26%26%
20%
15%
10%
5%
Efficacy in clinical experience

Data from large clinical trials are presented
as aggregate data
Means are calculated across a large
population
These calculations do not demonstrate
the response of individual patients to
IOP-lowering medications
Some patients reached much lower IOP
targets, as seen in the data ranges
Changing medical treatment

patterns in glaucoma
Improved IOP-lowering efficacy is the primary reason
that latanoprost has replaced timolol as the preferred
treatment for elevated IOP in glaucoma in many
practices
Latanoprost is approved for first-line use in many
countries and is the most prescribed medication for
reducing IOP
On average, the difference in IOP lowering between
latanoprost and timolol is only about 1 mmHg;
in clinical practice, the difference for any individual
patient may be much greater than 1 mmHg
Pivotal trials:
latanoprost versus timolol
Mean IOP reduction
+ SEM (mmHg)
Latanoprost
Timolol
0
2
4
6
8
10
7.7
(31%)
6.5
(26%)
1.2 mmHg
Difference = 0.9 mmHg
in previously untreated
patients
A difference in IOP of only about 1 mmHg has some practical

consequences. The odds of reaching a specific target IOP were
about twice as high with latanoprost as with timolol.
Hedman K, Alm A. Eur J Ophthalmol 2000; 10: 95104.
Switching within class:

prostaglandin analogues
Switching to another prostaglandin analogue
may be useful if target IOP is not achieved
Need to consider adherence and regression to the
mean
Some studies of bimatoprost and latanoprost

showed a mean 1 mmHg difference favouring
bimatoprost
In clinical practice, the difference for any individual
patient may be much greater
SEAGIG. Asia Pacific Glaucoma Guidelines. 20032004;
Gandolfi S et al. Adv Ther 2001; 18: 11021; Noecker RS et al. Am J Ophthalmol 2003; 135: 5563.
IOP-lowering effects of
common glaucoma drugs
A meta-analysis of randomised clinical
trials of frequently prescribed glaucoma
drugs concluded that:
bimatoprost, latanoprost and travoprost are
the most effective IOP-reducing agents in
patients with primary open-angle glaucoma
(POAG) or ocular hypertension (OHT)
timolol is nearly as effective as the
prostamide or prostaglandin analogues
van der Valk R et al. Ophthalmology 2005; 112: 117785
Meta-analysis: relative IOP

reduction after 1 month
Mean % change
(95% CI)
Peak
n = 6861
Trough
n = 6953
Betaxolol
23 (25 to 22)
20 (23 to 17)
Timolol
27 (29 to 25)
26 (28 to 25)
Bimatoprost
33 (35 to 31)
28 (29 to 27)
Latanoprost
31 (33 to 29)
28 (30 to 26)
Travoprost
31 (32 to 29)
29 (32 to 25)
Brimonidine
25 (28 to 22)
18 (21 to 14)
Dorzolamide
22 (24 to 20)
17 (19 to 15)
Brinzolamide
17 (19 to 15)
17 (19 to 15)
van der Valk R et al. Ophthalmology 2005; 112: 117785
Role of preservatives
To inhibit the growth and multiplication
of micro-organisms
Prevent ocular infections
To prolong shelf life

Prevent biodegradation
Maintain drug potency
Types of preservatives
Oxidative preservatives
Smaller molecules penetrate cell membranes of
microbes and modify lipids, proteins and DNA
Examples: stabilised oxychloro complex (SOC),
sodium perborate
Detergent preservatives
Larger molecules lyse cell membranes of
microbes
May be cytotoxic to humans
Noecker R. Adv Ther 2001; 18: 20515.
BAK concentration in common

glaucoma drugs
Levobunolol
Brimonidine
Bimatoprost
Brimonidine/timolol fixed combination
Dorzolamide
Dorzolamide/timolol fixed combination
Timolol maleate
Betaxolol
Brinzolamide
Timolol maleate gel-forming solution
Unoprostone
Travoprost
Latanoprost
Latanoprost/timolol fixed combination
0.004 % BAK
0.005 % BAK
0.005 % BAK
0.005 % BAK
0.0075 % BAK
0.0075 % BAK
0.01 % BAK
0.01 % BAK
0.01 % BAK
0.012 % BDD
0.015 % BAK
0.015 % BAK
0.02 % BAK
0.02 % BAK
BAK, benzalkonium chloride; BDD, benzododecinium bromide
Stabilised oxychloro complex

Relatively new
Used in multi-dose artificial tears since 1997
Advanced preservative
Effective at low concentrations (0.005%)

Reduced potential for irritation
Well suited for long-term use
Degrades into sodium chloride and water
when exposed to light
Rozen S et al. Invest Ophthalmol Vis Sci 1998; 39: B343;
Way WA et al. Invest Ophthalmol Vis Sci 2001; 42: S39.
SOC: a less cytotoxic preservative

SEMs of rabbit corneal epithelium (800)
Untreated
SOC
QID 7 days
BAK
QID 7 days
Way WA et al. Invest Ophthalmol Vis Sci 2001; 42: S39.
Brimonidine with SOC

Active ingredient
Brimonidine tartrate 0.15% (1.5 mg/ml)
Selective alpha-2 adrenergic agonist
Preservative
SOC 0.005% (0.05 mg/ml)
Indicated for the reduction of elevated IOP in patients

with open-angle glaucoma or OHT
May also be used concomitantly with other IOP-lowering
medications
Efficacy equivalent to brimonidine 0.2%
Katz LJ. J Glaucoma 2002; 11: 11926.
Travoprost with ionic buffered

preservative
Active ingredient
Travoprost 0.004%
Prostaglandin analogue
Preservative
Ionic buffered preservative system
Indicated in the USA for the reduction of elevated

IOP in patients with open-angle glaucoma or OHT
who are:
intolerant of other IOP-lowering medications, or
insufficiently responsive to another IOP-lowering medication
Efficacy equivalent to travoprost 0.004% with BAK

Lewis RA et al. J Glaucoma. In press.
Glaucoma and pregnancy

No systematic studies of the safety
and efficacy of topical prostaglandin
analogues have been undertaken
in pregnancy
IOP usually falls during pregnancy, so in
some cases treatment can be altered
or discontinued
Key points
Prostaglandin analogues provide superior circadian
IOP control
US National Eye Institute (NEI) trials showed that
decreasing IOP resulted in a clinically significant
reduction in progression of visual field loss
A one-eyed trial can be used to determine the
patients response to therapy where appropriate
Use of monotherapy is preferred where possible
Additional points
Tachyphylaxis
Reverse therapeutic trials?
Treatments for secondary glaucoma
Neuroprotection when is it relevant?
Alternative therapies?
Future treatments?
Protective autoimmunity

Medical Treatment For Glaucoma

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Medical Treatment For Glaucoma

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MEDICAL TREATMENT

Optimising medical treatment

Medical treatment of glaucoma

Effective for the majority of patients

SEAGIG. Asia Pacific Glaucoma Guidelines. 20032004.

Optimising medical treatment

Most likely to reach IOP target

Start with monotherapy wherever possible

SEAGIG. Asia Pacific Glaucoma Guidelines. 20032004.

Optimising medical treatment:

Start treatment in the worse eye

Optimising medical treatment:

Use more than one agent only if each has

SEAGIG. Asia Pacific Glaucoma Guidelines. 20032004.

Optimising medical treatment:

SEAGIG. Asia Pacific Glaucoma Guidelines. 20032004.

Optimising medical treatment:

Ensure the patient can perform the technique

Instilling drops at the same time each day

Medical treatment algorithm (1)

Stop hold in reserve

Medical treatment algorithm (2)

Combine any partially

Stop hold in reserve

Timolol, levobunolol, carteolol

Prostaglandins and other

SEAGIG. Asia Pacific Glaucoma Guidelines. 20032004.

Efficacy, safety and dosing

SEAGIG. Asia Pacific Glaucoma Guidelines. 20032004.

Monoamine oxidase inhibitor therapy

Absolutely contraindicated in bronchial

Relatively contraindicated in bronchial

SEAGIG. Asia Pacific Glaucoma Guidelines. 20032004.

Relatively contraindicated with

SEAGIG. Asia Pacific Glaucoma Guidelines. 20032004.

Heart failure, pulmonary oedema, renal

Relatively contraindicated in the

As for individual components

SEAGIG. Asia Pacific Glaucoma Guidelines. 20032004.

Pivotal trial results:

Pivotal trial results:

Pivotal trial results: prostaglandin

1. Data in FDA summary basis of drug approval;

Currently approved medications with

Difference in mean IOP

Data in FDA summary basis of drug approval.

Currently approved medications with

Difference in mean IOP

Data in FDA summary basis of drug approval.

Currently approved medications with

Data in FDA summary basis of drug approval.

Currently approved medications with

Difference in mean IOP

Data in FDA summary basis of drug approval.

Mean decrease from

Interaction between systemic medication

*In the timolol-treated group, patients concurrently on systemic beta-blockers

What is the evidence that one is more

Latanoprost versus travoprost

Latanoprost versus travoprost:

Mean IOP reduction

Bimatoprost versus latanoprost

Bimatoprost versus latanoprost: