Twelve-Month, Randomized, Controlled Trial of

Bimatoprost 0.01%, 0.0125%, and 0.03% in Patients

with Glaucoma or Ocular Hypertension
L. JAY KATZ, JOHN S. COHEN, AMY L. BATOOSINGH, CARLOS FELIX, VINCENT SHU, AND
RHETT M. SCHIFFMAN
PURPOSE:

To evaluate the intraocular pressure (IOP)lowering efficacy and safety of ophthalmic formulations
of bimatoprost 0.01% and 0.0125% compared with
bimatoprost 0.03%.
DESIGN: Prospective, randomized, double-masked, multicenter clinical trial.
METHODS: Patients with glaucoma or ocular hypertension were randomized to receive once-daily bimatoprost
0.01% (n 186), bimatoprost 0.0125% (n 188), or
bimatoprost 0.03% (n 187) for 12 months. The
primary efficacy measure was IOP. Safety measures
included adverse events and an objective assessment of
conjunctival hyperemia.
RESULTS: Baseline mean IOPs were similar among
treatment groups. Differences in mean IOP between the
bimatoprost 0.01% or 0.0125% groups and the bimatoprost 0.03% group were less than 0.9 mm Hg throughout
follow-up. Bimatoprost 0.01%, but not bimatoprost
0.0125%, was equivalent in efficacy to bimatoprost
0.03% based on predetermined criteria (limits of the
95% confidence interval of the between-group difference
in mean IOP within 1.5 mm Hg at all time points and
within 1 mm Hg at most time points). The overall
incidence of treatment-related adverse events was reduced significantly in the bimatoprost 0.01% and bimatoprost 0.0125% groups compared with the bimatoprost
0.03% group (P < .034). The percentage of patients
with a moderate to severe increase from the baseline
macroscopic hyperemia score was: bimatoprost 0.01%,
3.2%; bimatoprost 0.0125%, 9.0%; bimatoprost 0.03%,
9.1% (P .019 for bimatoprost 0.01% vs 0.03%).
CONCLUSIONS: Bimatoprost 0.01% was equivalent to
bimatoprost 0.03% in lowering IOP throughout 12
months of treatment and demonstrated improved tolerability, including less frequent and severe conjunctival
hyperemia. Bimatoprost 0.01% demonstrated a better
benefit-to-risk ratio than bimatoprost 0.0125%. (Am J

Accepted for publication Dec 1, 2009.

From the Wills Eye Hospital, Philadelphia, Pennsylvania (L.J.K.); the
Cincinnati Eye Institute, Cincinnati, Ohio (J.S.C.); and Allergan, Inc,
Irvine, California (A.L.B., C.F., V.S., R.M.S.).
Inquiries to L. Jay Katz, Glaucoma Service, Wills Eye Hospital, 840
Walnut Street, Suite 1110, Philadelphia, PA 19107; e-mail: ljk22222@
aol.com
0002-9394/10/$36.00
doi:10.1016/j.ajo.2009.12.003

2010 BY

Ophthalmol 2010;149:661 671. 2010 by Elsevier

Inc. All rights reserved.)

IMATOPROST IS A PROSTAMIDE THAT POTENTLY

lowers intraocular pressure (IOP).1 Since the introduction of bimatoprost 0.03% ophthalmic solution
(Lumigan; Allergan, Inc, Irvine, California, USA) in
2001, once-daily bimatoprost 0.03% has been demonstrated to be safe and effective in lowering IOP over the
long term in glaucoma and ocular hypertension (OHT).2 4
Evidence suggests that bimatoprost reduces IOP more
effectively than any other single medication available for
glaucoma management.111 In its pivotal trials for regulatory drug approval, once-daily bimatoprost 0.03% reduced
IOP by 2 to 3 mm Hg more than twice-daily timolol,2 and
in head-to-head comparison studies, bimatoprost provided
larger mean IOP reductions than the other once-daily
prostaglandin analogs, latanoprost6,7 and travoprost.10 Bimatoprost also has been shown to be effective in multipledrug therapy with other classes of ocular hypotensive
medications, including timolol.12,13
All of the prostaglandin analogs for the most part are
well tolerated.14 Side effects typically associated with
treatment include conjunctival hyperemia, increased eyelash length, increased iris pigmentation, and increased
periocular skin pigmentation.14 The most common side
effect is conjunctival hyperemia, which in some cases can
lead to noncompliance or discontinuation of treatment.
Bimatoprost 0.01% is a new formulation that was
developed with the goal of creating a formulation of
bimatoprost that would maintain the IOP-lowering efficacy achieved with bimatoprost 0.03% and have an improved overall safety profile, particularly improved ocular
surface tolerability. The strategy was to reduce the concentration of bimatoprost and increase the concentration
of benzalkonium chloride (BAK), a commonly used preservative that also can increase the corneal penetration15
and intraocular bioavailability of topically applied medication. In a phase 2 clinical study (Allergan Study 192024030), 4 investigational test formulations (bimatoprost
0.01%, bimatoprost 0.015% with edetate, bimatoprost
0.015%, and bimatoprost 0.02%) were compared with
bimatoprost 0.03% in patients with glaucoma or OHT.
The study was a 5-day, multicenter, double-masked, ac-

ELSEVIER INC. ALL

RIGHTS RESERVED.

661

tive-controlled, paired-eye comparison. The results suggested that bimatoprost 0.01% may have efficacy similar to
that of bimatoprost 0.03% and may be associated with less
ocular irritation and hyperemia, and further suggested that
the dose-response curve for tolerability of bimatoprost is
steep within this range of bimatoprost concentrations,
such that a slight reduction in bimatoprost concentration
from 0.015% may lead to significantly improved tolerability. These results led to the selection of bimatoprost 0.01%
and another test formulation, bimatoprost 0.0125%, for
further study.
The purpose of this study was to evaluate the IOPlowering efficacy and safety of bimatoprost 0.01% and
bimatoprost 0.0125% compared with bimatoprost 0.03%
in patients with glaucoma or OHT. This report focuses on
results for bimatoprost 0.01% and bimatoprost 0.03%
because these are the marketed formulations.

of a scheduled visit, respectively); ocular seasonal allergy

within the past 2 years; recent or anticipated alteration of
existing chronic systemic treatment that could affect IOP,
study medications, or study outcomes; any condition or
situation of the patient which, in the investigators opinion, could put the patient at a significant risk, could
confound study results, or could interfere significantly with
the patients participation in the study; history of inadequate IOP control while receiving bimatoprost monotherapy; and allergy or hypersensitivity to bimatoprost or
any component of the study medications. Patients who
were pregnant or nursing or who could become pregnant
also were excluded from the study.
At a screening visit, patients using ocular hypotensive
medications began a washout period of 4 days for parasympathomimetics and carbonic anhydrase inhibitors, 2 weeks
for sympathomimetics and -agonists, 4 weeks for -adrenergic antagonists and the fixed combination of timolol
and dorzolamide, and 6 weeks for prostaglandin analogs.

METHODS

PATIENT RANDOMIZATION AND STUDY TREATMENT:

At
baseline (day 0), at least 2 days after the screening visit,
patients who met all eligibility criteria were stratified into 6
groups based on IOP ( 25 mm Hg or 25 mm Hg) and
central corneal thickness ( 555 m, 555 to 600 m, or 600
m) averaged from both eyes. Patients within each stratum were randomized using a computer-generated randomization schedule in a 1:1:1 ratio to treatment with an
ophthalmic formulation of bimatoprost 0.01%, bimatoprost 0.0125%, or bimatoprost 0.03% (Lumigan 0.03%;
Allergan, Inc, Irvine, California, USA) for 12 months.
The formulations were physically indistinguishable and
differed only in the concentration of bimatoprost (0.01%,
0.0125%, and 0.03%) and BAK (0.02% in bimatoprost
0.01% and bimatoprost 0.0125% and 0.005% in bimatoprost 0.03%).
Medications were supplied in identical masked bottles.
Patients were instructed to instill study medication (1 drop
in each eye) each evening between 7 PM and 9 PM for the
duration of the study. The first dose of study medication
was instilled on day 0 after all baseline diurnal IOP
measurements were completed. Follow-up visits were
scheduled at weeks 2 and 6 and months 3, 6, 9, and 12.

STUDY DESIGN:

This prospective, randomized, multicenter (32 sites in the United States), double-masked,
parallel-group, phase 3 study compared bimatoprost 0.01%,
bimatoprost 0.0125%, and bimatoprost 0.03% in patients
with glaucoma or OHT. The investigators and sites that
took part in the study are listed in the Acknowledgments.
The study was conducted in accordance with applicable
Good Clinical Practice regulations and guidelines.
STUDY POPULATION:

Eligible patients were at least 18

years of age with a diagnosis of OHT, primary open-angle
glaucoma, chronic angle-closure glaucoma with patent
iridotomy or iridectomy, pseudoexfoliative glaucoma, or
pigmentary glaucoma in each eye. Patients were required
to have an 8 AM baseline IOP of 22 to 34 mm Hg or less in
each eye with asymmetry between eyes of no more than 5
mm Hg after washout of previous IOP-lowering medications. Best-corrected visual acuity equivalent to a Snellen
score of 20/100 or better in each eye also was required for
study entry.
Patients with functionally significant or progressive
visual field loss during the previous year; laser, intraocular,
or filtering surgery within the past 3 months; refractive
surgery at any time; or conditions that would interfere with
study measurements or interpretation of study data were
excluded from the study. Other exclusion criteria included:
clinically significant ocular surface findings at baseline
such as mild or greater hyperemia or irritation; uncontrolled systemic disease; anticipated use of contact lenses
during the study; intermittent use of systemic corticosteroids within the 21 days before any study visit; anticipated
use of topical ophthalmic corticosteroids during the study;
chronic use of ocular medications other than the study
medications (intermittent use of artificial tears and antihistamines was allowed, but not within 24 hours or 2 weeks
662

AMERICAN JOURNAL

OUTCOME MEASURES: The primary efficacy outcome

measures were mean IOP and mean change from baseline
IOP at each follow-up time point. Secondary efficacy
measures included diurnal IOP and response rate (percentage of patients achieving at least a 20% decrease from
baseline IOP). Intraocular pressure was measured using a
calibrated Goldmann applanation tonometer and a 2-person reading method16 at 8 AM, 12 PM, and 4 PM on all study
visits except month 9, when IOP was measured at 8 AM and
12 PM only. IOP was measured at least twice in each eye,
and if the difference between the first and second reading
was more than 2 mm Hg, a third reading was obtained. IOP
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TABLE 1. Demographics and Clinical Characteristics of Patients at Baseline in the 12-Month, Randomized, Controlled Study
Comparing Bimatoprost 0.01%, 0.0125%, and 0.03% in Patients with Glaucoma or Ocular Hypertension
Bimatoprost
0.01% (n 186)

Characteristics

Age (yrs)
Mean (SD)
Sex, n (%)
Male
Female
Race or ethnicity, n (%)
White
Black
Hispanic
Other
Iris color, n (%)
Brown
Dark brown
Blue
Hazel
Green
Blue/gray
Blue/gray-brown
Green-brown
Other
Diagnosis, n (%)
Glaucoma
Ocular hypertension
One eye each
Washout medication, n (%)e
No
Yes
Prostamide (bimatoprost)
Prostaglandin
-agonist
-blocker
Carbonic anhydrase inhibitor
Fixed-combination dorzolamide/timolol
Parasympathomimetic
Other
Central corneal thickness (m)
Mean (SD)

Bimatoprost
0.0125% (n 188)

Bimatoprost
0.03% (n 187)

64.7 (10.9)

64.2 (11.6)

79 (42.5%)
107 (57.5%)

72 (38.3%)
116 (61.7%)

89 (47.6%)
98 (52.4%)

130 (69.9%)
28 (15.1%)
25 (13.4%)
3 (1.6%)

141 (75.0%)
25 (13.3%)
17 (9.0%)
5 (2.7%)

138 (73.8%)
23 (12.3%)
23 (12.3%)
3 (1.6%)

77 (41.4%)
19 (10.2%)
40 (21.5%)
27 (14.5%)
6 (3.2%)
5 (2.7%)
4 (2.2%)
4 (2.2%)
4 (2.2%)

69 (36.7%)
23 (12.2%)
49 (26.1%)
20 (10.6%)
4 (2.1%)
11 (5.9%)
7 (3.7%)
1 (0.5%)
4 (2.1%)

77 (41.2%)
12 (6.4%)
56 (29.9%)
23 (12.3%)
5 (2.7%)
8 (4.3%)
2 (1.1%)
3 (1.6%)
1 (0.5%)

94 (50.5%)
91 (48.9%)
1 (0.5%)

102 (54.3%)
84 (44.7%)
2 (1.1%)

94 (50.3%)
87 (46.5%)
6 (3.2%)

47 (25.3%)
139 (74.7%)
32 (17.2%)
71 (38.2%)
21 (11.3%)
16 (8.6%)
16 (8.6%)
0 (0.9%)
1 (0.5%)
3 (1.6%)

53 (28.2%)
135 (71.8%)
23 (12.2%)
66 (35.1%)
19 (10.1%)
19 (10.1%)
26 (13.8%)
3 (1.6%)
0 (0.0%)
5 (2.7%)

55 (29.4%)
132 (70.6%)
28 (15.0%)
67 (35.8%)
17 (9.1%)
20 (10.7%)
22 (11.8%)
2 (1.1%)
0 (0.0%)
5 (2.7%)

559.6 (34.5)

560.3 (38.7)

561.3 (35.6)

Among-Group
P Value

.019
61.6 (11.7)a,b

.190

.734c

.732d

.314

NA

.904

NA not available; SD standard deviation.

P .009 for bimatoprost 0.01% vs bimatoprost 0.0125%.
b
P .026 for bimatoprost 0.01% vs bimatoprost 0.03%.
c
P value for black vs nonblack.
d
P value for dark (brown or dark brown) vs light (all other colors).
e
Patients could be washed out of more than 1 medication.
a

for each eye was determined as the mean of 2 readings or

the median of 3 readings. Diurnal IOP was defined as the
mean of the IOP at all time points at a particular visit.
Safety measures evaluated at each study visit included
adverse events, macroscopic hyperemia evaluated by gross
inspection in comparison with standard photographs,
biomicroscopy, visual acuity, pulse rate, and blood pressure. Other safety measures included iris pigmentation
VOL. 149, NO. 4

COMPARISON

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evaluated using photographs obtained at baseline and

months 3, 6, and 12; ophthalmoscopy performed at screening and months 3, 6, and 12; and visual field examinations
performed at baseline and months 3, 6, and 12. Adverse
events were classified using Medical Dictionary for Regulatory Activities (MedDRA) nomenclature. An adverse
event was determined to be treatment related if a reasonable probability existed that it might have been caused by

BIMATOPROST FORMULATIONS

FOR

LOWERING IOP

663

treatment. Macroscopic hyperemia, biomicroscopic findings, and ophthalmoscopic findings were rated on a 5-point
scale (0 none, 0.5 trace, 1 mild, 2 moderate, 3
severe). Conjunctival hyperemia grades were based on comparisons with standard photographs using the Allergan bulbar
hyperemia grading guide.
The acceptability of treatment was determined using a
questionnaire administered at the 3-month, 6-month, and
12-month visits. Patients were asked whether they would
be willing to continue on the study medication, and
physicians were asked whether they would be willing to
continue each patient on the study medication. The
responses were given on a 4-point scale of 0 not willing,
1 somewhat willing, 2 very willing, and 3
extremely willing. Physicians who were not willing to
continue administering the study medication to a patient
were asked to give their reason, choosing 1 or more
answers among possible responses of (1) IOP not low
enough, (2) redness of 1 or both eyes, (3) eyelash growth,
(4) iris color changes, (5) eyelid skin area (periorbital)
darkening, (6) patient quality of life, and (7) other.

FIGURE 1. Diagram showing patient flow through the 12month, randomized, controlled study comparing bimatoprost
0.01%, 0.0125%, and 0.03% in patients with glaucoma or
ocular hypertension.

STATISTICAL ANALYSES:

Statistical analyses were performed using SAS software version 9.1 (SAS Institute, Inc,
Cary, North Carolina, USA) and a 2-sided level of 0.05.
Nominal variables were analyzed using the Fisher exact
test or Pearson chi-square test. Patient discontinuations
over time were compared between groups using the logrank test. Ordinal variables were analyzed using KruskalWallis and Wilcoxon rank-sum tests. Continuous variables
other than IOP were analyzed using an analysis of variance
(ANOVA) with a fixed effect of treatment followed by
2-sample t tests.
IOP was analyzed for the intent-to-treat (ITT) study
population including all randomized patients using last
observation carried forward for missing data. Analysis of
both the intent-to-treat patient population and the perprotocol patient population is important in noninferiority
and equivalence studies,17 and thus a secondary analysis
evaluated IOP for the per-protocol study population (all
patients with no major protocol violation) using observed
values from visits without protocol violations. This analysis was used as a sensitivity analysis to confirm the results
of the ITT analysis. The average of the IOPs or the
changes in IOP from both eyes of the patient was used in
the analyses. Safety parameters were analyzed for all
patients who received study medication.
The 2 primary treatment comparisons were bimatoprost
0.01% versus bimatoprost 0.03% and bimatoprost 0.0125%
versus bimatoprost 0.03%. Mean IOP and mean change
from baseline IOP each were analyzed using an analysis of
variance model with a fixed effect of treatment. Confidence intervals (CIs) were created using contrasts from the
model. Equivalence in IOP-lowering efficacy was claimed
if the limits of the 95% CIs (or 97.5% CIs, when
adjustment for multiplicity was required) of the between664

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TABLE 2. Patient Disposition in the 12-Month,

Randomized, Controlled Study Comparing Bimatoprost
0.01%, 0.0125%, and 0.03% in Patients with Glaucoma or
Ocular Hypertension: Number (%) of Patients
Bimatoprost
0.01%

Bimatoprost
0.0125%

Bimatoprost
0.03%

Enrolled
186
188
187
Completed month 12
visit
171 (91.9%) 171 (91.0%) 162 (86.6%)
Discontinued
15 (8.1%)
17 (9.0%)
25 (13.4%)
Reason for
discontinuation
8 (4.3%)
8 (4.3%)
14 (7.5%)
Adverse eventa
Ocular
4 (2.2%)
6 (3.2%)
12 (6.4%)
Nonocular
5 (2.7%)
2 (1.1%)
3 (1.6%)
Lost to follow-up
2 (1.1%)
5 (2.7%)
4 (2.1%)
Intraocular pressure
2 (1.1%)
2 (1.1%)
0 (0.0%)
Protocol violation
0 (0.0%)
1 (0.5%)
3 (1.6%)
Personal reasons
1 (0.5%)
1 (0.5%)
1 (0.5%)
2 (1.1%)
0 (0.0%)
3 (1.6%)
Otherb
a
Adverse event not necessarily related to treatment. Patient
could be counted as discontinuing because of both an ocular
and nonocular adverse event.
b
Includes screening failure and patient moving out of state in the
bimatoprost 0.01% group and withdrawal of consent (2 patients) and
patient moving out of state in the bimatoprost 0.03% group.

group differences in mean IOP were within 1.5 mm Hg

at all time points, and the limits of the 95% CIs were
within 1.0 mm Hg at most time points. The Hochberg
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TABLE 3. Mean (Standard Deviation) Intraocular Pressure (mm Hg) and Between-Group Differences (Bimatoprost
0.01% Bimatoprost 0.03% and Bimatoprost 0.0125% Bimatoprost 0.03%) with 95% Confidence Interval

Visit

Baseline

Week 2

Week 6

Month 3

Month 6

Month 9
Month 12

Time

Bimatoprost
0.01%
(n 186)

Bimatoprost
0.0125%
(n 188)

Bimatoprost
0.03%
(n 187)

Difference: Bimatoprost
0.01% Bimatoprost
0.03% (95% CI) [97.5% CI]a

Difference: Bimatoprost
0.0125% Bimatoprost
0.03% (95% CI) [97.5% CI]a

8 AM
12 PM
4 PM
8 AM
12 PM
4 PM
8 AM
12 PM
4 PM
8 AM
12 PM
4 PM
8 AM
12 PM

25.1 (2.9)
23.0 (3.2)
22.3 (3.6)
17.8 (3.1)
17.1 (3.0)
16.9 (2.9)
17.6 (3.0)
16.8 (3.0)
16.7 (2.8)
17.3 (3.2)
16.7 (2.9)
16.4 (2.8)
17.7 (3.2)
17.0 (2.9)

25.1 (3.0)
23.0 (3.3)
22.4 (3.8)
17.7 (3.7)
17.1 (3.3)
16.9 (3.3)
17.8 (3.2)
16.8 (2.9)
16.8 (3.1)
17.6 (3.3)
16.6 (3.1)
16.6 (2.9)
18.1 (3.4)
17.2 (3.2)

25.0 (2.6)
23.2 (3.3)
22.3 (3.2)
17.3 (2.9)
16.3 (2.9)
16.2 (3.0)
17.2 (3.0)
16.5 (3.0)
16.4 (2.9)
17.0 (2.9)
16.1 (2.9)
16.2 (2.9)
17.4 (2.9)
16.3 (3.0)

4 PM
8 AM
12 PM
8 AM
12 PM
4 PM

16.6 (2.7)
17.9 (3.1)
17.1 (3.0)
17.7 (3.2)
17.2 (3.3)
17.1 (3.0)

16.9 (3.0)
18.3 (3.3)
17.3 (3.1)
18.0 (3.6)
17.4 (3.5)
17.2 (3.2)

16.3 (2.9)
17.8 (3.2)
16.9 (3.2)
17.3 (3.0)
16.9 (3.0)
16.7 (3.0)

0.14 (0.43 to 0.71)

0.23 (0.89 to 0.43)
0.04 (0.68 to 0.76)
0.56 (0.10 to 1.22)
0.84 (0.21 to 1.46)
0.73 (0.10 to 1.35)
0.37 (0.25 to 1.00)
0.29 (0.31 to 0.89)
0.23 (0.37 to 0.82)
0.33 (0.31 to 0.97)
0.55 (0.05 to 1.16)
0.28 (0.31 to 0.87)
0.39 (0.25 to 1.03)
0.63 (0.01 to 1.25)
[0.08 to 1.34]
0.35 (0.23 to 0.94)
0.13 (0.52 to 0.78)
0.22 (0.41 to 0.85)
0.41 (0.26 to 1.07)
0.29 (0.37 to 0.96)
0.44 (0.18 to 1.06)

0.09 (0.48 to 0.66)

0.18 (0.85 to 0.48)
0.09 (0.62 to 0.81)
0.44 (0.22 to 1.10)
0.86 (0.23 to 1.48)
0.67 (0.05 to 1.29)
0.54 (0.09 to 1.16)
0.37 (0.23 to 0.97)
0.32 (0.28 to 0.91)
0.55 (0.09 to 1.18)
0.52 (0.08 to 1.13)
0.43 (0.16 to 1.01)
0.73 (0.09 to 1.37)
0.89 (0.27 to 1.51)
[0.18 to 1.60]
0.65 (0.07 to 1.23)
0.51 (0.14 to 1.16)
0.37 (0.26 to 1.01)
0.70 (0.03 to 1.36)
0.51 (0.15 to 1.17)
0.51 (0.11 to 1.13)

CI confidence interval.
The 97.5% CI was used to correct for multiplicity when the limits of the 95% CI of either the bimatoprost 0.01% bimatoprost 0.03%
difference or the bimatoprost 0.0125% bimatoprost 0.03% difference were not within 1.5 mm Hg (Hochberg procedure).
a

procedure was used to correct for multiplicity of analyses: if either bimatoprost 0.01% or 0.0125% was not
equivalent to bimatoprost at a particular time point
based on the 95% CI, then the determination of
equivalency of the other formulation to bimatoprost
0.03% was based on the 97.5% CI.
A sample size of 158 patients in each treatment group
was expected to give 93% power for the equivalence test of
IOP-lowering efficacy at an individual time point using an
level of 0.025, an estimated standard deviation of 3.27
mm Hg, and procedure MTE1GT in the commercial
software nQuery Advisor version 5.0 (Statistical Solutions,
Saugus, Massachusetts, USA). Based on an anticipated
attrition rate of 15%, 558 patients were to be enrolled.

RESULTS

EFFICACY ANALYSES:

PATIENT CHARACTERISTICS AND DISPOSITION: A

total of 561 patients were enrolled in the 3 study groups.
Patient demographics and clinical characteristics at baseline generally were similar among the treatment groups
(Table 1). Patients ranged in age from 23 to 94 years
(mean, 63.5 years). Approximately 73% of the patients
were white, 14% were black, 57% were female, and 72%
required washout of previous ocular hypotensive medica-

VOL. 149, NO. 4

COMPARISON

tion, most commonly a prostaglandin (36%) or bimatoprost (15%). Slightly more than half of the patients (53%)
were diagnosed with glaucoma in 1 or both eyes. The only
statistically significant difference among treatment groups
was in age. The mean age of patients was slightly lower in
the bimatoprost 0.01% group (61.6 years) than in the
bimatoprost 0.0125% and 0.03% groups (64.7 years and
64.2 years, respectively; P .026), but this difference is
unlikely to be clinically relevant.
Patient flow through the study is shown in Figure 1. The
12-month study was completed by 91.9%, 91.0%, and
86.6% of patients in the bimatoprost 0.01%, 0.0125%, and
0.03% groups, respectively (Table 2). The most common
reasons for early discontinuation from the study were
ocular adverse events and loss to follow-up.

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There were no statistically significant differences in baseline mean IOPs between the
treatment groups (Table 3). The baseline mean IOP at 8
AM, 12 PM, and 4 PM, respectively, was 25.1 mm Hg, 23.0
mm Hg, and 22.3 mm Hg in the bimatoprost 0.01% group;
25.1 mm Hg, 23.0 mm Hg, and 22.4 mm Hg in the
bimatoprost 0.0125% group; and 25.0 mm Hg, 23.2 mm
Hg, and 22.3 mm Hg in the bimatoprost 0.03% group.
Differences in baseline mean IOP between the bimatoprost

BIMATOPROST FORMULATIONS

FOR

LOWERING IOP

665

Hg at all times of the day, and none of the differences

between treatments were statistically significant (Figure 2).
Bimatoprost 0.01% was equivalent in efficacy to bimatoprost 0.03% throughout the 12-month study. The limits of
the 95% CI of the difference in mean IOP between groups
were within 1.5 mm Hg at all 17 postbaseline time
points and within 1.0 mm Hg at 9 of the postbaseline
time points (Table 3). Bimatoprost 0.0125% was not
equivalent in efficacy to bimatoprost 0.03%, because the
limits of the 95% CI of the difference in mean IOP
between groups were within 1.5 mm Hg at 16 postbaseline time points and within 1.0 mm Hg at 2 of the
postbaseline time points (Table 3). Results from the
sensitivity analysis using only observed values from visits
without protocol violations (approximately 90% of all data
points) in the per-protocol patient population (99.5%
[558/561] of all randomized patients) confirmed these
results.
Bimatoprost 0.01% and 0.0125% were comparable with
bimatoprost 0.03% in secondary efficacy measures. Response rates were high in each treatment group. At month
12, at least a 20% decrease from baseline IOP was achieved
by 79.6%, 66.1%, and 58.1% of patients in the bimatoprost
0.01% group; 77.1%, 63.8%, and 58.5% of patients in the
bimatoprost 0.0125% group; and 82.4%, 73.8%, and
66.3% of patients in the bimatoprost 0.03% group at 8 AM,
12 PM, and 4 PM, respectively. The overall difference
between bimatoprost 0.01% and bimatoprost 0.03% in
change from baseline diurnal IOP across all 6 visits was
0.43 mm Hg, with a 95% CI upper limit of 0.93 mm Hg.
The overall difference between bimatoprost 0.0125% and
bimatoprost 0.03% was 0.56 mm Hg, with a 95% CI upper
limit of 1.06. Bimatoprost 0.01% was equivalent to bimatoprost 0.03% in mean diurnal IOP during follow-up,
with the limits of the 95% CI of the treatment difference
within 1.5 mm Hg at all 6 follow-up visits and within
1.0 mm Hg at 4 of the visits. Bimatoprost 0.0125% was not
equivalent to bimatoprost 0.03% in mean diurnal IOP,
because the limits of the 95% CI of the treatment
difference were within 1.5 mm Hg at all 6 follow-up
visits but within 1.0 mm Hg at only 1 of the visits.

FIGURE 2. Graph showing mean intraocular pressure (IOP)

during the day at baseline and month 12 in patients with
glaucoma or ocular hypertension who were treated with oncedaily bimatoprost 0.01%, 0.0125%, or 0.03% for 12 months.
There were no statistically significant differences in mean IOP
between the treatment groups at baseline or month 12. Error
bars standard error of the mean.

0.01% or 0.0125% groups and the bimatoprost 0.03%

group were less than 0.3 mm Hg at each hour.
Each of the study formulations provided clinically and
statistically significant reductions from baseline IOP at
each follow-up time point. The mean reduction from
baseline IOP ranged from 5.2 to 7.8 mm Hg with bimatoprost 0.01%, 5.2 to 7.5 mm Hg with bimatoprost 0.0125%,
and 5.6 to 8.0 mm Hg with bimatoprost 0.03%. At month
12, the mean reduction (% reduction) from baseline IOP
was 7.4 mm Hg (29%) for bimatoprost 0.01% and 7.6 mm
Hg (30%) for bimatoprost 0.03% at 8 AM, 5.8 mm Hg
(25%) for bimatoprost 0.01% and 6.3 mm Hg (27%) for
bimatoprost 0.03% at 12 PM, and 5.2 mm Hg (23%) for
bimatoprost 0.01% and 5.6 mm Hg (25%) for bimatoprost
0.03% at 4 PM. In the bimatoprost 0.125% group, the mean
reduction (percent reduction) from baseline IOP was 7.0
mm Hg (28%) at 8 AM, 5.6 mm Hg (24%) at 12 PM, and 5.2
mm Hg (23%) at 4 PM.
Mean IOPs during follow-up ranged from 16.4 to 17.9 mm
Hg with bimatoprost 0.01%, 16.6 to 18.3 mm Hg with
bimatoprost 0.0125%, and 16.1 to 17.8 mm Hg with bimatoprost 0.03%. Differences in mean IOP between bimatoprost
0.01% or 0.0125% and bimatoprost 0.03% were consistently
less than 0.9 mm Hg throughout the 12-month study (Table
3). Occasional statistically significant differences between
the 0.01% and 0.03% formulations were observed at the 12
PM time point at week 2 and month 6 and the 4 PM time
point at week 2. Statistically significant differences between the 0.0125% and 0.03% formulations were seen at
these same time points, as well as at the 8 AM time point
at months 6 and 12 and the 4 PM time point at month 6.
At month 12, differences in mean IOP between bimatoprost 0.01% and bimatoprost 0.03% were less than 0.5 mm
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SAFETY AND TOLERABILITY: All of the study formulations were well tolerated, but bimatoprost 0.01% and
bimatoprost 0.03% demonstrated a statistically significant
difference in discontinuation rates over time because of
ocular adverse events (P .043). Only 4 patients (2.2%)
in the bimatoprost 0.01% group compared with 12 patients
(6.4%) in the bimatoprost 0.03% group discontinued the
study early because of ocular adverse events. In the
bimatoprost 0.0125% group, 6 patients (3.2%) discontinued because of ocular adverse events. There were no
serious treatment-related adverse events in the study.
The overall incidence of treatment-related adverse
events was lower in the bimatoprost 0.01% group (38.4%)
than in the bimatoprost 0.03% group (50.8%), and the
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TABLE 4. Treatment-Related Adverse Events in the 12-Month, Randomized, Controlled

Study Comparing Bimatoprost 0.01%, 0.0125%, and 0.03% in Patients with Glaucoma or
Ocular Hypertension
Number (%) of Patients

Adverse Eventa

Bimatoprost
0.01% (n 185)

Bimatoprost
0.0125% (n 188)

Bimatoprost
0.03% (n 187)

Among-Group
P Value

Conjunctival hyperemia
Skin hyperpigmentation
Eye pruritus
Eyelid erythema
Eyelash growth
Punctate keratitis
Eye irritation
Foreign body sensation
Overallc

53 (28.6%)
5 (2.7%)
4 (2.2%)
5 (2.7%)
7 (3.8%)
3 (1.6%)
7 (3.8%)
0 (0.0%)
71 (38.4%)d

49 (26.1%)b
1 (0.5%)b
2 (1.1%)b
5 (2.7%)
2 (1.1%)
5 (2.7%)
4 (2.1%)
4 (2.1%)
75 (39.9%)b

70 (37.4%)
10 (5.3%)
10 (5.3%)
8 (4.3%)
6 (3.2%)
7 (3.7%)
3 (1.6%)
4 (2.1%)
95 (50.8%)

.044
.020
.035
.600
.229
.448
.388
.139
.030

All treatment-related adverse events reported for more than 2% of patients in any treatment group
are listed.
b
P .034 for bimatoprost 0.0125% vs bimatoprost 0.03%.
c
Patients with 1 or more treatment-related adverse events.
d
P .016 for bimatoprost 0.01% vs bimatoprost 0.03%.

difference between groups was statistically significant (P

.016). In the bimatoprost 0.0125% group, the overall
incidence of treatment-related adverse events was 39.9%
(P .034 vs bimatoprost 0.03%). There were no statistically
significant differences between the bimatoprost 0.01% group
and the bimatoprost 0.0125% group in the overall incidence
of treatment-related adverse events or in the incidence of any
individual treatment-related adverse event.
Conjunctival hyperemia was the most common treatment-related adverse event, and conjunctival hyperemia,
skin hyperpigmentation, and eye pruritus were the only
individual treatment-related adverse events with a statistically significant difference in incidence among treatment
groups (Table 4). Conjunctival hyperemia was reported in
53 patients (28.6%) in the bimatoprost 0.01% group
compared with 70 patients (37.4%) in the bimatoprost
0.03% group, skin hyperpigmentation was reported in 5
patients (2.7%) in the bimatoprost 0.01% group compared
with 10 patients (5.3%) in the bimatoprost 0.03% group,
and eye pruritus was reported in 4 patients (2.2%) in the
bimatoprost 0.01% group compared with 10 patients
(5.3%) in the bimatoprost 0.03% group, representing a
23.5%, 49.5%, and 59.6% reduction in the incidence of
conjunctival hyperemia, skin hyperpigmentation, and eye
pruritus, respectively, in the bimatoprost 0.01% group
compared with the bimatoprost 0.03% group. There were no
reports of severe treatment-related conjunctival hyperemia in
the bimatoprost 0.01% group (0% of patients) compared with
2 in the bimatoprost 0.0125% group (1.1% of patients) and 3
in the bimatoprost 0.03% group (1.6% of patients). Iris
hyperpigmentation (including iris disorder) was reported for 1
patient (0.5%) in the bimatoprost 0.01% group, 2 patients
(1.1%) in the bimatoprost 0.0125% group, and 2 patients
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FIGURE 3. Bar graph showing the incidence of moderate to

severe increase from baseline macroscopic conjunctival hyperemia
in patients with glaucoma or ocular hypertension who were treated
with bimatoprost 0.01%, 0.0125%, or 0.03% for 12 months. The
percentage of patients in each treatment group who had a moderate
to severe increase from the baseline macroscopic conjunctival
hyperemia score at any time in the study is shown. Bimatoprost
0.01% vs bimatoprost 0.03%, P .019.

(1.1%) in the bimatoprost 0.03% group. There were no

reports of iritis, uveitis, or cystoid macular edema in any
treatment group during the 12-month treatment period.
Macroscopic hyperemia was graded by comparison with
standard photographs. In an a priori evaluation, the mean
peak increase from baseline macroscopic hyperemia scores
across all follow-up visit intervals was 0.74 in the bimatoprost 0.01% group compared with 0.89 in the bimatoprost
0.03% group. The between-group difference was statistically significant (P .010, a posteriori repeated-measures
analysis of variance). In the bimatoprost 0.0125% group,

BIMATOPROST FORMULATIONS

FOR

LOWERING IOP

667

the mean peak increase from baseline macroscopic hyperemia scores across all follow-up visit intervals was 0.76
(P .050 vs bimatoprost 0.03%). Further, in an a
posteriori analysis, the percentage of patients demonstrating a moderate to severe increase from baseline hyperemia
(an increase in severity score of 2, 2.5, or 3 units) at any
time in the study was statistically significantly reduced in
the bimatoprost 0.01% group compared with the bimatoprost 0.03% group (3.2% vs 9.1%; P .019; Figure 3).
On biomicroscopy, conjunctival hyperemia was the
most frequent finding and the only finding to show a
statistically significant difference among treatment groups.
An increase in conjunctival hyperemia from baseline of 2
units or more was reported at some point during follow-up
for 8.6% (16/185) of patients in the bimatoprost 0.01%
group and for 17.6% (33/187) of patients in the bimatoprost 0.03% group (P .010, a posteriori analysis). In the
bimatoprost 0.0125% group, 10.2% of patients had an
increase in conjunctival hyperemia from baseline of 2 units
or more at some point during follow-up. Because by chance
the number of patients with no hyperemia at baseline was
higher in the bimatoprost 0.03% group than in the
bimatoprost 0.01% group, the analysis was repeated after
stratification for baseline hyperemia. The results of this
analysis also showed that the percentage of patients with a
moderate to severe increase in hyperemia was lower in the
bimatoprost 0.01% group (8.6%) than in the 0.03% group
(17.6%), and the difference between groups was statistically significant (P .023). The difference between
bimatoprost 0.0125% and bimatoprost 0.03% was not
statistically significant.
There were no statistically significant among-group
differences in changes from baseline visual acuity or visual
fields. On ophthalmoscopy, the cup-to-disc ratio was unchanged (change of less than 0.2 from the baseline value)
at month 12 for almost all patients in the study. An
increase in cup-to-disc ratio of at least 0.2 from baseline to
month 12 was observed for only 2 patients, both in the
bimatoprost 0.03% group. There were no clinically significant changes in mean heart rate or systolic or diastolic
blood pressure in any treatment group.

76.9% of patients in the bimatoprost 0.01%, 0.0125%, and

0.03% groups, respectively), they would be very or extremely willing to continue to administer the study medication to patients. Physicians were unwilling to continue
to administer the study medication to 13 patients in the
bimatoprost 0.01% group (7.1%), 9 patients in the bimatoprost 0.0125% group (4.9%), and 13 patients in the
bimatoprost 0.03% group (7.0%). The most common
reason for physicians being unwilling to continue study
treatment in these few cases was that the IOP was not
considered to be sufficiently low.

DISCUSSION
IN THIS STUDY, IOP-LOWERING EFFICACY WAS MAINTAINED

and tolerability was improved when the concentration of

bimatoprost was reduced from 0.03% to 0.01% (or 0.0125%)
in the test formulations. All 3 bimatoprost formulations were
well accepted by patients and physicians, and all were well
tolerated, but the incidence of treatment-related adverse
events was statistically and clinically significantly reduced in
the bimatoprost 0.01% and 0.0125% groups compared with
the bimatoprost 0.03% group, and fewer patients in the
bimatoprost 0.01% and 0.0125% groups discontinued because
of ocular adverse events.
The equivalency analysis of mean IOP that was performed required that the upper and lower limits of the 95%
CIs of between-group differences in mean IOP be within
1.5 mm Hg at all follow-up time points and within 1.0
mm Hg at most follow-up time points for equivalency to be
claimed. Using these strict criteria for equivalency, bimatoprost 0.01% (but not bimatoprost 0.0125%) was
determined to be equivalent to the original bimatoprost
0.03% formulation in efficacy throughout the 12-month
study. Both bimatoprost 0.01% and bimatoprost 0.03%
reduced mean IOP by approximately 30% at the 8 AM time
point after 12 months of treatment, and bimatoprost
0.0125% reduced mean IOP by approximately 28%.
Bimatoprost 0.01% demonstrated a favorable benefit-torisk ratio in the study, because it was as effective as
bimatoprost 0.03% in lowering IOP and had improved
tolerability. In general, the efficacy and tolerability of
bimatoprost 0.01% and bimatoprost 0.0125% were similar,
and bimatoprost 0.0125% also demonstrated improved
tolerability compared with bimatoprost 0.03%. These results may not be surprising because the concentration of
bimatoprost was only 25% higher in bimatoprost 0.0125%
than in bimatoprost 0.01%. Equivalent efficacy of bimatoprost 0.0125% and bimatoprost 0.03% was not demonstrated for reasons that are not understood but may involve
the strict criteria used to determine equivalency. Because
bimatoprost 0.01% provides full efficacy and improved
tolerability with minimized drug exposure, it is the focus of
the rest of the discussion.

ACCEPTABILITY OF TREATMENT: At the end of the

12-month study or study exit, most patients (80.3%,
82.5%, and 77.4% in the bimatoprost 0.01%, 0.0125%,
and 0.03% groups, respectively) reported that they would
be very or extremely willing to continue using their study
medication. Only 10 patients in the bimatoprost 0.01%
group (5.5%), compared with 18 patients in the bimatoprost 0.03% group (9.7%), were unwilling to continue on
their study medication, representing a 44% reduction in
the number of patients unwilling to continue treatment
with bimatoprost 0.01% compared with bimatoprost 0.03%.
In the bimatoprost 0.0125% group, 7 patients (3.8%) were
unwilling to continue using their study medication. Similarly,
physicians reported that in most cases (82.0%, 81.4%, and

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The most common side effect of bimatoprost treatment

is conjunctival hyperemia. Although the discontinuation
rate as a result of conjunctival hyperemia has been low in
clinical studies of bimatoprost 0.03%,2 in some cases,
conjunctival hyperemia can result in additional office visits
or patient discontinuation from treatment.18 Therefore,
the 23.5% relative reduction in the incidence of treatment-related conjunctival hyperemia adverse events (from
37.4% in the bimatoprost 0.03% group to 28.6% in the
bimatoprost 0.01% group) is clinically important. The
severity of conjunctival hyperemia also was decreased in
the bimatoprost 0.01% group compared with the bimatoprost 0.03% group. Peak increases from baseline macroscopic hyperemia scores were reduced significantly with
bimatoprost 0.01% when compared with bimatoprost
0.03%, and there was a statistically significant reduction in
the incidence of moderate to severe increases in macroscopic conjunctival hyperemia in the bimatoprost 0.01%
group compared with the bimatoprost 0.03% group. The
decrease in the percentage of patients with moderate to
severe increases in conjunctival hyperemia may have even
greater clinical relevance than the decrease in the overall
incidence of conjunctival hyperemia, because patients
typically tolerate the occurrence of trace to mild hyperemia, but are more apt to discontinue treatment if the
hyperemia is moderate or severe.
Overall, ocular side effects associated with bimatoprost
treatment were less common in the bimatoprost 0.01%
group than in the bimatoprost 0.03% group and led to
statistically significantly fewer discontinuations from treatment. The improvement in tolerability with bimatoprost
0.01% was not simply the result of a decrease in bimatoprost-associated conjunctival hyperemia, because when
conjunctival hyperemia was excluded from the analysis,
bimatoprost 0.01% still was associated with a statistically
significantly lower incidence of treatment-related, ocular
surfacerelated adverse events (13.0%) compared with
bimatoprost 0.03% (22.5%; P .017).
BAK, the preservative most commonly used in ophthalmic medications, has been demonstrated to enhance the
transcorneal penetration of medications in isolated corneal
preparations15 and may increase the bioavailability of
topically applied medications. Although BAK and ophthalmic solutions containing BAK have been shown to
have toxic effects on cultured cells19,20 and to cause
damage to the ocular surface in the rabbit model system,2123 well controlled phase 3 clinical studies have not
demonstrated harmful effects of BAK in study populations

of patients with glaucoma or OHT.24 26 For example, no

statistically significant differences between BAK-free and
BAK-containing formulations were seen in the incidence of
ocular24 or treatment-related25,26 adverse events in clinical
studies comparing tafluprost containing 0.01% BAK with
preservative-free tafluprost, or comparing travoprost containing 0.015% BAK with travoprost containing an alternative
preservative. In one of these studies, the frequency of discontinuations resulting from treatment-related adverse events
also was reported to be similar between travoprost containing
0.015% BAK and travoprost containing an alternative preservative (1.2% and 1.5%, respectively).26 Bimatoprost
0.01% contains the same 0.02% concentration of BAK as
latanoprost 0.005%, which has been used safely in glaucoma
treatment for many years.27,28 In a recent prospective, randomized, paired-eye study, symptoms of dryness and irritation
were statistically significantly worse (P .017) in eyes treated
with travoprost preserved with an alternative preservative
than in eyes treated with latanoprost preserved with 0.02%
BAK (Townley JR, et al. Invest Ophthalmol Vis Sci 2009;
50:E-Abstract 4651). In the present study, bimatoprost 0.01%
demonstrated improved tolerability over 12 months compared with bimatoprost 0.03%, despite the increased concentration of BAK. It is noteworthy that none of the patient
discontinuations from bimatoprost 0.01% treatment were the
result of adverse events that could be considered to be related
to corneal toxicity (e.g., corneal erosions or punctate keratitis). Taken together, the results of studies evaluating safety
and tolerability of the prostaglandin analogs suggest that the
active drug and its concentration may be a more important
predictor of ocular surface tolerability than the concentration
of BAK.
Major strengths of this study were the randomization
procedure in which patients were stratified by baseline IOP
and central corneal thickness, because these affect the
IOP-lowering response to medications in OHT and glaucoma,29,30 and the consistency in results from the intentto-treat and per-protocol study populations. The main
limitation of this study is that no confirmatory studies have
been carried out.
In summary, the results of this study indicate that
bimatoprost 0.01% is an improved formulation of bimatoprost. Bimatoprost 0.01% controlled IOP as effectively as
bimatoprost 0.03% with only a 0.43-mm Hg overall
difference in diurnal IOP lowering between treatments and
was tolerated better. Bimatoprost 0.01% also demonstrated
better efficacy compared with bimatoprost 0.03% than
bimatoprost 0.0125%.

SPONSORED BY ALLERGAN, INC, IRVINE, CALIFORNIA. DRS KATZ AND COHEN HAVE NO PROPRIETARY INTEREST IN BIMATOPROST
or in Allergan, Inc. Ms Batoosingh, Mr Felix, and Drs Shu, and Schiffman are employees of Allergan, Inc, and own stock in the company through matching
benefits. Involved in study design (A.L.B., R.M.S.); Statistical analysis (C.F., V.S.); Data interpretation (L.J.K., J.S.C., A.L.B., R.M.S.); and Preparation and
approval of the manuscript (L.J.K., J.S.C., A.L.B., C.F., R.M.S.). This clinical trial was carried out in accordance with Health Insurance Portability and
Accountability Act regulations at 32 sites. The study protocol was approved by the appropriate institutional review board at each site. All patients provided
informed consent before participation in the study. The trial is registered with the identifier NCT00300443 at http://www.clinicaltrials.gov. Kate Ivins, PhD,
provided medical writing assistance in the development of the manuscript. John G. Walt, MBA, Global Health Outcomes Strategy & Research Department,
Allergan, Inc, contributed to the design and interpretation of the patient-reported outcome measure (acceptability of treatment).

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PRINCIPAL INVESTIGATORS
Jason Bacharach (Petaluma, California); Allen Beck (Atlanta, Georgia); David E. Brodstein (Ogden, Utah); Louis B. Cantor (Indianapolis, Indiana);
George Cioffi (Portland, Oregon); John S. Cohen (Cincinnati, Ohio); David L. Cooke (Saint Joseph, Michigan); William F. Davitt III (El Paso, Texas);
Monte S. Dirks (Rapid City, South Dakota); Harvey B. DuBiner (Morrow, Georgia); Richard M. Evans (San Antonio, Texas); Robert Foerster
(Colorado Springs, Colorado); Mark S. Juzych (Detroit, Michigan); L. Jay Katz (Philadelphia, Pennsylvania); Richard Lewis (Sacramento, California);
Jeffrey R. Lozier (Poway, California); Arash Mansouri (Fredericksburg, Virginia); Frank J. Mares (Albuquerque, New Mexico); Donald L. McCormack
(Boulder, Colorado); Eugene E. Protzko (Havre De Grace, Maryland); Michael Rotberg (Charlotte, North Carolina); Kenneth Sall (Bellflower,
California); Howard Schenker (Rochester, New York); Robert Shields (Denver, Colorado); Steven T. Simmons (Slingerlands, New York); Alfred M.
Solish (Pasadena, California); Richard Sturm (Lynbrook, New York); Michael Tepedino (High Point, North Carolina); Thomas R. Walters (Austin,
Texas); Jeffrey C. Whitsett (Houston, Texas); Robert D. Williams (Louisville, Kentucky); and David L. Wirta (Newport Beach, California).

12. Wanichwecha-Rungruang B, Iemsomboon W. Efficacy and

safety of bimatoprost for the treatment of open-angle glaucoma and ocular hypertension: a three-month, open-label
study in community-based practices in Thailand. J Med
Assoc Thai 2005;88:1228 1235.
13. Hommer A, Ganfort Investigators Group I. A doublemasked, randomized, parallel comparison of a fixed combination of bimatoprost 0.03%/timolol 0.5% with non-fixed
combination use in patients with glaucoma or ocular hypertension. Eur J Ophthalmol 2007;17:53 62.
14. Holl G. The side effects of the prostaglandin analogues.
Expert Opin Drug Saf 2007;6:4552.
15. Nakamura T, Yamada M, Teshima M, et al. Electrophysiological characterization of tight junctional pathway of rabbit
cornea treated with ophthalmic ingredients. Biol Pharm Bull
2007;30:2360 2364.
16. Toor A, Chanis RA, Polikoff LA, Fahim MM, Sinha AP, Serle
JB. Additivity of pilocarpine to bimatoprost in ocular hypertension and early glaucoma. J Glaucoma 2005;14:243248.
17. Le Henanff A, Giraudeau B, Baron G, Ravaud P. Quality of
reporting of noninferiority and equivalence randomized trials. JAMA 2006;295:11471151.
18. Schwartz GF, Reardon G. A cost-effectiveness comparison of
bimatoprost versus latanoprost in patients with glaucoma or
ocular hypertension. Surv Ophthalmol 2004;49:621 623;
author reply 623 624.
19. Pisella PJ, Debbasch C, Hamard P, et al. Conjunctival proinflammatory and proapoptotic effects of latanoprost and preserved and unpreserved timolol: an ex vivo and in vitro study.
Invest Ophthalmol Vis Sci 2004;45:1360 1368.
20. Guenoun JM, Baudouin C, Rat P, Pauly A, Warnet JM,
Brignole-Baudouin F. In vitro study of inflammatory potential and toxicity profile of latanoprost, travoprost, and bimatoprost in conjunctiva-derived epithelial cells. Invest
Ophthalmol Vis Sci 2005;46:2444 2450.
21. Whitson JT, Cavanagh HD, Lakshman N, Petroll WM.
Assessment of corneal epithelial integrity after acute exposure to ocular hypotensive agents preserved with and without
benzalkonium chloride. Adv Ther 2006;23:663 671.
22. Liang H, Baudouin C, Pauly A, Brignole-Baudouin F. Conjunctival and corneal reactions in rabbits following short- and
repeated exposure to preservative-free tafluprost, commercially available latanoprost and 0.02% benzalkonium chloride. Br J Ophthalmol 2008;92:12751282.
23. Kahook MY, Noecker RJ. Comparison of corneal and conjunctival changes after dosing of travoprost preserved with sofZia,
latanoprost with 0.02% benzalkonium chloride, and preservative-free artificial tears. Cornea 2008;27:339 343.
24. Hamacher T, Airaksinen J, Saarela V, Liinamaa MJ, Richter U,
Ropo A. Efficacy and safety levels of preserved and preservative-

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Biosketch
L. Jay Katz, MD, FACS, is a Professor of Ophthalmology at Jefferson Medical College and Director of the Glaucoma
Service at Wills Eye Institute, Philadelphia, Pennsylvania. He received his MD degree from Yale University Medical
School and completed an internship in Internal Medicine at the University of Virginia, a residency in Ophthalmology at
Yale, and a Fellowship in Glaucoma at Wills Eye Hospital. He received the 2002 AAO Senior Achievement Award. His
research interests include glaucoma.

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