Considerations in glaucoma therapy: Fixed combinations versus their component medications

Article (PDF Available)inClinical Ophthalmology 4(1):1-9 · February 2010with35 Reads
DOI: 10.2147/OPTH.S6645 · Source: PubMed
Abstract
Fixed combinations of medications that lower intraocular pressure (IOP) are increasingly used in the treatment of glaucoma and ocular hypertension and offer several potential advantages over combined use of the separate component medications including enhanced convenience, improved adherence, reduced exposure to preservatives, and possible cost savings. This review aims to examine the current role of IOP-lowering fixed combinations in disease management. The results of studies that compared the efficacy and safety of IOP-lowering fixed combinations with their component medications are summarized, including those fixed combinations that consist of a prostaglandin analog and timolol. The fixed combinations currently available for use in the United States are fixed-combination dorzolamide/timolol (FCDT) and fixed-combination brimonidine/timolol (FCBT). Both of these fixed combinations reduce IOP more effectively than their component medications used separately as monotherapy. FCBT therapy also demonstrates a more favorable safety profile and reduced ocular allergy compared to monotherapy with brimonidine, a component medication. Few studies have directly compared the efficacy and safety of FCDT and FCBT, but available evidence suggests that FCBT is at least as effective as FCDT in lowering IOP and is more comfortable and better tolerated. Additional studies are needed to further evaluate the comparative efficacy and tolerability of FCDT and FCBT in the management of glaucoma and ocular hypertension.
© 2010 Higginbotham, publisher and licensee Dove Medical Press Ltd. This is an Open Access article
which permits unrestricted noncommercial use, provided the original work is properly cited.
Clinical Ophthalmology 2010:4 1–9
Clinical Ophthalmology
1
R E V I E W
Dovepress
open access to scientific and medical research
Open Access Full Text Article
submit your manuscript | www.dovepress.com
Dovepress
Considerations in glaucoma therapy: xed
combinations versus their component
medications
Eve J Higginbotham
Morehouse School of Medicine,
Atlanta, GA, USA
Correspondence: Eve J Higginbotham
Dean and Senior Vice President for
Academic Affairs, Morehouse School
of Medicine, 720 Westview Drive SW,
Atlanta, GA, USA 30310-1495
Tel +1 404-752-1728
Fax +1 404-752-1594
Email ejhigginbotham@msm.edu
Abstract: Fixed combinations of medications that lower intraocular pressure (IOP) are
increasingly used in the treatment of glaucoma and ocular hypertension and offer several
potential advantages over combined use of the separate component medications including
enhanced convenience, improved adherence, reduced exposure to preservatives, and possible
cost savings. This review aims to examine the current role of IOP-lowering fixed combinations in
disease management. The results of studies that compared the efficacy and safety of IOP-lowering
fixed combinations with their component medications are summarized, including those fixed
combinations that consist of a prostaglandin analog and timolol. The fixed combinations currently
available for use in the United States are fixed-combination dorzolamide/timolol (FCDT) and
fixed-combination brimonidine/timolol (FCBT). Both of these fixed combinations reduce IOP
more effectively than their component medications used separately as monotherapy. FCBT
therapy also demonstrates a more favorable safety profile and reduced ocular allergy compared
to monotherapy with brimonidine, a component medication. Few studies have directly compared
the efficacy and safety of FCDT and FCBT, but available evidence suggests that FCBT is at least
as effective as FCDT in lowering IOP and is more comfortable and better tolerated. Additional
studies are needed to further evaluate the comparative efficacy and tolerability of FCDT and
FCBT in the management of glaucoma and ocular hypertension.
Keywords: glaucoma, intraocular pressure, fixed combination, adherence, brimonidine
The goal of treatment in glaucoma and ocular hypertension is to reduce intraocular
pressure (IOP) to a target pressure sufficiently low to prevent glaucomatous progression.
The most commonly used classes of IOP-lowering medications are the prostaglandin
analogs, beta-adrenergic receptor antagonists (beta-blockers), alpha adrenergic receptor
agonists (alpha agonists), and carbonic anhydrase inhibitors (CAIs). For many patients,
a single medication is insufficient to reduce IOP to the target pressure, and the treatment
regimen includes 2, 3, or more medications from different classes.
In recent years the number and use of fixed combinations of IOP-lowering medications
for treatment in glaucoma and ocular hypertension has grown substantially. These fixed
combinations contain 2 medications in a single bottle and offer several advantages
over concomitant use of the medications from separate bottles. Most important is the
increase in patient convenience that results from the use of fewer bottles and eyedrops of
medication and sometimes from dosing fewer times each day. The improved convenience
of a regimen containing a fixed combination rather than 2 separate medications is
likely to lead to better adherence. Although few, if any, studies have directly evaluated
Number of times this article has been viewed
This article was published in the following Dove Press journal:
Clinical Ophthalmology
17 December 2009
Clinical Ophthalmology 2010:4
2
Higginbotham
Dovepress
submit your manuscript | www.dovepress.com
Dovepress
adherence to IOP-lowering xed combinations compared with
the component medications used separately, there is evidence
that adherence in glaucoma is better when regimens are simple
rather than complex.
1
A retrospective study using prescription
data from a large national healthcare provider concluded that
the rate of prescription refills was reduced when patients
added a second prescription to their IOP-lowering regimen.
2
In other disease states, studies have shown significantly
better adherence with fixed combinations (1 pill) than
with the separate components (2 pills). For example, in
systemic hypertension, another chronic asymptomatic
disease associated with low levels of long-term adherence
to therapy,
3
retrospective studies using pharmacy records
showed that patients were more apt to refill a prescription
for a fixed combination than 2 separate prescriptions for the
component medications,
4
and patients on a fixed combination
had medication available for more days of therapy compared
with patients on the separate component drugs.
5
Because there is no possibility of a washout effect and no
need to wait between instillation of the separate individual
medications, both efficacy and adherence may be enhanced
when a fixed combination is used rather than the separate
component medications. Use of a fixed combination may also
represent a safety improvement, because the patient’s overall
daily exposure to preservative may be decreased. Finally,
there are potential cost savings associated with the use of
fixed combinations, especially for patients with prescription
insurance who have 1 copay for a fixed combination rather
than 2 for separate medications. Moreover, in the United
States, the availability of a generic fixed combination of
dorzolamide and timolol increases access for those patients
who previously could not afford this therapeutic option.
A disadvantage that should be highlighted is that it is not
possible to change the drug concentration or dosing schedule
for one component medication independently of the other
when using a fixed combination. However, if adherence is
improved by simplifying the regimen, the advantages of
using a fixed combination outweigh this disadvantage.
Historical overview of IOP-lowering
xed combinations
Fixed combinations containing pilocarpine and another
IOP-lowering medication have been used historically in
the treatment of glaucoma. In the United States, however,
epinephrine/pilocarpine (E-pilo
®
; Ciba Vision) is not
currently commercially available, timolol/pilocarpine
(Timpilo
®
; Merck & Co., Inc.) never received United
States Food and Drug Administration (FDA) approval, and
betaxolol/pilocarpine (Betoptic Pilo
®
; Alcon Laboratories, Inc.)
was approved in 1997 but was never marketed. The primary
reason that pilocarpine combinations are no longer commonly
used is that the component drugs are not generally preferred
therapy. Although newer preparations of pilocarpine have
bypassed the need for frequent dosing of up to 4 times each
day, the side-effect profile of pilocarpine (most commonly
blurred vision and decreased night vision, less often eye
irritation and headache) still limits its usefulness in glaucoma
therapy. Epinephrine also often shows poor ocular tolerability.
The selective beta-blocker betaxolol continues to be available.
Although useful in selected patients with a history of pulmonary
disease, this medication is not as effective in IOP lowering as
nonselective beta-blockers such as timolol.
6
The fixed combinations currently available for IOP
lowering in the United States contain timolol and either
the CAI dorzolamide or the alpha agonist brimonidine.
Dorzolamide/timolol (Cosopt
®
; Merck & Co., Inc.) has been
available since 1998 for reducing IOP in patients who do not
respond adequately to beta-blockers alone, and it has become
widely used and accepted. Brimonidine/timolol (Combigan
®
;
Allergan, Inc.) became available more recently in 2007 for
reducing IOP in patients who require adjunctive or replace-
ment therapy due to inadequately controlled IOP. Fixed com-
binations of a once-daily prostaglandin analog (latanoprost,
bimatoprost, or travoprost) and timolol are available in many
countries but are not yet approved for use in the United States.
Studies related to the fixed combinations latanoprost/timolol,
bimatoprost/timolol, and travaprost/timolol are included in
this review because of their use in other countries.
Efcacy and safety of xed
combinations compared
with component medications
The efficacy and safety of fixed combinations relative to their
active components must be evaluated to obtain regulatory drug
approval. For drug approval by the FDA, a fixed combination
must have better efficacy than each of the component medi-
cations used as monotherapy. The fixed combination should
also be as effective as the component medications given
concomitantly in a 2-bottle regimen. The efficacy and safety
findings from comparison studies of fixed combinations and
their component medications
7–13
are summarized in Table 1.
Fixed-combination dorzolamide/timolol
(Cosopt)
Two separate 3-month, randomized, double-masked studies
reported by Boyle et al
7
and Clineschmidt et al
8
compared
Clinical Ophthalmology 2010:4
3
Fixed combinations in glaucoma therapy
Dovepress
submit your manuscript | www.dovepress.com
Dovepress
Table 1 Comparison studies of the efcacy and safety of xed combinations relative to their active components
Study (n) Study arms Study duration Timing of IOP
measurements
Efcacy in IOP lowering Tolerability
FCDT vs each
component
7
(335)
FCDT bid
Dorzolamide tid
Timolol bid
3 months 8:30 AM (trough) and
10:30 AM (peak) at baseline,
day 1, week 2, and months
1, 2, and 3
FCDT more effective than timolol
or dorzolamide at all measurements
No signicant difference among treatment
groups in the overall incidence of adverse
events
FCDT vs each
component
8
(253)
FCDT bid
Dorzolamide tid
Timolol bid
3 months 9 AM (trough) and 11 AM
(peak) at baseline, week 2,
and months 1, 2, and 3
FCDT more effective than timolol
or dorzolamide at 7 of 8 measurements
Similar incidence of adverse events with
FCDT vs dorzolamide; fewer adverse events
with timolol vs FCDT
FCLT vs each
component
9
(418)
FCLT qd (AM)
Latanoprost qd (PM)
Timolol bid
6 months
(masked phase)
8 AM, 10 AM, and 4 PM at
baseline and weeks 2, 13,
and 26; 8 AM at week 6
FCLT more effective than timolol
or latanoprost across 6 months of treatment
Bulbar conjunctival hyperemia reported for
twice as many latanoprost patients as FCLT
patients; lower incidence with timolol
FCLT vs each
component
10
(436)
FCLT qd (AM)
Latanoprost qd (AM)
Timolol bid
6 months
(masked phase)
8 AM, 10 AM, and 4 PM at
baseline and weeks 2, 13,
and 26; 8 AM at week 6
FCLT more effective than timolol
or latanoprost across 6 months of treatment
Conjunctival hyperemia reported for twice as
many FCLT patients as latanoprost patients;
lower incidence with timolol
FCBT vs each
component
11
(1159)
FCBT bid Brimoni-
dine tid Timolol bid
1 year 8 AM, 10 AM, 3 PM, and
5 PM at baseline, weeks
2 and 6, and months 3, 6,
and 12; 8 AM and 10 AM at
month 9
FCBT more effective than timolol at all
measurements and more effective than
brimonidine at all 8 AM, 10 AM, and 3 PM
measurements
Lower incidence of adverse events (ocular
allergy/inammation, oral dryness) and fewer
discontinuations due to adverse events with
FCBT vs brimonidine; fewer adverse events
with timolol vs FCBT
FCBimT vs each
component
12
(1061)
FCBimT qd (AM)
Bimatoprost qd (PM)
Timolol bid
3 months 8 AM, 10 AM, and 4 PM
at baseline, weeks 2 and
6, and month 3
FCBimT more effective than timolol at all
measurements and bimatoprost at 5 of
9 measurements
Lower incidence of adverse events
(conjunctival hyperemia) and fewer
discontinuations due to adverse events with
FCBimT vs bimatoprost; fewer adverse events
with timolol vs FCBimT
FCTT vs each
component
13
(263)
FCTT qd (AM)
Travoprost (qd)
Timolol (bid)
3 months 8 AM, 10 AM, and 4 PM
at baseline, weeks 2 and
6, and month 3
FCTT more effective than timolol at all
measurements and travoprost at 7 of
9 measurements
Similar incidence of conjunctival hyperemia
with FCTT vs travoprost; lower incidence of
conjunctival hyperemia with timolol vs FCTT
Abbreviations: FCDT, xed-combination dorzolamide/timolol (Cosopt); FCLT, xed-combination latanoprost/timolol (Xalacom); FCBT, xed-combination brimonidine/timolol (Combigan); FCBimT, xed-combination bimatoprost/timolol
(Ganfort); FCTT, xed-combination travoprost/timolol (DuoTrav); bid, twice daily; tid, 3 times daily; qd, daily.
Clinical Ophthalmology 2010:4
4
Higginbotham
Dovepress
submit your manuscript | www.dovepress.com
Dovepress
fixed-combination dorzolamide 2%/timolol 0.5% (FCDT) to
monotherapy with the component medications. The Boyle
study was carried out in 335 patients after washout of previ-
ous medications
7
and the Clineschmidt study in 253 patients
after a 3-week run-in on timolol.
8
FCDT and timolol were
dosed twice daily while dorzolamide was dosed thrice daily.
The results from both studies demonstrated that FCDT was
more effective than either timolol or dorzolamide alone in
reducing IOP at both peak and trough effect. The incidence
of treatment-related adverse events was higher in the FCDT
therapy group than in the timolol monotherapy group in the
Clineschmidt study and similar between groups in the Boyle
study. In each study, the overall incidence of treatment-related
adverse events was similar with FCDT and dorzolamide
monotherapy, and the incidence of the most common side
effects (ocular burning/stinging and taste perversion) was also
similar with FCDT and dorzolamide alone.
7,8
Interestingly,
in the Clineschmidt study, the incidence of conjunctivitis
was significantly lower in the FCDT group than in the
dorzolamide group (0% vs 6%, P = 0.034).
8
It should be
noted that the concentration of the preservative is the same in
FCDT and dorzolamide, although exposure to preservative
was greater with dorzolamide because it was dosed 3-times
daily (tid) vs twice daily (bid). Thus, the observation that
conjunctivitis was less frequent with the former drug suggests
that timolol may limit ocular inflammation or allergy when
it is administered in a fixed combination.
Othe r stud i e s have compa r ed FCDT w ith a
nonfixed combination of dorzolamide and timolol. In
a 12-week, randomized, double-masked study reported
by Hutzelmann et al
14
299 patients run-in on timolol for
2 weeks were randomized to treatment with FCDT bid or
concomitant dorzolamide bid and timolol bid. Based on
the average of month 2 and month 3 data, FCDT and the
nonfixed combination of dorzolamide and timolol were
equivalent in IOP lowering, with the difference in mean
IOP lowering between treatment groups 0.1 mmHg
at both peak and trough effect. There was no significant
difference between the treatment groups in the overall
incidence of treatment-related adverse events, but eye pain
was significantly less common in the FCDT group than
in the concomitant therapy group (0% vs 4%, P = 0.014),
and on biomicroscopy corneal superficial punctate keratitis
was also less common with FCDT than with concomitant
timolol and dorzolamide (1% vs 7%, P = 0.005). In contrast,
in a 3-month, randomized, double-masked study reported
by Strohmaier et al
15
that compared FCDT bid with con-
comitant dorzolamide tid and timolol bid in 242 patients,
FCDT treatment was approximately 1 mmHg less effective
than concomitant therapy with dorzolamide and timolol in
reducing IOP. The incidence of adverse events was similar
between treatment groups, but eyelid pain or discomfort
was significantly more frequent in the FCDT group than in
the concomitant therapy group (6% of FCDT patients vs
1% of concomitant therapy patients, P = 0.036).
Several open-label replacement studies have suggested
that patients may achieve additional IOP lowering when
they are switched from dorzolamide and a beta-blocker to
FCDT.
16–19
It should be noted that Phase IV trials such as these
are subject to bias, because the investigators are not masked
and the study design may influence the study outcomes. For
example, in 2 of the studies
16,17
patients were allowed to be
on a selective beta-blocker before switching to FCDT, and
in all 4 studies, there was a possibility of improved adher-
ence after patients entered the study and switched to FCDT.
Francis et al
19
reported a randomized parallel-group study
of FCDT and concomitant therapy as well as a study of
FCDT replacement of concomitant therapy, and although the
efficacy results favored FCDT in the replacement study, the
randomized controlled trial demonstrated equivalent efficacy
of FCDT and concomitant dorzolamide plus timolol therapy.
Overall, the results of these studies suggest that FCDT and
concomitant dorzolamide plus timolol therapy have similar
efficacy in lowering IOP.
Fixed-combination latanoprost/timolol
(Xalacom)
The first fixed combination of a prostaglandin analog and
timolol to be developed was fixed-combination latanoprost
0.005%/timolol 0.5% (FCLT) (Xalacom
®
; Pfizer, Inc.). To
date, none of the fixed combinations of a prostaglandin
analog and timolol have received FDA approval for use in
the United States.
In a 6-month, randomized, double-masked study reported
by Higginbotham et al
9
of FCLT versus its component
medications used as monotherapy, 418 patients run-in for
2 to 4 weeks on timolol bid were switched to FCLT once
daily (qd) in the morning, latanoprost qd in the evening, or
timolol bid. After 6 months, the mean change from baseline
diurnal IOP was only approximately 1 mmHg larger in the
FCLT group than in the latanoprost group. Similar results
were obtained in a second study of 436 patients that was
reported by Pfeiffer,
10
which was comparable in design to
the Higginbotham study except that latanoprost monotherapy
was dosed in the morning. FCLT reduced diurnal IOP by
1.2 mmHg more than latanoprost monotherapy and 1.9 mmHg
Clinical Ophthalmology 2010:4
5
Fixed combinations in glaucoma therapy
Dovepress
submit your manuscript | www.dovepress.com
Dovepress
more than timolol monotherapy. In both studies, FCLT
lowered IOP substantially more than timolol alone. The dif-
ferences in IOP lowering between FCLT and latanoprost alone
were also statistically significant, but latanoprost monotherapy
was nearly as effective as FCLT. More recently, a small,
randomized, head-to-head study in 28 patients also showed
only a small difference in efficacy (1 mmHg) between FCLT
and latanoprost alone.
20
No statistical analysis of adverse events was reported in
these studies. Bulbar conjunctival hyperemia was reported for
twice as many patients in the latanoprost group (18) as in the
FCLT group (9) in the Higginbotham study,
9
but conjunctival
hyperemia was reported for twice as many FCLT patients (4)
as latanoprost patients (2) in the Pfeiffer study.
10
Therefore
side effects do not appear to be reduced with FCLT compared
with latanoprost monotherapy.
A randomized, double-masked, crossover study in
195 patients showed that FCLT qd in the morning does not lower
IOP as effectively as concomitant treatment with latanoprost
qd in the evening and timolol bid.
21
However, a subsequent
12-week, randomized, double-masked, parallel-group study
in 517 patients demonstrated that FCLT qd in the evening is
as effective in lowering IOP as concomitant treatment with
latanoprost qd in the evening and timolol bid.
22
Fixed-combination brimonidine/timolol
(Combigan)
A study reported by Sherwood et al
11
compared fixed-
combination brimonidine 2%/timolol 0.5% (FCBT) with
its component medications used separately as monotherapy.
In this 12-month, randomized, double-masked study,
1159 patients with glaucoma or ocular hypertension were
washed out of any previous IOP-lowering medication and
randomized to treatment with FCBT bid, brimonidine 2%
tid, or timolol 0.5% bid. Throughout 12 months of treat-
ment, twice-daily FCBT was significantly more effective
than either twice-daily timolol or thrice-daily brimonidine
in reducing IOP. Mean IOP reductions from baseline were
significantly greater with FCBT compared with timolol
at all measurements (P 0.002) and compared with
brimonidine at all measurements except those at 5 PM, after
the afternoon dose of brimonidine monotherapy (P 0.001).
As might be expected due to the addition of a second drug,
the fixed combination was less well tolerated than timolol
monotherapy. Interestingly, however, FCBT demonstrated
an improved safety profile compared with brimonidine
monotherapy. There was a significantly lower incidence of
treatment-related adverse events (53.0% vs 62.8%; P = 0.006)
and discontinuations for adverse events (14.3% vs 30.4%;
P 0.001) in patients treated with FCBT than in those
treated with brimonidine alone. The rate of ocular allergy
(allergic conjunctivitis) was 45% lower with FCBT than with
brimonidine monotherapy (P = 0.020).
The reasons for the decrease in drug-related allergy in
patients treated with FCBT compared with brimonidine
alone are not fully understood. The decrease in allergy
may have been due in part to decreased ocular exposure
to brimonidine, since FCBT was dosed twice daily and
brimonidine was dosed thrice daily as recommended in its
prescribing information. However, in a study of 102 patients
prospectively treated with twice-daily FCBT compared with
a historical control group of 102 patients treated with twice-
daily brimonidine monotherapy, the rate of ocular allergy was
lower with FCBT than with brimonidine monotherapy even
when both treatments were dosed twice daily.
23
A study reported by Goni
24
compared FCBT with a
nonfixed combination of brimonidine and timolol. In this
12-week, randomized, double-masked study, 371 patients
run-in on any monotherapy for at least 3 weeks were switched
to treatment with FCBT bid or concomitant brimonidine bid
and timolol bid. Throughout 12 weeks of treatment, FCBT
and the nonfixed combination of brimonidine and timolol
were equivalent in IOP lowering. Differences between
treatment groups were 0.30 mmHg for mean change from
baseline IOP and 0.35 mmHg for mean IOP, and none
were statistically significant. For patients who were run-in
on a beta-blocker, the switch to FCBT provided a mean
additional IOP reduction of 4.4 to 5.7 mmHg. Both fixed and
nonfixed brimonidine/timolol treatment were well tolerated,
and there were no differences in adverse events between
treatment groups.
Fixed-combination bimatoprost/timolol
(Ganfort)
The prostaglandin analog bimatoprost has been combined
with timolol in fixed-combination bimatoprost 0.03%/timolol
0.5% (FCBimT) (Ganfort
®
; Allergan, Inc.). In a 3-month,
randomized, double-masked study reported by Brandt et al
12
of FCBimT versus its component medications used as
monotherapy, 1061 patients were treated with FCBimT qd
in the morning, bimatoprost qd in the evening, or timolol
bid. After 3 months, the mean change from baseline diurnal
IOP in the FCBimT group (8.1 mmHg) was larger than in
the timolol group (6.4 mmHg) but not the bimatoprost group
(7.9 mmHg). Although FCBimT was consistently more
effective than timolol at reducing IOP, the mean reduction
Clinical Ophthalmology 2010:4
6
Higginbotham
Dovepress
submit your manuscript | www.dovepress.com
Dovepress
from baseline IOP was significantly larger with FCBimT than
with bimatoprost alone at only 5 of 9 follow-up timepoints.
However, FCBimT demonstrated improved tolerability
compared with bimatoprost monotherapy. Both the overall
incidence of treatment-related adverse events and the
incidence of discontinuations due to adverse events were
significantly reduced in the FCBimT group compared with
the bimatoprost group. The most frequent side effect of
treatment, conjunctival hyperemia, was reported for 22.7%
of FCBimT patients compared with 38.5% of bimatoprost
patients.
In a 3-week, randomized, double-masked, parallel-group
study reported by Hommer et al
25
FCBimT was compared
with nonfixed bimatoprost and timolol or with bimatoprost
alone in 445 patients. FCBimT qd in the morning reduced
IOP as effectively as concomitant treatment with bimato-
prost qd in the evening and timolol bid at the 3 follow-up
timepoints in the study (hours 1, 2, and 8 at week 3).
25
On
biomicroscopy, the incidence of a clinically significant
increase in conjunctival hyperemia was significantly lower
with FCBimT (8.5%) than with bimatoprost monotherapy
(18.9%) and numerically lower than with the nonfixed com-
bination of bimatoprost and timolol (12.5%).
Fixed-combination travoprost/timolol
(DuoTrav)
The prostaglandin analog travoprost has been combined
with timolol in fixed-combination travoprost 0.004%/timolol
0.5% (FCTT) (DuoTrav
®
; Alcon Laboratories, Inc.). In a
3-month, randomized, double-masked study reported by
Barnebey et al
13
of FCTT versus its component medications
used as monotherapy, 263 patients were treated with FCTT
qd in the morning, travoprost qd in the evening, or timolol
bid. FCTT reduced IOP substantially more than timolol
alone throughout the study. At month 3, the mean reduc-
tion from baseline IOP was approximately 1.1 to 2.4 mmHg
larger in the FCTT group than in the travoprost group,
but the difference was statistically significant at only
2 of 3 timepoints, and the reductions were measured from a
baseline IOP that was approximately 0.6 mmHg higher in the
FCTT group. No statistical analysis of adverse events in the
study was reported. The incidence of conjunctival hyperemia
was 14.1% in the FCTT group, 11.6% in the travoprost group,
and 1.1% in the timolol group.
Two studies have evaluated the efficacy and safety of
FCTT qd in the morning compared with concomitant
treatment with travoprost qd in the evening and timolol qd
in the morning.
26,27
In the study reported by Schuman et al
26
the mean reduction from baseline IOP was greater with
concomitant therapy than with FCTT by up to approximately
1.0 mmHg at 5 of 9 follow-up timepoints and statistically
similar between groups at the remaining timepoints.
Similarly, in the study reported by Hughes et al
27
mean IOPs
were significantly lower in the concomitant therapy group
than in the FCTT group by up to approximately 1.0 mmHg
at 4 of 9 timepoints during treatment. These results suggest
that FCTT is slightly less effective than concomitant therapy
with travoprost and timolol. The overall incidence of adverse
events was similar between treatment groups in both studies,
although in one study the incidence of conjunctival hyper-
emia was lower with FCTT (14.3%) than with concomitant
therapy (23.4%).
26
Comparison of dorzolamide/timolol
and brimonidine/timolol
In a 2-month, open-label, surveillance study (CEED II) of
fixed brimonidine/timolol use in 2133 patients at 123 centers
in Canada, patients switched from FCDT monotherapy
to FCBT monotherapy achieved average additional IOP
lowering of 2.2 to 2.6 mmHg.
28
As discussed previously,
open-label drug replacement studies do not provide strong
evidence of comparative drug efficacy, but the safety and
tolerability findings of the study may be more informative.
On a questionnaire given in the study, patients reported
less burning, stinging, and metallic taste after switching
from FCDT to FCBT, suggesting thatxed brimonidine/
timolol may be better tolerated than xed dorzolamide/
timolol.
28
In support of this suggestion, in a randomized, double-
masked, paired-eye study in 30 normal subjects, subject
scores of ocular discomfort at 30 to 40 seconds after
eyedrop instillation were significantly lower with fixed
brimonidine/timolol than with fixed dorzolamide/timolol
(P 0.001).
29
Although it is possible that the threshold for
tolerating side effects is lower in normal subjects than in
glaucoma patients with a potentially blinding eye disease,
these results suggest that FCBT eyedrops are more comfort-
able than FCDT eyedrops upon instillation.
29
The difference
between the fixed combinations in ocular comfort may result
from the difference in the pH of the formulations. Burning
and stinging are commonly associated with use of acidic
ophthalmic solutions,
30,31
and FCDT is formulated at a pH
of approximately 5.65. In contrast, the pH of FCBT ranges
from 6.5 to 7.3 during its shelf life. The neutral pH of the
fixed brimonidine/timolol formulation is likely to account
for its better tolerability.
Clinical Ophthalmology 2010:4
7
Fixed combinations in glaucoma therapy
Dovepress
submit your manuscript | www.dovepress.com
Dovepress
The comparative efficacy and tolerability of FCDT and
FCBT has not been well studied in head-to-head trials. In a
randomized, investigator-masked, crossover study comparing
FCDT and FCBT in 30 patients, there were no statistically
significant differences in efficacy after 4 weeks of treatment.
32
The study was underpowered to detect a 2 mmHg difference
in efficacy between the fixed combinations.
32
Nonetheless,
the similarity in the mean diurnal IOP reductions provided
by the fixed combinations (7.4 mmHg for FCDT and 7.8
mmHg for FCBT) suggest that FCDT and FCBT had similar
efficacy in reducing IOP. Ocular stinging/burning was sig-
nificantly more common with fixed dorzolamide/timolol
(9 patients) than with fixed brimonidine/timolol (1 patient,
P = 0.027). In a randomized parallel-group comparison study,
after 3 months of treatment the mean IOP was lower (15.6
vs 17.2 mmHg, P = 0.040) and the mean reduction from
baseline IOP was greater (7.7 vs 6.7 mmHg, P = 0.040) in
patients treated with FCBT monotherapy than in patients
treated with FCDT monotherapy.
33
On a comfort/tolerability
questionnaire, patients treated with fixed brimonidine/timolol
reported significantly less stinging (P 0.001), burning
(P = 0.015), and unusual taste (P = 0.005) compared with
patients treated with fixed dorzolamide/timolol.
Overall, the results of the clinical studies that have
been published suggest that fixed brimonidine/timolol pro-
vides similar or greater IOP lowering compared with fixed
dorzolamide/timolol and also demonstrates better ocular
tolerability upon instillation. The greater comfort of fixed
brimonidine/timolol eyedrops might lead to better adherence
to treatment. Moreover, fixed brimonidine/timolol has a better
safety profile than brimonidine monotherapy. The lower rate
of ocular allergy associated with fixed brimonidine/timolol
compared with brimonidine alone is clinically significant,
because chronic use of brimonidine is sometimes limited
by the occurrence of ocular allergy. These favorable safety
and efficacy findings suggest that fixed brimonidine/timolol
may have an important role in glaucoma management.
Additional studies are needed to further evaluate the relative
efficacy and tolerability of fixed brimonidine/timolol and
fixed dorzolamide/timolol in lowering IOP as well as patient
adherence and persistence with treatment.
Monotherapy remains the preferred initial choice
of treatment in glaucoma; these fixed combinations
should generally be used only when monotherapy has not
provided low enough IOP. Both fixed dorzolamide/timolol
and fixed brimonidine/timolol effectively reduce IOP when
used alone
7,8,11
or adjunctively with a prostaglandin analog,
28,34
the most common rst-line therapy.
35
Further, both fixed
dorzolamide/timolol
7,8
and fixed brimonidine/timolol
11
reduce
IOP more effectively than monotherapy with their component
medications.
Comment
The use of fixed combinations is preferred over separate
use of both components primarily to facilitate adherence
and persistence with treatment. Adherence is an important
concern in glaucoma because up to 80% of patients may
not take their medication as prescribed.
1
One of the primary
reasons for nonadherence in glaucoma is the inconvenience
associated with eyedrop instillation.
36
It is more convenient
(both easier and faster) to instill 1 drop of a fixed combination
than 2 drops from separate bottles of the component medi-
cations. Moreover, results of a recent study have suggested
that a substantial proportion of patients on multiple drops
(22%) wait less than 3 minutes after taking an IOP-lowering
medication before instilling a second medication.
37
For those
patients, a washout effect may occur, but no washout effect is
possible when only 1 drop is given rather than 2. Finally, for
some patients cost is also a significant factor reducing adher-
ence with prescription medications.
38
The average wholesale
price (AWP) of medications changes over time, and based on
the AWP, the cost of a fixed combination is not necessarily
less than the cost of buying the components separately.
39,40
However, for patients with prescription insurance and copays,
the cost of a fixed combination is likely to be less than the
combined cost of the component medications, reducing one
possible barrier to compliance with treatment. The availabil-
ity of a generic for FCDT is a potential advantage of use of
this fixed combination, as it may further reduce the potential
for cost to be a barrier to compliance.
A fixed combination should contain drugs that are safe
and effective and that work well in combination with each
other. The lack of availability of fixed combinations con-
taining pilocarpine in the United States can probably be
explained by the poor tolerability profile of pilocarpine. In
contrast, fixed combinations of the prostaglandin analogs
and timolol have not been approved for use in the United
States. Based on the studies submitted to the FDA related
to timolol/latanoprost, it is not clear that the improvement
in efficacy with the prostaglandin analog/timolol fixed com-
binations relative to prostaglandin analog monotherapy is
clinically significant. However, given the approval of these
fixed combinations in other countries, it may be that subsets
of patients are responsive to this therapy. Furthermore, the
convenience of having 2 medications in 1 bottle cannot be
underestimated.
Clinical Ophthalmology 2010:4
8
Higginbotham
Dovepress
submit your manuscript | www.dovepress.com
Dovepress
In summary, fixed combinations are important adjuncts
to the armamentarium of available glaucoma therapies and
offer critical options for patients who require more than one
medication to control intraocular pressure.
Acknowledgment
Kate Ivins, PhD, provided freelance medical writing
assistance.
Disclosures
The author declares no proprietary interests in the medica-
tions discussed in this review. The author is a consultant for
Alcon, Allergan, and Pfizer and has received speaker fees
and grant support from each of these companies. Allergan
provided funds for a medical writer to assist in the prepara-
tion of this review. The author had complete and sole control
over the content of the review.
References
1. Olthoff CM, Schouten JS, van de Borne BW, Webers CA. Noncompliance
with ocular hypotensive treatment in patients with glaucoma or
ocular hypertension an evidence-based review. Ophthalmology.
2005;112(6):953–961.
2. Robin AL, Covert D. Does adjunctive glaucoma therapy affect
adherence to the initial primary therapy? Ophthalmology. 2005;112(5):
863–868.
3. Van Wijk BL, Klungel OH, Heerdink ER, de Boer A. Rate and
determinants of 10-year persistence with antihypertensive drugs.
J Hypertens. 2005;23(11):2101–2107.
4. Dezii CM. A retrospective study of persistence with single-pill combina-
tion therapy vs concurrent two-pill therapy in patients with hypertension.
Manag Care. 2000;9(9 Suppl):2–6.
5. Taylor AA, Shoheiber O. Adherence to antihypertensive therapy with
fixed-dose amlodipine besylate/benazepril HCl versus comparable
component-based therapy. Congest Heart Fail. 2003;9(6):324–332.
6. Strahlman E, Tipping R, Vogel R. A double-masked, randomized
1-year study comparing dorzolamide (Trusopt), timolol, and
betaxolol. International Dorzolamide Study Group. Arch Ophthalmol.
1995;113(8):1009–1016.
7. Boyle JE, Ghosh K, Gieser DK, Adamsons IA. A randomized trial
comparing the dorzolamide-timolol combination given twice daily
to monotherapy with timolol and dorzolamide. Dorzolamide-Timolol
Study Group. Ophthalmology. 1998;105(10):1945–1951.
8. Clineschmidt CM, Williams RD, Snyder E, Adamsons IA. A randomized
trial in patients inadequately controlled with timolol alone comparing
the dorzolamide-timolol combination to monotherapy with timolol or
dorzolamide. Dorzolamide-Timolol Combination Study Group. Oph-
thalmology. 1998;105(10):1952–1959.
9. Higginbotham EJ, Feldman R, Stiles M, Dubiner H; Fixed Combi-
nation Investigative Group. Latanoprost and timolol combination
therapy vs monotherapy: one-year randomized trial. Arch Ophthalmol.
2002;120(7):915–922.
10. Pfeiffer N; European Latanoprost Fixed Combination Study Group.
A comparison of the fixed combination of latanoprost and timolol
with its individual components. Graefes Arch Clin Exp Ophthalmol.
2002;240(11):893–899.
11. Sherwood MB, Craven ER, Chou C, et al. Twice-daily 0.2% brimonidine-
0.5% timolol fixed-combination therapy vs monotherapy with timolol
or brimonidine in patients with glaucoma or ocular hypertension:
a 12-month randomized trial. Arch Ophthalmol. 2006;124(9):1230–1238.
12. Brandt JD, Cantor LB, Katz LJ, Batoosingh AL, Chou C, Bossowska I;
Ganfort Investigators Group II. Bimatoprost/timolol fixed combination:
a 3-month double-masked, randomized parallel comparison to its
individual components in patients with glaucoma or ocular hypertension.
J Glaucoma. 2008;17(3):211–216.
13. Barnebey HS, Orengo-Nania S, Flowers BE, et al. The safety and effi-
cacy of travoprost 0.004%/timolol 0.5% fixed combination ophthalmic
solution. Am J Ophthalmol. 2005;140(1):1–7.
14. Hutzelmann J, Owens S, Shedden A, Adamsons I, Vargas E;
Comparison of the safety and efficacy of the fixed combination of
dorzolamide/timolol and the concomitant administration of dorzolamide
and timolol: a clinical equivalence study. International Clinical Equiva-
lence Study Group. Br J Ophthalmol. 1998;82(11):1249–1253.
15. Strohmaier K, Snyder E, DuBiner H, Adamsons I. The efficacy and
safety of the dorzolamide-timolol combination versus the concomitant
administration of its components. Dorzolamide-Timolol Study Group.
Ophthalmology. 1998;105(10):1936–1944.
16. Choudri S, Wand M, Shields MB. A comparison of dorzolamide-
timolol combination versus the concomitant drugs. Am J Ophthalmol.
2000;130(6):832–833.
17. Martone J, Mead A. Combination treatment may improve efficacy. Rev
Ophthalmol. 2001;8(September):82–84.
18. Bacharach J, Delgado MF, Iwach AG. Comparison of the efficacy
of the fixed-combination timolol/dorzolamide versus concomitant
administration of timolol and dorzolamide. J Ocul Pharmacol Ther.
2003;19(2):93–96.
19. Francis BA, Du LT, Berke S, Ehrenhaus M, Minckler DS; Cosopt
Study Group. Comparing the fixed combination dorzolamide-timolol
(Cosopt) to concomitant administration of 2% dorzolamide (Trusopt)
and 0.5% timolol a randomized controlled trial and a replacement
study. J Clin Pharm Ther. 2004;29(4):375–380.
20. Magacho L, Reis R, Shetty RK, Santos LC, Avila MP. Efficacy of
latanoprost or fixed-combination latanoprost-timolol in patients
switched from a combination of timolol and a nonprostaglandin
medication. Ophthalmology. 2006;113(3):442–445.
21. Diestelhorst M, Larsson LI; European Latanoprost Fixed Combination
Study Group. A 12 week study comparing the fixed combination of
latanoprost and timolol with the concomitant use of the individual
components in patients with open angle glaucoma and ocular
hypertension. Br J Ophthalmol. 2004;88(2):199–203.
22. Diestelhorst M, Larsson LI; European-Canadian Latanoprost Fixed
Combination Study Group. A 12-week, randomized, double-masked,
multicenter study of the fixed combination of latanoprost and timolol
in the evening versus the individual components. Ophthalmology.
2006;113(1):70–76.
23. Motolko MA. Comparison of allergy rates in glaucoma patients
receiving brimonidine 0.2% monotherapy versus xed-combination
brimonidine 0.2%-timolol 0.5% therapy. Curr Med Res Opin.
2008;24(9):2663–2667.
24. Goni FJ; Brimonidine/Timolol Fixed Combination Study Group. 12-week
study comparing the fixed combination of brimonidine and timolol with
concomitant use of the individual components in patients with glaucoma
and ocular hypertension. Eur J Ophthalmol. 2005;15(5):581–590.
25. Hommer A; Ganfort Investigators Group I. A double-masked, random-
ized, 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(1):53–62.
26. Schuman JS, Katz GJ, Lewis RA, et al. Efficacy and safety of a fixed
combination of travoprost 0.004%/timolol 0.5% ophthalmic solution
once daily for open-angle glaucoma or ocular hypertension. Am J
Ophthalmol. 2005;140(2):242–250.
27. Hughes BA, Bacharach J, Craven ER, et al. A three-month, multi-
center, double-masked study of the safety and efficacy of travoprost
0.004%/timolol 0.5% ophthalmic solution compared to travoprost
0.004% ophthalmic solution and timolol 0.5% dosed concomitantly in
subjects with open angle glaucoma or ocular hypertension. J Glaucoma.
2005;14(5):392–399.
Clinical Ophthalmology 2010:4
Clinical Ophthalmology
Publish your work in this journal
Submit your manuscript here: http://www.dovepress.com/clinical-ophthalmology-journal
Clinical Ophthalmology is an international, peer-reviewed journal
covering all subspecialties within ophthalmology. Key topics include:
Optometry; Visual science; Pharmacology and drug therapy in eye
diseases; Basic Sciences; Primary and Secondary eye care; Patient
Safety and Quality of Care Improvements. This journal is indexed on
PubMed Central and CAS, and is the official journal of The Society of
Clinical Ophthalmology (SCO). The manuscript management system
is completely online and includes a very quick and fair peer-review
system, which is all easy to use. Visit http://www.dovepress.com/
testimonials.php to read real quotes from published authors.
9
Fixed combinations in glaucoma therapy
Dovepress
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
28. Ahmed I. CEED II: an in-depth look at the latest findings. Clin Surg J
Ophthalmol. 2007;25(1):1–5.
29. Chan K, Testa M, McCluskey P. Ocular comfort of combination
glaucoma therapies: brimonidine 0.2%/timolol 0.5% compared
with dorzolamide 2%/timolol 0.5%. J Ocul Pharmacol Ther.
2007;23(4):372–376.
30. Shafi T, Koay P. Randomised prospective masked study comparing
patient comfort following the instillation of topical proxymetacaine
and amethocaine. Br J Ophthalmol. 1998;82(11):1285–1287.
31. Silver LH. Ocular comfort of brinzolamide 1.0% ophthalmic suspension
compared with dorzolamide 2.0% ophthalmic solution: results from two
multicenter comfort studies. Brinzolamide Comfort Study Group. Surv
Ophthalmol. 2000;44 Suppl 2:S141–S145.
32. Arcieri ES, Arcieri RS, Pereira AC, Andreo EG, Finotti IG, Filho WF.
Comparing the fixed combination brimonidine-timolol versus fixed
combination dorzolamide-timolol in patients with elevated intraocular
pressure. Curr Med Res Opin. 2007;23(4):683–689.
33. Nixon DR, Yan DB, Chartrand JP, Piemontesi RL, Simonyi S,
Hollander DA. Three-month, randomized, parallel-group comparison
of brimonidine-timolol versus dorzolamide-timolol fixed-combination
therapy. Curr Med Res Opin. 2009;25(7):1645–1653.
34. Lesk MR, Koulis T, Sampalis F, Sampalis JS, Bastien NR. Effectiveness
and safety of dorzolamide-timolol alone or combined with latanoprost
in open-angle glaucoma or ocular hypertension. Ann Pharmacother.
2008;42(4):498–504.
35. McKee HD, Gupta MS, Ahad MA, Saldaña M, Innes JR. First-choice
treatment preferences for primary open-angle glaucoma in the United
Kingdom. Eye. 2005;19(8):923–924.
36. Patel SC, Spaeth GL. Compliance in patients prescribed eyedrops for
glaucoma. Ophthalmic Surg. 1995;26(3):233–236.
37. Sleath B, Robin AL, Covert D, Byrd JE, Tudor G, Svarstad B. Patient-
reported behavior and problems in using glaucoma medications.
Ophthalmology. 2006;113(3):431–436.
38. Gellad WF, Haas JS, Safran DG. Race/ethnicity and nonadherence to
prescription medications among seniors: results of a national study.
J Gen Intern Med. 2007;22(11):1572–1578.
39. Fiscella RG, Green A, Patuszynski DH, Wilensky J. Medical therapy cost
considerations for glaucoma. Am J Ophthalmol. 2003;136(1):18–25.
40. Rylander NR, Vold SD. Cost analysis of glaucoma medications. Am J
Ophthalmol. 2008;145(1):106–113.
    • "Several patients do not respond to one type of medication and need a combination therapy for effective IOP control. It has been demonstrated that fixed combination agents reduce IOP more effectively than either of their component medica- tions used separately as monotherapy [Higginbotham, 2010; Woodward and Chen, 2007]. Several fixed combination glaucoma drugs are currently available in the USA and include: Cosopt (timolol maleate 0.5% and dorzolamide hydrochloride 2%; Merck Sharp & Dohme Corp., North Wales, PA, USA), Combigan (brimonidine tartrate 0.2% and timolol maleate 0.5%; Allergan Inc., Irvine, CA, USA), and Simbrinza (brimonidine tartrate 0.2% and brinzolamide 1%; Alcon Laboratories, Inc., Fort Worth, TX, USA). "
    [Show abstract] [Hide abstract] ABSTRACT: Lowering intraocular pressure (IOP) is the only proven therapeutic intervention for glaucomatous optic neuropathy. Despite advances in laser and microsurgical techniques, medical IOP reduction remains the first-line treatment option for the majority of patients with open-angle glaucoma. Prostaglandin analogs are the most efficacious topical agents and carry a remarkable safety profile. Topical beta-blockers, alpha-agonists, and carbonic anhydrase inhibitors are often employed as adjunctive agents for further IOP control. Newer preserved and nonpreserved formulations are available and appear to be less toxic to the ocular surface. Oral carbonic anhydrase inhibitors, miotic agents, and hyperosmotics are infrequently used due to a host of potentially serious adverse events. Medical therapies on the horizon include rho-kinase inhibitors, neuroprotective interventions, and gene therapies.
    Article · Jan 2014
    • "Timolol+dorzolamide FDC was the most commonly prescribed FDC. It is more convenient (both easier and faster) to instill 1 drop of a fixed combination than 2 drops from separate bottles of the component medications.[14] So, FDCs if rational, offer benefits of convenience, cost and safety. "
    [Show abstract] [Hide abstract] ABSTRACT: To study drug use pattern in patients of primary open angle glaucoma (POAG) and to analyze the cost of different anti-glaucoma medications. This prospective study was carried in the glaucoma clinic of a tertiary care teaching hospital over a period of 9 months. The data collected for patients with POAG included the patient's demographic details and the drugs prescribed. Data were analyzed for drug use pattern and cost drugs used. In a total 180 prescriptions (297 drugs) analyzed, most drugs (83.83%) were prescribed by topical route as eye drops. β blockers (93.88%) were found to be the most frequently prescribed for POAG. Timolol (82.22%) was the most frequently prescribed drug and timolol with acetazolamide (17.22%) was the most commonly prescribed drug combination. Fixed dose combinations constituted 26.66% of prescriptions. β blockers were found to be cheaper than other anti-glaucoma drugs while prostaglandins analogs were the costliest. Instructions about the route, frequency and duration of treatment were present in all prescriptions. However, instructions regarding instillation of eye drops were missing in all prescriptions.
    Full-text · Article · Mar 2013
    • "This, in and of itself, can lead to a vicious cycle, because more complex regimens with multiple medications may present an even greater challenge to adherence. (Tsai, 2006; Higginbotham, 2010) Intermittent dosing will not lead to sustained lowering of IOP, and deterioration of the visual field may increase. If the patient presents at the next visit with an optimal IOP, but there is evidence of visual field progression, it is impossible to distinguish whether the target IOP needs to be lowered by adding therapy, or if the target IOP is appropriate and the progression is due to nonadherence. "
    Full-text · Chapter · Nov 2011 · Indian Journal of Pharmacology
Show more