Drugs Aging 2006; 23 (12): 977-995

ADIS DRUG EVALUATION 1170-229X/06/0012-0977/$39.95/0

© 2006 Adis Data Information BV. All rights reserved.

Topical Dorzolamide 2%/Timolol 0.5%

Ophthalmic Solution
A Review of its Use in the Treatment of Glaucoma and
Ocular Hypertension
James E. Frampton and Caroline M. Perry
Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer
Health, Conshohocken, Pennsylvania, USA

Various sections of the manuscript reviewed by:

A. Akman, Department of Ophthalmology, Baskent University, Ankara, Turkey; R.D. Fechtner, Institute of
Ophthalmology and Visual Science, New Jersey Medical School-UMDNJ, Newark, New Jersey, USA; R.M.
Feldman, Department of Ophthalmology and Visual Science, University of Texas Medical School at Houston,
Houston, Texas, USA; R. Fiscella, Department of Pharmacy Practice, University of Illinois at Chicago,
Chicago, Illinois, USA; I. Goldberg, Department of Ophthalmology, University of Sydney, Sydney, New
South Wales, Australia; A. Harris, Department of Ophthalmology, Indiana University School of Medicine,
Indianapolis, Indiana, USA; I. Januleviciene, Eye Clinic of Kaunas University of Medicine, Kaunas, Lithuania;
W.C. Stewart, Carolina Eye Institute, University of South Carolina School of Medicine, Columbia, South
Carolina, USA.

Data Selection
Sources: Medical literature published in any language since 1980 on ‘dorzolamide/timolol’, identified using MEDLINE and EMBASE,
supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of
published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing
the drug.
Search strategy: MEDLINE and EMBASE search terms were ‘dorzolamide’ and ‘timolol’ in title. AdisBase search terms were ‘dorzolamide/
timolol’ or ‘dorzolamide’ and ‘timolol’ in title. Searches were last updated 8 Nov 06.
Selection: Studies in patients with glaucoma or ocular hypertension who received topical dorzolamide/timolol. Inclusion of studies was
based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were
preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Dorzolamide, timolol, glaucoma, ocular hypertension, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

Contents
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 978
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 980
2. Pharmacodynamic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 981
3. Pharmacokinetic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 982
3.1 Dorzolamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 982
3.2 Timolol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 982
4. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 982
4.1 Versus Monotherapy and Concomitant Therapy with the Individual Components . . . . . . . . . . 983
4.2 Versus Prostaglandin Monotherapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 984
4.2.1 Versus Latanoprost 0.005% . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 984
4.2.2 Versus Bimatoprost 0.03% . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 986
978 Frampton & Perry

4.2.3 Versus Travoprost 0.004% . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 986

4.3 Versus Other Concomitant Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 987
4.4 Versus Other Fixed Combinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 987
4.4.1 Latanoprost 0.005%/Timolol 0.5% . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 987
4.4.2 Brimonidine 0.2%/Timolol 0.5% . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 988
5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 988
5.1 Ocular and Local Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 988
5.1.1 Comparisons with Other Ocular Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 989
5.2 Systemic Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 989
6. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 990
7. Place of Dorzolamide/Timolol in the Management of Glaucoma and Ocular Hypertension . . . . . 990

Summary
Abstract Topically administered dorzolamide 2%/timolol 0.5% (dorzolamide/timolol
ophthalmic solution; Cosopt®) is a fixed combination of two ocular hypotensive
drugs (the carbonic anhydrase inhibitor dorzolamide and the β-adrenoceptor
antagonist timolol) that have an additive effect on lowering intraocular pressure
(IOP) when administered together. This product is indicated for the treatment of
elevated IOP in patients with open-angle glaucoma or ocular hypertension (OH)
who are insufficiently responsive to topical β-adrenoceptor antagonist monother-
apy. As such, it can be considered for use in individuals who, as a consequence of
failing to achieve target IOP with β-adrenoceptor antagonist monotherapy, require
the addition or substitution of another class of topical antiglaucoma medication.
Clinical trials have demonstrated that dorzolamide/timolol (1 drop per eye twice
daily) is an effective and generally well tolerated fixed combination for lowering
IOP in patients with open angle glaucoma or OH, including individuals uncon-
trolled on β-adrenoceptor antagonist monotherapy. Compared with concomitant
therapy with the individual components, the primary advantage of fixed combina-
tion dorzolamide/timolol is convenience.

Pharmacological Dorzolamide/timolol comprises dorzolamide, a highly selective inhibitor of car-

Properties bonic anhydrase isoenzyme II, and timolol, a nonselective β-adrenergic antago-
nist. Both components decrease elevated IOP by inhibiting aqueous humour
production; they each achieve this by a different mechanism of action and have an
additive effect when administered together. Dorzolamide/timolol also improves
some markers of ocular blood flow (an effect likely attributable to the dorzo-
lamide component).
After topical administration, both components enter the systemic circulation.
Systemically absorbed dorzolamide undergoes slow hepatic metabolism; both the
single N-desethyl metabolite and the parent drug accumulate in erythrocytes,
although the resulting inhibition of carbonic anhydrase isoenzyme I and II (by
N-desethyldorzolamide and dorzolamide, respectively) is not sufficient to disrupt
normal physiological function. Dorzolamide and its metabolite are eliminated
primarily by the kidneys.
Timolol has a high systemic bioavailability via the ocular route and may cause
typical systemic β-adrenoceptor antagonist effects. The mean peak plasma timolol
concentration was 0.46 and 0.35 μg/L after the morning and afternoon dose,
respectively, in six subjects who received topical timolol 0.5% twice daily.

© 2006 Adis Data Information BV. All rights reserved. Drugs Aging 2006; 23 (12)
Dorzolamide 2%/Timolol 0.5%: A Review 979

Therapeutic Efficacy
Randomised clinical trials of 1.5–6 months’ duration have compared the
IOP-lowering efficacy of dorzolamide 2%/timolol 0.5% 1 drop per eye twice daily
with that of other topically administered ophthalmic therapies in patients with
glaucoma (almost exclusively primary open angle glaucoma) or OH enrolled at
one or more centres. All of these studies were preceded by a run-in period on
timolol 0.5% twice daily or an ocular hypotensive medication washout period.
When evaluated in large, single- or double-masked, parallel-group compari-
sons, the IOP-lowering effect of dorzolamide/timolol was superior to that of
monotherapy with each of the individual components (administered at their
recommended dosing frequencies), equivalent to that of dorzolamide 2% two or
three times daily plus timolol 0.5% twice daily given concomitantly, equivalent to
that of monotherapy with latanoprost 0.005% once daily, and generally equivalent
to that of brimonidine 0.2% twice daily plus timolol 0.5% twice daily given
concomitantly. Whereas reductions in IOP significantly favoured monotherapy
with bimatoprost 0.03% once daily (in patients inadequately controlled on β-adre-
noceptor antagonist monotherapy) and fixed combination therapy with lata-
noprost 0.005%/timolol 0.5% once daily in large, double-masked, parallel-group
comparisons, the IOP-lowering effect of dorzolamide/timolol was generally simi-
lar to that of these agents in small, single- or double-masked, cross-over compari-
sons. The IOP-lowering effect of dorzolamide/timolol was less than that of
latanoprost 0.005% once daily plus brimonidine 0.2% twice daily given concomi-
tantly in small, double-masked, parallel-group, comparisons.
Variable results were seen when dorzolamide/timolol was compared with
monotherapy with travoprost 0.004% once daily or with fixed combination
therapy with brimonidine 0.2%/timolol 0.5% (brimonidine/timolol) twice daily in
small, single-blind, cross-over or parallel-group studies. Dorzolamide/timolol was
either more or less effective than travoprost 0.004%, but similarly or less effective
than brimonidine/timolol, in lowering IOP.
Reductions in IOP seen with the fixed combination were maintained for up to
1 year in a non-blind extension of one study.

Tolerability Topically administered dorzolamide/timolol is generally well tolerated and has an

adverse event profile reflecting that of the individual components. No additional
tolerability issues specific to the fixed combination have been identified. The most
common adverse events in patients with glaucoma or OH who received dorzo-
lamide/timolol in large, randomised clinical trials were ocular and local reactions,
including burning and/or stinging of the eyes (mostly of mild or moderate
intensity and transient; likely due to the dorzolamide component) and dysgeusia.
In large comparative trials, the incidences of drug-related ocular burning and/
or stinging and dysgeusia with dorzolamide/timolol were mostly higher than those
with latanoprost 0.005% and consistently higher than those with bimatoprost
0.03% or brimonidine 0.2% plus timolol 0.5% given concomitantly. Similarly,
ocular burning, ocular stinging and unusual taste were reported more often by
dorzolamide/timolol recipients than brimonidine/timolol recipients, based on
preliminary reports of small comparative studies. More dorzolamide/timolol than
latanoprost/timolol recipients experienced transient eye pain, although conjuncti-
val hyperaemia was less common with dorzolamide/timolol than with bimatoprost
0.03%. The tolerability profile of dorzolamide/timolol was similar to that of

© 2006 Adis Data Information BV. All rights reserved. Drugs Aging 2006; 23 (12)
980 Frampton & Perry

brimonidine 0.2% plus latanoprost 0.005% given concomitantly in small compar-

ative studies.
Systemic adverse events such as headache, nausea and urolithiasis (likely due
to the dorzolamide component) and bradycardia/sinus bradycardia, cardiac fail-
ure, heart block, hypotension, and respiratory symptoms/failure (likely due to the
timolol component) have been reported, albeit infrequently, with dorzolamide/
timolol during clinical trials or post-marketing experience.

1. Introduction management for patients with glaucoma and/or

Glaucoma, the second leading cause of blindness
worldwide,[1] refers to a group of eye disorders
characterised by progressive optic neuropathy and
visual field loss. The incidence of glaucoma in-
creases with advancing age;[2,3] along with age-relat-
ed cataracts, age-related macular degeneration and
diabetic retinopathy, glaucoma is one of the four
most frequent causes of chronic visual impairment
in the elderly.[3] Primary open-angle glaucoma
(POAG), the most common adult-onset type of
glaucoma, occurs with a prevalence of ≈2% in per-
sons aged >40 years (US data[4]) and 3–4% in per-
sons >65 years of age (UK data[5,6]). POAG accounts
for 75% of the incidence of glaucoma in Western
developed countries.[7]
Risk factors for glaucoma include advancing age
(>40 years), ocular hypertension (OH; intraocular
pressure [IOP] >21mm Hg), family history, African
heritage, nearsightedness and diabetes mellitus.[8]
There is also increasing evidence to suggest the
involvement of reduced diastolic perfusion pres-
sure[9] and, possibly, disturbances of ocular blood
flow.[10,11] Elevated IOP is considered the most im-
portant glaucoma risk factor and, moreover, it is the
only one readily amenable to treatment. Lowering
IOP is therefore the goal of glaucoma therapy;[12,13]
several large, randomised studies, including two in
patients with ‘normal tension’ glaucoma, have pro-
vided evidence that reduction of IOP reduces the
rate of disease progression (see review by Schwartz
and Budenz[12]).
Despite advances in laser and incisional surgery,
pharmacotherapy remains the cornerstone of IOP
OH.[12] The major classes of topical antiglaucoma
medications lower IOP by decreasing the production
of aqueous humour (β-adrenoceptor antagonists,
carbonic anhydrase inhibitors [CAIs]), increasing its
outflow (cholinergic agonists, prostaglandin deriva-
tives), or both (α2-adrenergic agonists).[12] Pharma-
cological treatment usually begins with a single
topical agent; in this respect, prostaglandin deriva-
tives (e.g. latanoprost, bimatoprost and travoprost)
are replacing β-adrenoceptor antagonists as the drug
of first choice.[12,14] Switching to another ocular
monotherapy is indicated if target IOP (at which the
progression of glaucomatous damage will be
delayed or halted) is not reached, while combination
therapy is necessary if monotherapy fails to induce
or maintain target IOP or if there is progression of
visual field defects.[15] Since combined therapy oft-
en requires more complex, sometimes inconvenient,
treatment schedules involving increased frequency
of instillation of eye drops, a number of fixed com-
binations of ocular hypotensive agents have been
developed with the aim of improving convenience
(and thus compliance) relative to concomitant ther-
apy with the same two agents. The CAI dorzolamide
combined with the nonselective β-adrenoceptor an-
tagonist timolol is one such preparation.[16]
This review summarises the pharmacological
properties of fixed combination dorzolamide 2%/
timolol 0.5% ophthalmic solution (dorzolamide/
timolol; Cosopt® 1) and focuses on its clinical pro-
file in adult patients with glaucoma or OH.

1 The use of trade names is for product identification purposes only and does not imply endorsement.

© 2006 Adis Data Information BV. All rights reserved. Drugs Aging 2006; 23 (12)
Dorzolamide 2%/Timolol 0.5%: A Review 981

Table I. Pharmacodynamic properties of topical dorzolamide and timolol[7,15,16,19]

Property Dorzolamide Timolol
Drug class Carbonic anhydrase inhibitor; highly selective for Nonselective β-adrenoceptor antagonist (β1 and
CA-II β2); no local anaesthetic, membrane stabilising or
sympathomimetic properties
Mechanism of action Decreases aqueous humour production; lowers Lowers IOP by inhibiting aqueous humour
IOP by inhibiting CA-II in the ocular ciliary process production
Ocular haemodynamic effects Improves ocular blood flow (some markers) No effect on ocular blood flow
Systemic effects Inhibits CA-II in erythrocytes Reduces heart rate and blood pressure
CA-II = carbonic anhydrase isoenzyme II; IOP = intraocular pressure.

2. Pharmacodynamic Profile baseline in another randomised, cross-over compari-

The main pharmacodynamic properties of topi-
cally administered dorzolamide and timolol are
summarised in table I. Although both agents de-
crease elevated IOP by decreasing aqueous humour
production,[17] they each appear to have a different
mechanism of action at the molecular level and have
an additive effect when administered together.[16]
The reduction in aqueous humour flow (and IOP)
with the combination of dorzolamide 2% and
timolol 0.5% is significantly greater than that with
either agent alone.[18] The effects of fixed combina-
tion dorzolamide/timolol on IOP, as demonstrated in
clinical studies, are discussed in section 4.
Topically administered dorzolamide/timolol im-
proved some markers of ocular blood flow in small
studies in patients with POAG (n = 15–30).[20-23] For
example, retinal arteriovenous passage (AVP) time
from the superior temporal artery to the correspond-
ing vein was significantly shorter following 1 month
of double-masked treatment with dorzolamide/
timolol twice daily than with timolol 0.5% twice
daily (1.76 vs 2.13s; p = 0.01).[20] The fixed combi-
nation did not alter choroidal perfusion or re-
trobulbar haemodynamics relative to the timolol
0.5% baseline in this randomised, cross-over com-
parison (n = 15).[20] However, this finding contrasts
with that of a randomised, cross-over comparison
with latanoprost 0.005% (n = 30),[21] in which 1
month of non-blind treatment with dorzolamide/
timolol significantly (p = 0.003) increased pulsatile
ocular blood flow (which is ≈85% choroidal) by
2.05 μL/s relative to the timolol 0.5% baseline.
Dorzolamide/timolol also significantly improved re-
trobulbar haemodynamic parameters relative to
son with latanoprost 0.05% (n = 22).[23] Specifically,
the fixed combination increased end-diastolic veloc-
ity (EDV) and decreased the resistance index (RI) in
both the ophthalmic artery (OA) and the short poste-
rior ciliary artery (SPCA) [p ≤ 0.00031 vs baseline
for changes in all parameters]. Improvements in
ocular blood flow markers following treatment with
dorzolamide/timolol twice daily generally exceeded
those observed with latanoprost 0.005% once dai-
ly.[21,23] In one randomised, cross-over compari-
son,[21] the fixed combination was as effective as
latanoprost 0.005% in terms of increasing pulsatile
chorionic blood flow relative to a timolol 0.5%
baseline (2.05 μL/s vs 2.15 μL/s; p > 0.05), but more
effective with regard to increasing pulse volume
(0.77μL vs 0.14μL; p < 0.05). In the other randomis-
ed, cross-over comparison,[23] latanoprost 0.005%
(unlike dorzolamide/timolol) did not show a statisti-
cally significant influence on EDV and RI in the OA
and SPCA.
The improvements in ocular haemodynamic pa-
rameters with the fixed combination appear to re-
flect the activity of the dorzolamide 2% component,
which has been shown to reduce retinal AVP
time,[24] increase blood flow in the optic nerve head
and the choroid,[25] and improve some retrobulbar
haemodynamic parameters[26-28] in patients with
POAG[24,26-28] or OH.[25] When included as a compa-
rator, timolol 0.5% had no significant effect on
ocular blood flow markers in these studies.[24-26]
Improvements in ocular haemodynamic parame-
ters with either dorzolamide/timolol or the dorzo-
lamide 2% component were mostly unaccompanied
by enhancements in visual function.[20,24,25] There
was, however, a significant (p = 0.007) increase in

© 2006 Adis Data Information BV. All rights reserved. Drugs Aging 2006; 23 (12)
982
contrast sensitivity testing at six cycles/degree with
dorzolamide 2% relative to timolol 0.5% after 1
month of treatment.[24]
3. Pharmacokinetic Profile
No information on the pharmacokinetic proper-
ties of the fixed combination of dorzolamide/timolol
has been published; accordingly, the following sec-
tions discuss the properties of the individual compo-
nents.
3.1 Dorzolamide
After topical ocular administration, dorzolamide
enters the systemic circulation via drainage through
the nasolacrimal duct and absorption from the naso-
pharyngeal mucosa.[7] The plasma concentration of
dorzolamide remained below the detection level of
5 μg/L after instillation of a single dose (three drops/
eye) or multiple doses (four drops/eye/day for
14 days) of dorzolamide 2% or 3% in a total of 12
healthy volunteers.[29] However, at 11 μg/L, the
plasma dorzolamide concentration was more than
twice this limit of detection after 6 months of treat-
ment with the recommended dorzolamide 2% dos-
age regimen of one drop per eye three times daily
(section 6) in four patients with glaucoma.[30]
Systemically absorbed dorzolamide binds mainly
to carbonic anhydrase (CA) II in red blood
cells.[16,31] Plasma protein binding of the drug is
33%.[32] Dorzolamide is metabolised slowly by the
cytochrome P450 (CYP) 2B1/2, CYP2E1 and
CYP3A2 isoenzymes in the liver to a single N-
desethyl metabolite, which also accumulates in
erythrocytes where it binds primarily to CA I.[16]
The mean erythrocyte concentrations of the drug
and its metabolite in patients with glaucoma or
OH (n = 4–9[30] and 56[33]) were of the order of
20–25 μmol/L and 5–10 μmol/L, respectively, dur-
ing topical treatment with the recommended dosage
regimen of dorzolamide 2% for up to 18 months.
However, the resulting inhibition of CA activity is
only moderate and sufficient activity remains to
preserve normal physiological functioning, thereby
avoiding systemic adverse events (section 5).[31]
© 2006 Adis Data Information BV. All rights reserved.
Frampton & Perry
Dorzolamide and N-desethyldorzolamide are ex-
creted predominantly via the renal route;[31] accord-
ingly, use of the fixed combination is not recom-
mended (in the US) or is contraindicated (in Europe)
in patients with severe renal impairment (section 6).
3.2 Timolol
Like dorzolamide, timolol is absorbed systemi-
cally after topical ocular administration; it has a high
systemic bioavailability via this route (78% in
healthy volunteers [n = 8][34]) due to avoidance of
first-pass hepatic metabolism and can display sys-
temic effects, such as bradycardia and mild hypoten-
sion[16] (section 5.2). Mean peak plasma timolol
concentrations (Cmax) were 0.46 and 0.35 μg/L after
the morning and afternoon dose, respectively, in six
subjects who received topical timolol 0.5% twice
daily (number of drops not reported).[32]
Instillation of two drops of timolol 0.5% into the
eyes of 20 patients undergoing cataract surgery pro-
duced timolol concentrations ranging from ≈150 ng/
100mg of aspirated aqueous humour in the first
1–2 hours to 10 ng/100mg aspirated aqueous hu-
mour towards the end of 7 hours.[35]
Between 5% and 46% of the calculated absorbed
dose of timolol 0.5% was excreted renally over
24 hours following ocular administration of the drug
(two drops in each eye).[19]
4. Therapeutic Efficacy
The ocular hypotensive efficacy of fixed combi-
nation dorzolamide/timolol has been compared with
that of monotherapy with dorzolamide 2%,[36,37] tim-
olol 0.5%,[36,37] latanoprost 0.005%,[38-43] bimato-
prost 0.03%[44,45] and travoprost 0.004%,[42,43,46] that
of concomitant therapy with dorzolamide 2% plus
timolol 0.5%,[47,48] and brimonidine 0.2% plus either
timolol 0.5%[49,50] or latanoprost 0.005%[51] and that
of fixed combination latanoprost 0.005%/timolol
0.5% (latanoprost/timolol)[52,53] and brimonidine
0.2%/timolol 0.5% (brimonidine/timolol) in ran-
domised, clinical trials conducted at one[42,43,46,54] or
more[36-41,44,45,47-53,55] centres. With the exception of
the two comparisons of dorzolamide/timolol with
Drugs Aging 2006; 23 (12)
Dorzolamide 2%/Timolol 0.5%: A Review
brimonidine/timolol,[54,55] all of these trials have
been published in full.
Adults with glaucoma or OH who did not have
contraindications to any of the study medications
were enrolled in these studies. Almost all of the
glaucoma patients recruited had POAG, although
one investigation[43] only included individuals with
pseudoexfoliation glaucoma. Based on those stud-
ies for which full details are available,[36-53] the
mean or median age of trial participants ranged
from 58.5–66.5 years. These individuals were re-
quired to have an elevated baseline IOP of
≥20mm Hg[36-53] (typically measured at morning
trough [just prior to drug administration]
and[36,37,47,48]/or[38,40,41,44-46,49-51,53] at morning peak [2
hours after drug administration]) after completing a
2- to 6-week run-in period on timolol 0.5% twice
daily[36,40,42,44,47-50,53] or a washout period of 3–28
days (depending on drug class).[37-39,41,43,45,46,51,52]
Similarly, patients with raised IOP who were re-
cruited into the comparisons of dorzolamide/timolol
with brimonidine/timolol completed a washout peri-
od of up to 4 weeks.
In all studies, dorzolamide/timolol was instilled
in the affected eye(s) twice daily at (where stat-
ed[38,39,44,46,49,50]) the recommended dose (one drop;
section 6). All other study medications were also
topically administered as ophthalmic solutions.
In most studies, the primary efficacy endpoint
was the mean change (absolute and/or percent-
age reduction) in IOP from time-matched baseline
values[36,37,44,47-50] (e.g. at morning trough[36] or
peak[49-51]), the mean change in diurnal IOP from
baseline[38,39,41,46,52,53] or the between-group differ-
ence in the mean reduction in daytime diurnal IOP
from baseline.[40,45]
Some studies included prespecified statistical
tests for superiority,[36,37] equivalence[38,47,48] (‘com-
parability’[49,50]) or non-inferiority/superiority.[44]
4.1 Versus Monotherapy and Concomitant
Therapy with the Individual Components
Dorzolamide/timolol was superior to monother-
apy with dorzolamide 2% three times daily or
timolol 0.5% twice daily,[36,37] and equivalent to
© 2006 Adis Data Information BV. All rights reserved.
983
concomitant therapy with dorzolamide 2% twice or
three times daily plus timolol 0.5% twice daily,[47,48]
in lowering IOP in large (n > 233 evaluable pa-
tients), double-masked, parallel-group studies (table
II). Decreases in IOP were near maximal after
2 weeks’ treatment with the fixed combination; after
3 months’ treatment, mean reductions in morning
trough and peak IOPs from baseline were in
the ranges 2.8–7.7mm Hg (10.6–27.4%) and
4.4–9.0mm Hg (17.3–32.7%), respectively (table
II).
When the fixed combination was compared with
monotherapy with the individual components,[36,37]
the between-group differences in the mean reduc-
tions in IOP from baseline at morning trough and
peak at 2 weeks and 3 months favoured dorzo-
lamide/timolol twice daily over dorzolamide 2%
three times daily and timolol 0.5% twice daily (table
II). At morning trough at 3 months, for example, the
negative upper and lower limits of the 95% CIs
for the between-group differences (fixed combina-
tion – individual component) in the mean per-
cent reductions in IOP from baseline (–15.3, –8.7
[p < 0.001][37] and –10.15, –1.12[36] vs dorzolamide
2%; –8.2, –1.6 [p = 0.003][37] and –7.63, –0.19[36] vs
timolol 0.5%; all treated patients analysis last obser-
vation carried forward) indicated the superiority of
the fixed combination over the individual compo-
nents. Dorzolamide/timolol was likewise superior to
each monotherapy at all other timepoints measured
in one study[37] (p ≤ 0.024) and superior to at least
one monotherapy at all other timepoints measured in
another study.[36]
Mean reductions in IOP from baseline at morning
trough and peak were similar in patients receiving
dorzolamide/timolol twice daily relative to those
receiving concomitant therapy with dorzolamide 2%
twice or three times daily plus timolol 0.5% twice
daily[47,48] (table II). Using the average of the 2- and
3-month follow-up data, there was >99.9%[47] and
>98.6%[48] confidence that the between-group dif-
ference (concomitant therapy – fixed combination)
in the mean reduction in IOP from baseline (morn-
ing trough, 0.01mm Hg [90% CI –0.52, 0.55][47]
and –0.67mm Hg [95% CI –1.41, 0.06];[48] morn-
Drugs Aging 2006; 23 (12)
984 Frampton & Perry

Table II. Ocular hypotensive efficacy of a fixed combination of topical dorzolamide 2%/timolol 0.5% (DOR/TIM) ophthalmic solution versus
monotherapy or concomitant therapy with the individual components in adult patients (pts; mean age 61.2–63.7 years) with bilateral open-
angle glaucoma or ocular hypertension. Results from randomised, double-masked, parallel-group, multicentre studies of 3 months’ dura-
tion.a The primary efficacy measure was the mean change in intraocular pressure (IOP) from the time-matched baseline values in the ‘worst’
eye[36,37,47,48] (or the right eye if both eyes were equal[36,37,48]). ‘All patients treated’ last observation carried forward analyses are presented.
IOP was measured at zero hours (between 8:30am and 9am) and 2 hours later; when the study drug was administered, these timepoints
corresponded to trough (immediately before the dose) and peak values. The dose (number of drops) of DOR/TIM was not stated
Study Treatment regimen No. of Mean IOP at baseline Mean IOP reduction from baseline
evaluable (mm Hg) (mm Hg [%])
pts 0h 2h at 2wk at 3mo
0h 2h 0hb 2h
Comparisons with monotherapy
Boyle et al.[37] DOR/TIM bid 111–114 27.9 27.1 8.1 [28.5c] 9.1 [33.1c] 7.7 [27.4c] 9.0 [32.7c]
DOR tid 109 28.1 27.3 4.6 [16.1] 6.0 [21.9] 4.6 [15.5] 5.4 [19.8]
TIM bid 110–111 27.9 27.3 6.4 [22.4] 7.0 [24.6] 6.4 [22.2] 6.3 [22.6]
Clineschmidt et al.[36] DOR/TIM bid 99–103 25.5 25.0 2.9 [10.9c] 4.0 [15.8c] 2.8 [10.6c] 4.4 [17.3c]
DOR tid 51 25.5 24.7 1.9 [6.6] 2.8 [10.8] 1.4 [4.9] 2.0 [7.4]
TIM bid 93–98 25.3 24.3 1.4 [5.4] 1.9 [8.1] 1.7 [6.7] 1.6 [6.6]

Comparisons with concomitant therapy

Hutzelmann et al.[47]d DOR/TIM bid 151 25.6 24.7 3.8 [14.6] 5.2 [20.9] 4.2 [16.3] 5.4 [21.6]
DOR bid + TIM bid 148 25.3 24.5 3.6 [14.0] 5.1 [20.6] 4.2 [16.3] 5.4 [21.8]
Strohmaier et al.[48]d DOR/TIM bid 114–120 26.0 25.1 3.1 [12.0] 4.6 [18.1] 3.6 [13.8] 5.0 [19.7]
DOR tid + TIM bid 119–121 26.1 25.1 3.9 [14.6] 4.8 [18.9] 4.1 [15.5] 4.9 [19.1]
a Pts were randomised after completing a 3wk washout period,[37] or a 2wk[47,48] or 3wk[36] run-in period with timolol 0.5% twice daily.
b Specified[36] (or implied[37]) primary efficacy timepoint.
c DOR/TIM was superior to DOR and TIM at this timepoint, i.e. the upper and lower limits of the 95% CIs for the between-group
differences (DOR/TIM – DOR or TIM) in the mean percent change in IOP from baseline were negative.
d Study designed to test equivalence.
bid = twice daily; tid = three times daily.

ing peak, 0.08mm Hg [90% CI –0.45, 0.60][47]
and –0.05mm Hg [95% CI –0.81, 0.71],[48] all pa-
tients treated analysis-observed cases) was within
±1.5mm Hg, indicating the equivalence of fixed
combination and concomitant therapy. Additionally,
there was >97.1% confidence that fixed combina-
tion therapy was equivalent to concomitant therapy
8 hours after the morning dose of all study medica-
tions and 2 hours after the afternoon dose of dorzo-
lamide 2% administered three times daily.[48] The
between-group difference (concomitant therapy –
fixed combination) in the mean reduction in IOP
from baseline was –0.73mm Hg (95% CI –1.53,
0.07) [all treated patients analysis-observed cases].
In a non-blind extension of one of the trials,[48]
where all patients received dorzolamide/timolol, re-
ductions in IOP seen with the fixed combination at
the end of the 3-month double-masked phase were
maintained for up to 1 year.
4.2 Versus Prostaglandin Monotherapies
4.2.1 Versus Latanoprost 0.005%
Dorzolamide/timolol twice daily was equivalent
to latanoprost 0.005% once daily in two double-
masked comparisons that followed a washout period
(table III).[38] There was >99% confidence that the
between-group difference in the mean reduction in
daytime diurnal IOP (0800–1600h) from baseline
at 3 months was within ±1.5mm Hg (study 1,
–0.04mm Hg [95% CI –0.85, 0.77] in favour of
dorzolamide/timolol; study 2, –0.57mm Hg [95%
CI –1.31, 0.16] in favour of dorzolamide/timolol).
Additional post hoc analyses of pooled data from
these trials showed that dorzolamide/timolol and
latanoprost 0.005% were similar with respect to the
percentages of patients achieving target levels of
IOP reduction and the pattern of daytime diurnal
IOP reduction.[56] Both treatments were also equally

© 2006 Adis Data Information BV. All rights reserved. Drugs Aging 2006; 23 (12)
Dorzolamide 2%/Timolol 0.5%: A Review 985

effective in patients with high IOP at baseline (e.g.
≥27, ≥28 or ≥30mm Hg).[56]
Similarly, dorzolamide/timolol twice daily was
as effective as latanoprost 0.005% once daily at
lowering IOP in two large, non-blind, parallel-group
comparisons in patients with a baseline IOP
≥21mm Hg following a run-in period on timolol
0.5% twice daily (n = 226)[40] or a washout period
(n = 229).[39] Between-group differences in the
mean reduction in daytime diurnal IOP
(0830[39]–1700h or 1000[40]–1700h) from baseline
were –0.4mm Hg (–4.3mm Hg with latanoprost
0.005% vs –4.0mm Hg with dorzolamide/timolol;
95% CI –1.1, 0.4) at 3 months in the comparison that
followed a run-in period on timolol 0.5%,[40] and
0.58mm Hg (–6.9 vs –6.4mm Hg; 95% CI –0.1,
1.26) at 2 months in the comparison that followed a
washout period.[39]
In both studies,[39,40] between-group differences
in mean reductions in IOP from baseline were simi-
lar at each timepoint with the exception of 1700h
(i.e. 9-hour, post-dose timepoint), when they

Table III. Ocular hypotensive efficacy of a fixed combination of topical dorzolamide 2%/timolol 0.5% (DOR/TIM) ophthalmic solution versus
that of other ocular hypotensive medications in adult patients (pts; mean or median age 60.0–64.3 years) with glaucoma (almost exclusively
bilateral, open-angle) or ocular hypertension. Results from randomised, single (investigator)-blind[49,50,52] or double-masked,[38,44] parallel-
group, multicentre studies of 3[38,44,50,52] or 6[49] months’ duration.a The primary efficacy variable was the reduction in intraocular pressure
(IOP). ‘All patients treated’,[38,50] modified intent-to-treat (ITT)[49,52] or ITT[44] last observation carried forward analyses are presented. IOP
was measured at zero hours (between 7am and 9am) and 2 hours later; when the study drug was administered, these timepoints
corresponded to trough (immediately before the dose) and peak values. Where stated, the dose of DOR/TIM was one drop[38,44,49,50]
Study Treatment No. of Mean IOP Mean IOP reduction from baseline (mm Hg [%])
regimen evaluable at baseline
pts (mm Hg)
0h 2h at 1mo at 3mo at 6mo
0h 2h 0h 2h 0h 2h
Comparisons with latanoprost 0.005% (LAT) monotherapy
Fechtner et al.[38] DOR/TIM bid 121 26.1b 7.0b,c [26.8c] 7.2b,d [27.5]
(study 1)e LAT od 125 25.6b 6.6b,c [25.8c] 7.2b,d [28.1]
Fechtner et al.[38] DOR/TIM bid 138 25.3b 7.6b,c [30.0c] 7.9b,d [31.2]
(study 2)e LAT od 143 24.7b 7.0b,c [28.3c] 7.2b,d [29.1]
Comparison with bimatoprost 0.03% (BIM) monotherapy
Coleman et al.[44] DOR/TIM bid 87 24.8 23.2 4.8 [19.4] 5.1 [22.0] 5.0 [20.2] 5.6 [24.1]
BIM od 90 25.0 23.6 7.1*** [28.4] 6.5** [27.5] 6.8*** [27.2] 6.4 [27.5]
Comparisons with concomitant brimonidine 0.2% plus timolol 0.5% (BRI+TIM)
Sall et al.[49]e DOR/TIM bid 138–143 25.2 24.4 3.3 [13.1] 4.8 [19.7] 3.7 [14.7] 5.0d [20.5] 3.1 [12.3] 4.6 [18.9]
BRI+TIM bid 136–147 25.0 24.3 3.7 [14.7] 5.5 [22.6] 4.2 [16.8] 5.4 [22.2]d 3.8 [15.2] 5.1 [21.0]
Solish et al.[50]e DOR/TIM bid 224–235 24.8 24.1 3.6 [14.5] 4.9 [20.4] 3.3 [13.3] 4.3d,f [17.8]
BRI+TIM bid 231–243 24.5 24.1 3.7 [15.1] 5.4 [22.4] 3.5 [13.7] 5.3d [22.1]
Comparison with fixed combination latanoprost 0.005%/timolol 0.5% (LAT/TIM)
Shin et al.[52] DOR/TIM bid 126 27.5b 8.4b,d [30.3]
LAT/TIM od 125 27.9b 9.4* b,d [33.5*]
a Pts were randomised after completing a 3wk[38] or 4wk[52] washout period, or a ≥2wk[44] or 3wk[49,50] run-in period with timolol 0.5%
twice daily.
b Daytime diurnal value (mean of measurements made at 0, 2, 6 and 8h,[38] or 0, 4 and 8h[52]).
c Estimated from a graph.
d Specified[49,50,52] (or implied[38]) primary efficacy endpoint.
e Study designed to test equivalence.
f DOR/TIM was not equivalent to BRI+TIM at this timepoint, i.e. the upper and lower limits of the 95% CI for the between-group
difference (DOR/TIM – BRI+TIM) in the mean reduction in IOP from baseline were not within ±1.5mm Hg.
bid = twice daily; od = once daily; * p ≤ 0.047, ** p = 0.007, *** p < 0.001 vs DOR/TIM.

© 2006 Adis Data Information BV. All rights reserved. Drugs Aging 2006; 23 (12)
986
favoured latanoprost 0.005% once daily (0.7mm Hg
[95% CI not reported; p = 0.045; per protocol analy-
sis[40]] and 0.84mm Hg [95% CI 0.1, 1.57; p = 0.025;
intent-to-treat analysis[39]]). In contrast, dorzo-
lamide/timolol lowered 24-hour diurnal IOP by a
small but significantly greater amount than lata-
noprost 0.005% in a small (n = 34), single-blind,
cross-over comparison in patients with a baseline
IOP ≥24mm Hg following a washout period.[41] The
mean 24-hour diurnal IOP at the end of the 6-week
treatment period was 15.3mm Hg in the dorzo-
lamide/timolol group versus 15.9mm Hg in the lata-
noprost 0.005% group (p = 0.05). There were
no other significant differences between the two
treatments with the exception of the mean IOP at
the 2200h timepoint, which also favoured the
fixed combination over monotherapy (14.6 vs
16.6mm Hg; p = 0.006).[41]
4.2.2 Versus Bimatoprost 0.03%
Dorzolamide/timolol twice daily lowered IOP
less consistently than did bimatoprost 0.03% once
daily in a double-masked, parallel-group compari-
son following a run-in period on timolol 0.5% twice
daily.[44] Mean reductions in IOP from baseline at
morning trough and peak were greater with bi-
matoprost 0.03% at all timepoints, with the excep-
tion of the morning peak timepoint at 3 months[44]
(table III; 1-week and 2-month follow-up results not
shown). Dorzolamide/timolol provided a less stable
reduction in IOP over the whole day, as evidenced
by significantly lower mean IOP values in bi-
matoprost 0.03% recipients at the 0-, 8- and 12-hour
post-dose timepoints at 3 months (p ≤ 0.038).[44] The
percentage of recipients reaching target IOPs of ≤17
to ≤20mm Hg was similar between the dorzolamide/
timolol and bimatoprost 0.03% treatment groups
based on measurements at 0-, 2- and 12-hour post-
dose timepoints at 3 months; however, a significant-
ly (p ≤ 0.008) greater percentage of bimatoprost
0.03% recipients reached the lower target pressures
of ≤13mm Hg (0% vs 8%), ≤14mm Hg (2% vs
17%), ≤15mm Hg (9% vs 24%) and ≤16mm Hg
(14% vs 31%).[44]
Although the design of this study is consistent
with situations encountered in clinical practice, a
© 2006 Adis Data Information BV. All rights reserved.
Frampton & Perry
relevant concern is whether the selection of patients
who are inadequately controlled on timolol 0.5%
twice daily provides a valid basis on which to judge
the relative merits of a timolol-containing therapy
versus bimatoprost 0.03%.[44] Moreover, the study
authors acknowledged that they did not conduct a
reverse therapeutic trial and hence did not know the
number of trial participants who were nonrespon-
ders to this β-adrenoceptor antagonist.[44] Contrast-
ing with the results of this trial, reductions in day-
time diurnal IOP (0800–1600h) and IOP at two of
the three measured timepoints (morning peak and
8 hours post-dose) were not significantly different
with dorzolamide/timolol twice daily versus bi-
matoprost 0.03% once daily in a small (n = 35),
double-masked, cross-over, three-centre, 8-week
study that followed an initial washout period.[45]
4.2.3 Versus Travoprost 0.004%
The IOP-lowering effect of dorzolamide/timolol
twice daily was greater than that of travoprost
0.004% once daily in one[43] of two small (n = 50[43]
and 56[46]), single-blind, parallel-group, single-cen-
tre studies that followed a washout period. After
6 months of treatment, the reduction in mean diurnal
IOP (average of measurements made at 8am, 10am
and 4pm) from baseline with dorzolamide/timolol
was superior to that with travoprost 0.004% (11.5 vs
9.3mm Hg; p < 0.05).[43] The IOP-lowering effect of
dorzolamide/timolol was also greater than that of
another comparator, latanoprost 0.005% once daily
(reduction in mean diurnal IOP from baseline,
8.2mm Hg; p < 0.05 vs dorzolamide/timolol); the
IOP-lowering effect of the two prostaglandin ana-
logues was similar. Of note, this study exclusively
enrolled patients with pseudoexfoliation glaucoma.
Dorzolamide/timolol was, however, less effec-
tive than travoprost 0.004%[42,46] in the other single-
blind, parallel-group, single-centre comparison,[46]
and less effective than both travoprost 0.004% and
latanoprost 0.005% in a small (n = 38), single-blind,
cross-over, single-centre comparison that followed a
run-in period on timolol 0.5% twice daily.[42] In the
parallel-group comparison,[46] the reductions in
mean diurnal IOP (average of measurements made
at 8am, 12pm, 4pm and 8pm) from baseline were
Drugs Aging 2006; 23 (12)
Dorzolamide 2%/Timolol 0.5%: A Review
significantly less with dorzolamide/timolol than
with travoprost 0.004% after both 3 (23.1% vs
32.7%; p < 0.01) and 6 (21.7% vs 30.7%; p < 0.01)
weeks of treatment. Similarly, in the cross-over
comparison,[42] the decrease in mean diurnal IOP
(average of measurements made at 8am, 10am and
4pm) from baseline following 3 months of treatment
with dorzolamide/timolol (14.3%; p < 0.0001 vs
baseline) was significantly less than that with
travoprost 0.004% (18.4%; p < 0.0001 vs baseline
and dorzolamide/timolol) and latanoprost 0.005%
(22.1%; p < 0.0001 vs baseline and dorzolamide/
timolol).[42] Again, the IOP-lowering effect of the
two prostaglandin analogues was similar.
4.3 Versus Other Concomitant Therapies
Dorzolamide/timolol twice daily was generally
equivalent to concomitant therapy with brimonidine
0.2% twice daily plus timolol 0.5% twice daily in
lowering IOP in two large, single-blind, parallel-
group trials preceded by a run-in period on timolol
0.5% twice daily (table III).[49,50] The fixed combi-
nation was equivalent to concomitant therapy at all
six of the timepoints measured in the first study;[49]
the 95% CI for the between-group difference in the
mean reduction in IOP from baseline was –0.42,
1.14 at morning peak at 3 months, and –0.29, 1.25 at
morning peak at 6 months. Equivalence was also
demonstrated at 3 of the 4 timepoints measured in
the second study,[50] with the exception of morning
peak at 3 months (primary efficacy endpoint), when
the 95% CI for the between-group difference in the
mean reduction in IOP from baseline was 0.40, 1.53
(p < 0.001 in favour of concomitant therapy).
Dorzolamide/timolol twice daily was, however,
less effective than concomitant therapy with lata-
noprost 0.005% once daily plus timolol 0.5% twice
daily in lowering IOP in two small (n = 23 and 40),
double-masked, parallel-group, multicentre trials
preceded by a washout period.[51] At the end of the
3-month treatment period, the mean reduction
in morning peak IOP was 6.5mm Hg (from a base-
line of 25.6mm Hg) in 18 patients receiving the
fixed combination versus 9.0mm Hg (baseline,
26.4mm Hg) in 22 patients receiving concomitant
© 2006 Adis Data Information BV. All rights reserved.
987
therapy in study 1 (p = 0.044), and 6.6mm Hg (base-
line, 25.1mm Hg) in 11 patients receiving the
fixed combination versus 9.1mm Hg (baseline,
27.2mm Hg) in 12 patients receiving concomitant
therapy in study 2 (p = 0.047).
4.4 Versus Other Fixed Combinations
4.4.1 Latanoprost 0.005%/Timolol 0.5%
The reduction in daytime diurnal IOP
(0800–1600h[52] or 0800–2000h[53]) with dorzo-
lamide/timolol twice daily versus latanoprost/
timolol once daily significantly favoured the latter in
a large (n = 253), single-blind, parallel-group trial
preceded by a washout period[52] (table III). Howev-
er, the between-group difference after 3 months’
treatment (primary endpoint) was only 1.0mm Hg
(95% CI 0.4, 1.69; p = 0.005) and the clinical
relevance of this small difference is questionable.[52]
Daytime diurnal IOP was not significantly different
following treatment with these two fixed combina-
tions in a small (n = 33) double-masked, cross-over
comparison that followed a run-in period on timolol
0.5% twice daily.[53]
With regard to other endpoints in these studies,
mean reductions in IOP were significantly less with
dorzolamide/timolol than with latanoprost/timolol at
morning trough (8.1 vs 9.6mm Hg; p = 0.007) and
the 8-hour post-dose timepoint (8.3 vs 9.5mm Hg;
p = 0.014) after 3 months’ treatment in the larger
trial,[52] but not at the corresponding timepoints after
2 months’ treatment in the smaller trial.[53] Con-
versely, mean IOP values favoured dorzolamide/
timolol over latanoprost/timolol at morning peak
(17.3 vs 17.8mm Hg; p = 0.04) and the 4-hour post-
dose timepoint (16.7 vs 17.5mm Hg; p = 0.03) after
2 months’ treatment in the smaller comparison,[53]
but not at the 4-hour post-dose timepoint after
3 months’ treatment in the larger comparison (18.6
vs 18.5mm Hg).[52]
In the larger trial,[52] consistently fewer dorzo-
lamide/timolol than latanoprost/timolol recipients
achieved specific reductions (range ≥5% to ≥40%)
in daytime diurnal IOP at 3 months; these between-
group differences were statistically significant for
the ≥15% (92% vs 99%; p < 0.05), ≥20% (80% vs
Drugs Aging 2006; 23 (12)
988
92%; p ≤ 0.01), ≥25% (66% vs 81%; p ≤ 0.01) and
≥30% (50% vs 67%; p ≤ 0.01) reduction levels
(values estimated from a graph).
4.4.2 Brimonidine 0.2%/Timolol 0.5%
Dorzolamide/timolol twice daily reduced IOP by
a similar amount to,[55] or to a lesser extent than,[54]
brimonidine/timolol twice daily, according to pre-
liminary results from two small (n = 30[55] and
40[54]), single-blind trials of parallel, single-cen-
tre[54] or cross-over, multicentre[55] design. These
trials were of 1[55] or 3[54] months’ duration; while
the IOP-lowering efficacy of dorzolamide/timolol
was similar to that of brimonidine/timolol after
1 month of treatment in both studies,[54,55] it was less
than that of brimonidine/timolol after 3 months of
treatment in the longer trial (results from a post-
er).[54] The mean reduction in morning peak IOP
from baseline at 3 months was 3.0mm Hg in the
dorzolamide/timolol group versus 6.8mm Hg in the
brimonidine/timolol group (p = 0.02). Mean IOP
values at baseline were similar in the two treatment
groups (21.6 vs 22.0mm Hg), whereas mean IOP
values at 3 months were significantly higher in the
dorzolamide/timolol group than in the brimonidine/
timolol group (18.4 vs 15.2mm Hg; p = 0.006).[54]
5. Tolerability
Dorzolamide/timolol twice daily was generally
well tolerated in large (n = 177–492) trials of
3–6 months’ duration which evaluated this fixed
combination in relation to the individual compo-
nents, given either as monotherapy or concomitant-
ly, or against other ocular hypotensive agents (see
section 4 for study details).[36-40,44,47-50,52] Between
33% and 77% of patients receiving dorzolamide/
timolol in these studies reported adverse events (re-
gardless of cause);[36-40,47-50] 10–68% reported drug-
related adverse events.[36-39,47-50]
These adverse events were generally mild to
moderate in intensity; only 0–4% of dorzolamide/
timolol recipients reported serious adverse events
(irrespective of causality).[36-40,44,47-50] In several
studies,[38,39,44,49] no dorzolamide/timolol recipients
reported drug-related serious adverse events; in an-
other study,[50] the only dorzolamide/timolol-related
© 2006 Adis Data Information BV. All rights reserved.
Frampton & Perry
serious adverse event to occur was dyspnoea in
an elderly woman. In the remaining stud-
ies,[36,37,40,45,47,48,51-53] serious adverse events were
not reported,[47,48,51-53] the incidence of serious ad-
verse events (drug-related or otherwise) was not
reported,[36,37] or serious adverse events were not
experienced by dorzolamide/timolol recipients.[40,45]
Between 1% and 7% withdrew from treatment
due to adverse events;[36-39,44,47-50,52] between 1% and
5% withdrew due to drug-related adverse events
(e.g. ocular burning and/or stinging, ocular swelling,
eye pain and cloudy vision).[36-39,48-50,52]
The adverse event profile of dorzolamide/timolol
mirrors that of the individual components and con-
sists primarily of ocular and local adverse events
(section 5.1). However, systemic adverse events
(section 5.2) can occur following systemic absorp-
tion of the individual components (section 3).
5.1 Ocular and Local Adverse Events
Burning and/or stinging[36-38,40,44,47-50] of the eye
(5–41%) and dysgeusia[36-38,44,47-50] (2–38%) were
the most commonly reported ocular and local ad-
verse events. Burning and/or stinging was transient
and of mild or moderate intensity in the majority of
cases.[36-38] These particular adverse events appear
to be caused primarily by the dorzolamide compo-
nent of dorzolamide/timolol.[16] Accordingly, their
incidence with the fixed combination (12–30%) was
similar to that with dorzolamide 2% and timolol
0.5% given concomitantly (8–12%)[47,48] and dorzo-
lamide 2% given alone (14%[37] and 24%[36]), but
significantly greater than that with timolol 0.5%
given alone (6%, p = 0.008 vs dorzolamide/timolol
[18%][37] and 8%, p = 0.001 vs dorzolamide/timolol
[30%][36]).
Other eye-related adverse events (e.g. blurred
vision, foreign body sensation, itching and tearing)
typically occurred in <10% of patients treated with
dorzolamide/timolol;[36-38,40,47,48,50] eyelid pain or
discomfort was the only ocular adverse event that
occurred more frequently in patients receiving the
fixed combination than in those receiving dorzo-
lamide 2% and timolol 0.5% given concomitantly
(6% vs 1%; p = 0.036).[48]
Drugs Aging 2006; 23 (12)
Dorzolamide 2%/Timolol 0.5%: A Review
Long-term tolerability data are limited, although
the fixed combination was generally well tolerated
for up to 1 year in a non-blind extension of one
study.[48] Additionally, treatment with dorzolamide
2% three times daily or timolol 0.5% twice daily
demonstrated good corneal tolerability in a
randomised, double-masked, 1-year multicentre
study in 298 patients with glaucoma and normal
corneas at baseline.[57]
5.1.1 Comparisons with Other Ocular Therapies
The incidence of drug-related ocular burning
and/or stinging and dysgeusia with dorzolamide/
timolol was mostly higher than that with latanoprost
0.005% monotherapy (in two of two trials [studies 1
and 2])[38] and consistently higher than that with
bimatoprost 0.03%[44] and concomitant brimonidine
0.2% plus timolol 0.5%[49,50] in large, parallel-group
comparisons. Ocular burning was more common
with dorzolamide/timolol than with latanoprost
0.005% (study 1: 23% vs 7%; study 2: 10% vs 2%
[both p < 0.05]),[38] while both ocular burning and
stinging were more common with the fixed combi-
nation than with bimatoprost 0.03% (burning,
13.8% vs 2.2% [p = 0.004]; stinging, 10.3% vs 2.2%
[p = 0.025]) or with concomitant brimonidine
0.2% plus timolol 0.5% (burning, 41% vs 20%
[p < 0.001][49] and 14.0% vs 2.4% [11.6% differ-
ence, 95% CI 6.9, 16.7][50]); stinging, 22% vs 12%
[p = 0.024][49] and 4.9% vs 1.6% [3.3% difference,
95% CI 0.1, 7.0][50]). Similarly, dysgeusia was more
frequent with dorzolamide/timolol than with lata-
noprost 0.005% (study 1 only: 10% vs 2%
[p < 0.05]),[38] bimatoprost 0.03% (5.7% vs 0%;
p = 0.027) and concomitant brimonidine 0.2% plus
timolol 0.5% (26% vs 10% [p < 0.001][49] and 4.5%
vs 0% [4.5% difference, 95% CI 2.0, 7.9][50]).
Nevertheless, discontinuations due to adverse
events were more frequent among patients receiving
the fixed combination than those receiving lata-
noprost 0.005% in one trial only (study 2: 6% vs
0%; p < 0.05).[38] Moreover, drug-related conjuncti-
val hyperaemia occurred less frequently in dorzo-
lamide/timolol recipients than bimatoprost 0.03%
recipients (17.2% vs 34.4%; p = 0.009),[44] while the
overall incidence of adverse events (including drug-
© 2006 Adis Data Information BV. All rights reserved.
989
related and serious events), as well as discontinua-
tions due to adverse events, were similar in patients
treated with the fixed combination or concomitant
brimonidine 0.2% plus timolol 0.5%.[49,50]
The tolerability profile of dorzolamide/timolol
was similar to that of concomitant brimonidine 0.2%
plus latanoprost 0.005%, based on two small, paral-
lel-group comparisons.[51] Likewise, the adverse
event profile of dorzolamide/timolol was generally
similar to that of latanoprost/timolol;[52] the only
significant between-treatment group difference was
a higher frequency of transient eye pain with dorzo-
lamide/timolol (11.7% vs 4.0%; p = 0.034).[52] Ocu-
lar burning (p < 0.001[54]) and stinging (p = 0.02[55]
and p < 0.001[54]), as well as unusual taste
(p < 0.001[54]), were reported more often by dorzo-
lamide/timolol recipients than brimonidine/timolol
recipients in small, parallel[54] or cross-over[55] com-
parisons of these fixed combinations (preliminary
results).
5.2 Systemic Adverse Events
Systemic adverse events, including head-
ache,[37,52] dizziness,[36,39] depression,[48] sinusi-
tis,[45] influenza-like symptoms/upper respiratory
tract infection,[37,45] chest pain,[39] gastrointestinal
symptoms (e.g. nausea, dyspepsia, abdominal
pain)[36,37,40,45,48,51] and urolithiasis[48] occurred infre-
quently or rarely in clinical trials with dorzolamide/
timolol (in ≈1% to 5% of patients, where stated).
Drug-related bradycardia/sinus bradycardia was re-
ported in one trial[39] (12.0% vs 1.8% with lata-
noprost 0.005%; p < 0.01), and respiratory symp-
toms (e.g. dyspnoea) were reported in three patients
in separate trials.[40,45,50] Cardiac failure, heart block,
hypotension and respiratory failure have also been
reported infrequently (i.e. in <1% of patients), with
dorzolamide/timolol during clinical trials or post-
marketing experience.[32]
Although inhibition of CA in erythrocytes by
dorzolamide is not expected to produce systemic
adverse events (section 2), reports of headache, nau-
sea and urolithiasis with dorzolamide/timolol are
likely to have been attributable to the dorzolamide
component.[16] Moreover, dorzolamide, like other
Drugs Aging 2006; 23 (12)
990
CAIs, is a sulfonamide derivative and therefore may
be associated with sulfonamide-like reactions, in-
cluding hypersensitivity and idiosyncratic reac-
tions.[16]
6. Dosage and Administration
Dorzolamide/timolol is indicated for the treat-
ment of elevated IOP in patients with open-angle
glaucoma[32,58] (or pseudoexfoliation glaucoma [in
Europe][58] or OH [in the US][32]) who are insuffi-
ciently responsive to β-adrenoceptor antagonist
monotherapy. The recommended dosage regimen is
one drop of the fixed combination twice daily in the
(conjunctival sac of the[58]) affected eye.[32,58] If an-
other topical ocular drug is being used, the drugs
should be administered at least 10 minutes
apart.[32,58]
Based on its timolol component, dorzolamide/
timolol is contraindicated in patients with a history
of bronchial asthma, severe chronic obstructive pul-
monary disease, overt cardiac failure, sinus brady-
cardia, second- or third-degree atrioventricular
block or cardiogenic shock.[32,58] Additionally, it is
either contraindicated (in Europe)[58] or not recom-
mended (in the US)[32] in patients with severe renal
impairment (creatinine clearance <30 mL/min); it is
also contraindicated in Europe in patients with
hyperchloraemic acidosis.[58] Dorzolamide/timolol
should be used with caution in patients with hepatic
impairment.[32,58]
Although specific drug interaction studies have
not been performed with dorzolamide/timolol, la-
beling information[32,58] recommends against the
concomitant administration of the fixed combina-
tion with either an oral CAI or a topical β-adre-
noceptor antagonist due to the potential for additive
intraocular and/or systemic effects. There is also the
potential for additive effects and the production of
hypotension and/or marked bradycardia with
timolol in patients receiving oral calcium channel
antagonists, catecholamine-depleting drugs, antiar-
rhythmics, digitalis glycosides, parasympath-
omimetics, opioids or monoamine oxidase inhibi-
tors.[32,58]
© 2006 Adis Data Information BV. All rights reserved.
Frampton & Perry
For more information on the prescribing of
dorzolamide/timolol, local prescribing information
should be consulted.
7. Place of Dorzolamide/Timolol in the
Management of Glaucoma and
Ocular Hypertension
Glaucoma is currently incurable; hence, long-
term management of this disease is aimed at improv-
ing patients’ quality of life by halting optic neuropa-
thy and preserving the visual function that remains.
US[59] and UK[13] guidelines recommend a minimum
initial IOP reduction of 20–30% from baseline, but
additional lowering (to ≥40%) is justified in patients
with severe existing or rapidly occurring optic nerve
damage, very high IOP or a family history of
glaucoma, as well as in Black patients.[59]
In most cases, IOP-lowering therapy begins with
ocular hypotensive drugs and proceeds to argon
laser trabeculoplasty and, finally, incisional surgery
(e.g. trabeculectomy) in the event that IOP is not
adequately controlled or if there is progression of
visual field defects.[12,15] The main factors that influ-
ence the choice of initial agent are efficacy, tolera-
bility/safety, convenience of administration and
cost.[12] Based on such considerations, topical β-
adrenoceptor antagonists have traditionally been the
most commonly prescribed first-line antiglaucoma
drugs in patients without cardiac or respiratory dis-
ease.[60] They are, however, being supplanted in this
role by prostaglandin derivatives (e.g. latanoprost,
bimatoprost, travoprost),[12,13] mainly due to the po-
tential of β-adrenoceptor antagonists (particularly
that of nonselective agents, e.g. timolol) to cause
systemic adverse events. Prostaglandins also offer
the potential advantage of once-daily administra-
tion; evidence is emerging that persistence and ad-
herence are substantially better with these agents
than with other classes of antiglaucoma drugs.[61]
CAIs (e.g. dorzolamide, brinzolamide) and α-adren-
ergic agonists (e.g. brimonidine, dipivefrine) are
regarded as second-line treatment options in patients
unresponsive to, or intolerant of, β-adrenoceptor
antagonists and prostaglandin derivatives or in
whom these agents are contraindicated.[62,63] With
Drugs Aging 2006; 23 (12)
Dorzolamide 2%/Timolol 0.5%: A Review
the advent of newer agents, cholinergic agonists
(e.g. pilocarpine) have been relegated to third-line
agents that are seldom used in the US and Western
Europe.[12,64]
Combination therapy may be required if first- or
second-line monotherapy with the aforementioned
agents fails to maintain optimal control of IOP or
prevent further progression of visual field loss.
When dual therapy is indicated, fixed combinations
have several potential advantages in relation to con-
comitant therapy with the same two drugs. Because
they are easier to administer, fixed combination
eyedrops may be a more convenient treatment, po-
tentially improving compliance as well as the effi-
ciency of drug delivery. Exposure to preservative
may also be reduced.[65,66]
Several topical fixed combination therapies com-
bining the nonselective β-adrenoceptor antagonist
timolol with another agent are already available in
some countries. These products include dorzo-
lamide/timolol and brimonidine 0.2%/timolol 0.5%
(brimonidine/timolol), which are administered twice
daily, and latanoprost/timolol, which is adminis-
tered once daily.[65,67] Each is indicated for use in
patients insufficiently responsive to β-adrenoceptor
antagonists — a situation commonly encountered in
clinical practice[44] — and hence can be considered
as an alternative treatment option to switching to
another ocular monotherapy (when combination
therapy is deemed appropriate). Other fixed combi-
nations containing timolol are currently awaiting
approval (travoprost 0.004%/timolol 0.5%) or being
developed (bimatoprost 0.03%/timolol 0.5%).[65,67]
Older fixed combination products combining pi-
locarpine with adrenaline (epinephrine), betaxolol
or timolol are no longer widely used.[66]
Dorzolamide/timolol is the first commercially
available fixed combination of a topical CAI and
a nonselective β-adrenoceptor antagonist. Both
dorzolamide and timolol are effective and well es-
tablished ocular hypotensive drugs that have an ad-
ditive IOP-lowering effect when administered to-
gether (section 2). Accordingly, the efficacy of
dorzolamide/timolol exceeds that of monotherapy
(and is equivalent to that of concomitant therapy)
© 2006 Adis Data Information BV. All rights reserved.
991
with the individual components (section 4.1). The
fixed combination also improves some ocular
haemodynamic parameters (due to the activity of the
dorzolamide component; section 2); however, de-
spite considerable interest in ocular blood flow in
terms of a possible role in the pathogenesis of
glaucoma[10] and the effects of ocular and systemic
medications,[11] there is as yet no evidence to sug-
gest that any treatment method other than IOP low-
ering alters the progression of POAG.[13]
In short-term, ‘head-to-head’ clinical trials, the
IOP-lowering effect of dorzolamide/timolol in pa-
tients with glaucoma (almost exclusively POAG) or
OH was in general equivalent or similar to that of
monotherapy with latanoprost 0.005% (section
4.2.1) or concomitant therapy with brimonidine
0.2% plus timolol 0.5% (section 4.3), although it
was less than that of concomitant therapy with lata-
noprost 0.005% plus brimonidine 0.2% in small,
parallel-group comparisons (section 4.3). Contrast-
ing results were found in studies comparing dorzo-
lamide/timolol with bimatoprost 0.03% (section
4.2.2) or fixed combination latanoprost/timolol (sec-
tion 4.4) with two large trials demonstrating signifi-
cantly greater reductions in IOP in favour of the
comparator,[44,52] while two smaller trials showed
generally similar reductions.[45,53] The differing in-
clusion criteria between these trials may, in part,
explain the contrasting results that were observed. In
particular, the cut off for elevated baseline IOP
varied between studies, which may have influenced
the magnitude of the IOP reduction observed and
therefore the size of the between-group differences.
Studies using a timolol run-in period have also been
criticised as creating a negative bias against treat-
ment arms containing timolol. However, dorzo-
lamide/timolol is recommended for use in patients
who are insufficiently responsive to β-adrenoceptor
antagonist therapy (such as timolol); hence, trials
using a β-adrenoceptor antagonist run-in period are
consistent with the recommended clinical practice.
These methodological considerations notwithstand-
ing, it is unclear whether the observed differences in
IOP-lowering effect are of sufficient clinical signifi-
cance to influence the choice of ocular hypotensive
Drugs Aging 2006; 23 (12)
992
medication for a given individual independently of
other factors, particularly with regard to differentiat-
ing between the two fixed combination products.
Small-scale comparisons of dorzolamide/timolol
with travoprost 0.004% (section 4.2.3) and fixed
combination brimonidine/timolol (section 4.4.2; not
approved in the US) have also yielded variable
results; larger studies are needed to better define the
relative efficacy of these therapies. Comparisons of
dorzolamide/timolol with travoprost/timolol, bi-
matoprost/timolol, brinzolamide or dipivefrine have
thus far not been performed and/or reported.
Because large diurnal fluctuations in IOP have
been identified as an independent risk factor for
glaucoma progression,[68] the ability to maintain di-
urnal control of IOP is a desirable characteristic of
any ocular hypotensive medication. In this regard,
dorzolamide/timolol was generally as effective as
latanoprost 0.005% in large, parallel-group compar-
isons (section 4.2.1), but more or less effective than
this prostaglandin analogue and travoprost 0.004%
in small, cross-over or parallel-group comparisons
(section 4.2.3). Dorzolamide/timolol lowered diur-
nal IOP less consistently than bimatoprost 0.03%
and latanoprost/timolol in large, parallel-group
comparisons; however, the between-treatment
group differences (≈1.5mm Hg or less in favour of
the comparator) were small. Again, it is unclear
whether the observed differences in diurnal IOP-
lowering effect are of sufficient clinical relevance to
influence the choice of ocular hypotensive medica-
tion independent of other factors.
Prescribing information states that dorzolamide/
timolol is indicated in patients who are insufficiently
responsive to monotherapy with topical β-adre-
noceptor antagonists (section 6). In practice, howev-
er, it has also been prescribed to patients who were
previously untreated or receiving one of a number of
mono- or combination therapies.[69] Initiating treat-
ment with the fixed combination may be most ap-
propriate in patients with high IOP at baseline;[56,70]
this is a situation when, on rare occasions, dorzo-
lamide/timolol may be useful as an alternative to
prostaglandin derivatives for first-line treatment. An
additive effect on IOP lowering was observed when
© 2006 Adis Data Information BV. All rights reserved.
Frampton & Perry
dorzolamide/timolol was concomitantly adminis-
tered with ocular hypertensive agents with a com-
plementary mechanism of action, such as lata-
noprost 0.005%[69,71] and brimonidine 0.2%.[71]
Using a fixed-combination topical ocular hypo-
tensive is more convenient than concomitant ther-
apy with the individual components, and may lead to
improved compliance.[16] Of interest, an additional
IOP-lowering effect was seen when patients receiv-
ing concomitant therapy with the individual compo-
nents were switched to the fixed combina-
tion;[69,72,73] this is suggestive of a compliance im-
provement.[72] Studies of dorzolamide/timolol
formally focusing on compliance have not been
conducted, but would be useful in terms of substan-
tiating the value of the formulation.
Dorzolamide/timolol is generally well tolerated
during treatment for up to 1 year. The adverse event
profile reflects that of the individual components; no
additional tolerability issues specific to the fixed
combination have been identified (section 5). Ocular
and local reactions that were mostly mild and tran-
sient were the most commonly reported adverse
events with dorzolamide/timolol, which was usually
less well tolerated than monotherapy with either
latanoprost 0.005% or bimatoprost 0.03% and con-
comitant therapy with brimonidine 0.2% plus
timolol 0.5% with regard to burning and/or stinging
of the eye and taste disturbance, and less well toler-
ated than latanoprost/timolol with respect to eye
pain, in large, parallel-group comparisons that ex-
cluded patients with contraindications to β-adre-
noceptor antagonists. Dorzolamide/timolol was,
however, as well tolerated as concomitant brimoni-
dine 0.2% plus latanoprost 0.005% in small, paral-
lel-group comparisons (section 5).
Since both timolol and dorzolamide are systemi-
cally absorbed (section 3.1), the potential for these
components to cause systemic adverse events must
be considered when prescribing the fixed combina-
tion. The systemic effects of timolol, in particular,
are a tolerability concern in clinical practice and
adverse cardiorespiratory effects have been report-
ed, albeit infrequently, with dorzolamide/timolol
during clinical trials (despite the exclusion of pa-
Drugs Aging 2006; 23 (12)
Dorzolamide 2%/Timolol 0.5%: A Review
tients with contraindications to β-adrenoceptor an-
tagonists) and during post-marketing experience
(section 3). Therefore, as is the case for all (ap-
proved) fixed combination products containing
timolol, dorzolamide/timolol should not be pre-
scribed to individuals with contraindications to (sys-
temic) β-adrenoceptor antagonists.[32,58] Additional-
ly, ophthalmologists should be aware of the risk,
albeit low, of dorzolamide/timolol causing adverse
cardiorespiratory events in patients without known
contraindications to timolol and to monitor such
persons for the development of predisposing condi-
tions. Dorzolamide is a sulfonamide and may cause
allergic reactions in those who are hypersensitive to
this class of drug.[16]
Economic modelling studies reported in full[74] or
in part[75,76] indicate less than favourable results for
dorzolamide/timolol, probably because the ran-
domised studies on which they were retrospectively
based showed efficacy advantages for the compara-
tors (bimatoprost 0.03% and latanoprost/timolol;
see section 4). Cost-effectiveness studies comparing
dorzolamide/timolol with other therapies that have
shown similar efficacy (e.g. latanoprost 0.005%,
concomitant brimonidine 0.2% plus timolol 0.5%)
have not been performed. Moreover, true estimates
of cost-effectiveness require the comparison in
question to prospectively collect both economic and
clinical data.
In conclusion, fixed combination dorzolamide/
timolol can be considered for use in individuals
who, as a consequence of failing to achieve target
IOP with β-adrenoceptor antagonist monotherapy,
require the addition or substitution of another class
of topical antiglaucoma medication. Clinical trials
have demonstrated that dorzolamide/timolol (1 drop
per eye twice daily) is an effective and generally
well tolerated fixed combination for lowering IOP in
patients with open angle glaucoma or OH, including
individuals uncontrolled on β-adrenoceptor antago-
nist monotherapy. Compared with concomitant ther-
apy with the same two drugs, the primary advantage
of dorzolamide/timolol is convenience.
© 2006 Adis Data Information BV. All rights reserved.
993
Disclosure
During the peer review process, the manufacturers of the
agent under review were offered an opportunity to comment
on this article; changes based on any comments received were
made on the basis of scientific and editorial merit.
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Correspondence: James E. Frampton, Wolters Kluwer
Health | Adis, 41 Centorian Drive, Private Bag 65901,
Mairangi Bay, Auckland 1311, New Zealand.
E-mail: demail@adis.co.nz
Drugs Aging 2006; 23 (12)