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Ophthalmology Volume 105, Number 10, October 1998

ditional IOP reduction. In controlled clinical trials, dorzol- Before entering the study, patients discontinued all ocular hy-
amide provided additional IOP reduction when used as potensive medications according to the following schedule: 21
adjunctive therapy to timolol regardless of which of the two days for beta-blockers and oral carbonic anhydrase inhibitors, 7
drugs was used as the initial therapy. 2–4 In addition to the days for epinephrine or dipivefrin, and 72 hours for pilocarpine,
demonstrated efficacy of dorzolamide and timolol, the carbachol, or aceclidine. After this washout period, patients re-
turned to the clinic on day 1 for baseline examinations. Baseline
safety profiles of these agents are well-established. IOP measurements were recorded at 8:30 AM (hour 0) and 10:30
Dorzolamide and timolol have been formulated as a AM (hour 2) to correspond to morning trough and peak measure-
combination product (COSOPT, Merck & Co., Inc, White- ments. Patients with an IOP of greater than or equal to 24 mmHg
house Station, NJ) that would provide a more convenient in at least one eye (the same eye) at hours 0 and 2 were then
dosing regimen for patients requiring multiple medications. randomly assigned, according to a computer-generated allocation
5
Kass and associates have shown that although patient non- schedule, to receive one of the following three masked treatments:
compliance is a factor regardless of the medication pre- 0.5% timolol–2.0% dorzolamide twice daily plus placebo once
scribed, the rate of compliance (mean standard deviation) daily; 0.5% timolol twice daily plus placebo once daily; or 2.0%
with timolol administered twice daily (84.3% 14.0%) is dorzolamide three times daily.
The formulation of timolol used was TIMOPTIC (Merck &
greater than the rate of compliance with pilocarpine (77.7% Co., Inc, Whitehouse Station, NJ), a phosphate-buffered solu-
18.7%), which was administered four times daily. An tion (pH 6.8) of timolol maleate. The formulation of dorzola-
even greater decrease in compliance with increasing dosing mide used was TRUSOPT, a buffered (pH 5.6), slightly viscous,
frequency was reported by Cramer et al. These investiga- aqueous solution of dorzolamide hydrochloride. The fixed com-
6
tors found that compliance with epilepsy medications de- bination of dorzolamide–timolol was formulated by adding
creased from 87% for medications taken once daily to 39% timolol maleate to the TRUSOPT formulation and therefore was
for medications taken four times daily. Furthermore, pa- a slightly viscous solution with a pH of 5.6. All formulations
tients’ compliance to take their medication during the dos- were isotonic; benzalkonium chloride was the preservative. In a
ing interval window (i.e., 9–15, 6–10, and 4–8 hours for study in pigmented rabbits, the bioavailability of timolol and
twice-daily, three-times-daily, and four-times-daily regi- dorzolamide in the iris–ciliary body was very comparable
mens, respectively) also decreased with increased dosing whether the drugs were administered as separate components or
frequency. Although reducing the number of products and as the fixed combination (Sugrue MF, et al. Invest Ophthalmol
7
Vis Sci 1998;39:S926).
the number of required daily instillations is unlikely to The first dose of test drug was administered in the afternoon on
eliminate the problem of noncompliance entirely, the com- day 1. All patients were dispensed medication labeled with instil-
bination formulation may improve the rate of compliance lation instructions and packaged by allocation number in identical
and consequently improve IOP control. bottles. A disclosure panel, which identified the contents of each
The combination has previously been evaluated in bottle beneath a mask, was separated from each bottle at the time
patients inadequately controlled with timolol mono- of dispensing and was kept with the patients’ records. In the event
therapy (Strohmaier K, et al. Invest Ophthalmol Vis Sci of an emergency requiring the identification of test drug, the
1996;37:S1102). The current trial was designed to eval- disclosure panel could have been swabbed with alcohol to remove
uate the combination in comparison to its components in the mask and show the contents of the bottle. No labels were
unmasked during the study. Measurements were obtained imme-
a broader patient population than has been studied pre- diately predose at morning trough (hour 0) and 2 hours after the
viously, namely those withdrawn from ocular hypoten- morning dose at morning peak (hour 2). Ocular symptoms, signs,
sive therapy. and adverse experiences were also recorded at each visit. An
adverse experience was defined as any unfavorable and unintended
change in the structure, function, or chemistry of the body, or
worsening of a pre-existing condition, temporally associated with
Materials and Methods any use of study medication whether or not considered related to
the use of the study drug. Additional safety measurements included
a physical examination, a complete ophthalmic examination, com-
This was a 3-month, parallel, randomized, double-masked, ac- puterized visual fields, and laboratory evaluations (blood chemis-
tive-controlled study conducted at 27 centers in the United try and hematology) during the washout period and at poststudy.
States, all of which received ethical review committee approval
of the protocol; informed consent was obtained from all patients
before beginning the study. Males and postmenopausal or ster- Statistical Analysis
ilized females 21 to 85 years of age with bilateral open-angle
glaucoma or ocular hypertension were eligible for enrollment. Ocular hypotensive effect was assessed using the percent change
Among the ocular conditions for which patients were excluded in IOP from the time-matched baseline values (hours 0 and 2). The
were visual acuity worse than 20/80 in both eyes, history or percent change from baseline was calculated using the patient’s
evidence of acute or chronic angle closure glaucoma, or history worse eye. If only one eye met the entry criterion, then that eye
or evidence of intraocular surgery or significant ocular trauma was defined as the worse eye. However, if both eyes met the
within 6 months of study start. However, patients may have had criterion, then the worse eye was defined as the eye with the higher
intraocular laser therapy up to 3 months before study start. IOP at hour 0 on day 1. If both eyes were equal at that time, the eye
Other reasons for exclusion included any contraindication to with the higher IOP at hour 2 on day 1 was selected. If both eyes
timolol or carbonic anhydrase inhibitors, known severe or se- were equal at hour 2, then the right eye was selected.
rious hypersensitivity to sulfonamides, concomitant therapy The statistical software package SAS, Version 6.10 (SAS In-
with medications known to affect IOP, and previous exposure to stitute Inc, Cary, NC), was used to evaluate the data. The differ-
the dorzolamide–timolol combination. ences in mean percent change in IOP from baseline between the

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