The Safety and Efficacy of Brinzolamide 1%/Timolol 0.5% Fixed Combination Versus Dorzolamide 2%/Timolol 0.5% in Patients with Open-Angle Glaucoma or Ocular Hypertension

Abstract

Purpose:

The aim of this study was to compare the intraocular pressure (IOP) lowering efficacy and to determine patient preference based on ocular discomfort with fixed combination brinzolamide/timolol and fixed combination dorzolamide/timolol in patients with open-angle glaucoma or ocular hypertension who required a change in therapy due to elevated IOP while receiving IOP-lowering medication.

Methods:

This was a 3-month, randomized, double-blinded, active-controlled, parallel-group trial. Patients had open-angle glaucoma or ocular hypertension, which could not be controlled with monotherapy and were randomized to twice daily therapy with either brinzolamide 1%/timolol 0.5% or dorzolamide 2%/timolol 0.5%. IOP assessments were taken at 8 AM, 10 AM, and 4 PM at week 2 as well as at months 1, 2, and 3. Patients completed ocular discomfort assessments (based on stinging, burning, feeling of heat or warmth, or sharp pain) on their current IOP lowering therapy at baseline.

Results:

Of the 114 patients enrolled, 57 received Brinz/Tim and 57 received Dorz/Tim twice daily. Both medications produced statistically relevant IOP reductions, which were similar in both groups at each visit. The IOP reductions with Brinz/Tim ranged from 6.42 to 9.74 mmHg (26.09%–37.46%), whereas Dorz/Tim produced mean IOP reductions ranging from 8.16 to 12.41 mmHg (31.19%–41.44%) (P>0.05). Brinz/Tim showed significantly less ocular irritation (0.5% vs. 15.7%, respectively; P=0.0004) than Dorz/Tim.

Conclusions:

Both Brinz/Tim and Dorz/Tim showed similar significant and clinically relevant IOP-lowering efficacy, whereas Brinz/Tim provided superior outcomes in terms of ocular comfort.

Introduction

Glaucoma is a progressive optic neuropathy and a leading cause of blindness worldwide.¹ Intraocular pressure (IOP)-lowering therapy is currently the only accepted treatment modality for ocular hypertension and open-angle glaucoma. There are several IOP-lowering drugs currently in use. Although monotherapy is the first line of choice in the management of glaucoma, a substantial number of patients eventually require more than one therapy to sufficiently control IOP.² Current fixed combination treatments include a beta-blocker in combination with either a carbonic anhydrase inhibitor or a prostaglandin analog. Potential benefits of fixed combinations include reduction in exposure to preservatives, fewer drops per day, and elimination of the washout effect.^3,4 The 2 major advantages of monotherapy regimens are better compliance and tolerability, which are well-known obstacles to patient compliance. Since antiglaucomatous eye drops are used for a long period of time, chronic side effects are a major concern. Among these side effects, ocular surface discomfort (ie, burning, stinging) is relatively common. These symptoms are caused by either the drug itself or preservatives within the preparation.⁵

Timolol is a nonselective topical beta-adrenergic receptor blocker that is used to treat open-angle glaucoma by reducing aqueous humor production in the ciliary epithelium.⁶ Brinzolamide and dorzolamide are widely used topical antiglaucomatous drugs that reversibly inhibit carbonic anhydrase enzymes and lower IOP by decreasing aqueous humor secretion.⁷ The fixed combination of timolol and dorzolamide (timolol 5 mg/mL+dorzolamide 20 mg/mL, Cosopt^®; MSD Europe, Inc.) was introduced in 1998. More recently, another fixed combination of timolol 0.5% and brinzolamide 1% has been established (Azarga^®; Alcon Laboratories, Inc.).

In this study, we compared the tolerability and IOP-lowering efficacy of the 2 commonly fixed combination eye drops: a) brinzolamide/timolol (Brinz/Tim), and b) dorzolamide/timolol (Dorz/Tim). We aimed to determine patient preference, if any, between the 2 treatments after administration of each medication in individuals with open-angle glaucoma or ocular hypertension.

Methods

This was a prospective, double-blinded, randomized, crossover study conducted at our clinic between October 2011 and January 2012. The study was performed in compliance with the ethical principles of the Declaration of Helsinki and was approved by the institutional review board. All patients provided written informed consent before participation. Screening visit examinations included a review of the ocular and medical history, Snellen visual acuity measurement, IOP measurement with a calibrated Goldmann applanation tonometer, gonioscopy, slit-lamp biomicroscopy, dilated fundus examination, ultrasound pachymetry, visual field testing (Humphrey VFA, SITA Standard 30-2, Humphrey Instruments), retinal nerve fiber layer analysis (RTVue SD-OCT; Optovue, Inc.) and administration of a pregnancy test (if applicable).

The inclusion criteria for the subjects were as follows: >18 years of age, previously diagnosed bilateral or unilateral primary open-angle glaucoma (IOP>22 mmHg at the time of diagnosis) and unable to lower IOP (IOP>22 mmHg) adequately with the recent monotherapy antiglaucomatous drugs, which were successful at the beginning of the therapy, no history of glaucoma surgery before the study, and Snellen visual acuity 0.1 or better in the study eye(s). Patients were excluded if they met any of the following criteria: hypersensitivity to timolol maleate, topical or oral carbonic anhydrase inhibitors, sulfonamide derivatives, or to any components of the study medications; chronic, recurrent, or severe ocular inflammatory disease; clinically relevant or progressive retinal pathology; history of ocular surgery or trauma within 6 months; laser surgery within 3 months; visual acuity less than 0.6 logMAR; optic nerve with a cup-disc ratio greater than 0.8; history of uncontrolled diabetes or respiratory, cardiovascular, hepatic, or renal disease precluding the safe administration of a beta-blocker; and treatment with stable doses of any medication within 30 days of the start of the study that could affect IOP.

A total of 114 patients were enrolled and 101 completed the study. Fifty-seven patients were randomized to receive Brinz/Tim and 57 to receive Dorz/Tim. All patients were Caucasians and demographic information for each group is given in Table 1.

Table 1.

Demographic Data of the Study Population

Characteristics	Brinz/Tim	Dorz/Tim	P^a
Mean, age (y)±SD (range)	54.8±8.5	55.7±5.4	0.354
Sex (%)
Female	56.1	45.7	0.387
Male	43.9	54.3	0.654
Diagnosis, (%)
Ocular hypertension	20.4	22.7	0.646
Open-angle glaucoma	70.5	68.3	0.687
Open-angle glaucoma with pigment dispersion	4	3.2	0.987
Open-angle glaucoma with pseudoexfoliation	5.1	5.8	0.453

P-value from Fisher exact test (^aP<0.05).

Brinz/Tim, brinzolamide 1%+timolol 0.5%; Dorz/Tim, dorzolamide 2%+timolol 0.5%.

All previous IOP-lowering medications were stopped for patients who met the eligibility criteria. A standard washout schedule was monitored as follows: 5 days for miotics and topical or oral carbonic anhydrase inhibitors; 14 days for alpha and alpha/beta adrenergic agonists; and 28 days for beta-adrenergic antagonists, prostaglandins, and fixed combination products.

After the washout period, eligible patients were randomly assigned to receive either Brinz/Tim (eye drops solution, Cosopt^®) or Dorz/Tim (eye drops suspension, Azarga^®) once every morning at 8 AM and once every evening at 8 PM for the 12-week treatment period. Randomization was obtained by using a ratio of 1:1.

The first follow-up visits occurred 2 weeks after the initial examination, and additional follow-ups were conducted at 1^st, 2^nd, and 3^rd months of treatment. A detailed ocular examination, including IOP measurement, was performed and adverse reactions were noted at all visits; IOP readings were obtained by the same blinded, experienced observer (B.A. or E.G.) at 8 AM (before morning dosing of the study medication), at 10 AM (2 h after dosing of study medication), and at 4 PM. If only one eye of the patient was dosed, then the dosed eye was selected for analysis; if both eyes were dosed, then the eye with the higher mean IOP at any time point was included. In cases where IOP was equal in both eyes at all 3 time points, the right eye was selected. At the first visit, patients were trained on the completion of an ocular discomfort evaluation. To perform this evaluation, patients were asked to rate the presence and magnitude of ocular discomfort (blurred vision, eye irritation, eye pain, foreign body sensation in eyes, and ocular hyperemia) on a 5-point scale (0: none, 1: mild, 2: moderate, 3: severe, 4: very severe). Criteria for discontinuation from the study medication included uncontrolled IOP, adverse events/reaction, decision unrelated to an adverse event, lost to follow-up, and noncompliance.

NCSS (Number Cruncher Statistical System) 2007 & PASS (Power Analysis and Sample Size) 2008 statistical software programs were used for statistical analysis. The Student's t-test was used to compare the data in between groups, the paired sample t-test was used for comparison of data in groups.

Results

A comparison of the mean IOP measurements at baseline and at each visit and time points are shown in Table 2. The upper 95% confidence limits of treatment group differences were below +1.0 mmHg, which was the limit of clinical relevance used to establish noninferiority in this study. The mean baseline IOP ranged from 24.6 to 29.9 mmHg in both groups. The mean IOP at all visits and time points ranged from 16.26 to 18.98 mmHg after dosing with Brinz/Tim and from 16.35 to 19.0 mmHg after dosing with Dorz/Tim (Table 3).

Table 2.

Comparison of Mean Intraocular Pressure (mm Hg) by Treatment Group at All Visits and Time Points

	Brinz/Tim	Dorz/Tim			%95 CI
Intraocular pressure	mean±SD	mean±SD	Difference	P^a	Lower	Upper
Baseline IOP (mm Hg)
8:00	27.40±2.39	29.95±3.16	0.55	0.521	−0.6	0.7
10:00	26.00±0.91	27.93±2.69	0.93	0.765	−0.6	0.5
16:00	24,61±0.82	26.16±2.04	0.25	0.234	−0.7	0.3
2nd week
8:00	18.98±2.26	19.00±1.05	−0.02	0.958	−0.68	0.64
10:00	17.98±2.26	17.81±0.93	0.17	0.590	−0.47	0.82
16:00	18.19±2.12	18.00±0.84	0.19	0.525	−0.41	0.79
1st month
8:00	17.98±2.21	17.93±2.06	0.05	0.894	−0.76	0.87
10:00	16.92±2.50	16.94±2.08	−0.02	0.966	−0.91	0.87
16:00	17.15±2.80	17.13±2.11	0.02	0.965	−0.93	0.97
2nd month
8:00	17.34±2.76	17.54±1.83	−0.2	0.664	−1.10	0.70
10:00	16.55±2.76	16.54±2.04	0.01	0.983	−0.92	0.94
16:00	16.74±2.54	16.74±1.92	0.0	0.991	−0.87	0.86
3rd month
8:00	17.70±1.03	17.56±1.34	0.14	0.539	−0.32	0.60
10:00	16.26±1.02	16.35±1.48	−0.09	0.722	−0.57	0.40
16:00	16.45±0.84	16.56±1.62	−0.11	0.681	−0.60	0.39

P-value from Student's t test (^aP<0.01).

IOP, intraocular pressure; CI, confidence interval; SD, standard deviation.

Table 3.

Comparison of Mean Intraocular Pressure Change in Each Group

	Brinz/Tim				Dorz/Tim
Intraocular pressure	Mean	Mean change	% mean change	P^a	Mean	Mean change	% mean cahnge	P^a
Baseline IOP (mm Hg)
8:00	27.4	—	—	—	29.95	—	—	—
10:00	26	—	—	—	27.93	—	—	—
16:00	24.61	—	—	—	26.16	—	—	—
2nd week
8:00	18.98	−8.42	−30.73	0.001^a	19	−10.95	−36.56	0.001^a
10:00	17.98	−8.02	−30.85	0.001^a	17.81	−10.12	−36.23	0.001^a
16:00	18.19	−6.42	−26.09	0.001^a	18	−8.16	−31.19	0.001^a
1st month
8:00	17.98	−9.42	−34.38	0.001^a	17.93	−12.02	−40.13	0.001^a
10:00	16.92	−9.08	−34.92	0.001^a	16.94	−10.99	−39.35	0.001^a
16:00	17.15	−7.46	−30.31	0.001^a	17.13	−9.03	−34.52	0.001^a
2nd month
8:00	17.34	−10.06	−36.72	0.001^a	17.54	−12.41	−41.44	0.001^a
10:00	16.55	−9.45	−36.35	0.001^a	16.54	−11.39	−40.78	0.001^a
16:00	16.74	−7.87	−31.98	0.001^a	16.74	−9.42	−36.01	0.001^a
3rd month
8:00	17.7	−9.7	−35.40	0.001^a	17.56	−12.39	−41.37	0.001^a
10:00	16.26	−9.74	−37.46	0.001^a	16.35	−11.58	−41.46	0.001^a
16:00	16.45	−8.16	−33.16	0.001^a	16.56	−9.6	−36.70	0.001^a

P-value from Paired Samples Test (^aP<0.01).

Both medications produced statistically relevant IOP reductions, which were similar in both groups at each visit and time point (Table 3). At all study visits and time points, Brinz/Tim produced mean IOP reductions ranging from 6.42 to 9.74 mmHg (26.09%–37.46%, respectively), whereas Dorz/Tim produced mean IOP reductions ranging from 8.16 to 12.41 mmHg (31.19%–41.44%, respectively) (P>0.05).

A total of 13 patients discontinued the study; of these, 6 patients were in the Brinz/Tim group and 7 in the Dorz/Tim group. The reasons for discontinuation were inadequate control of IOP (3 patients in the Brinz/Tim group and 4 patients in the Dorz/Tim group), decision unrelated to an adverse event (one patient in each group), lost to follow-up (2 patients in the Brinz/Tim group and one patient in the Dorz/Tim group), and noncompliance (one patient in the Dorz/Tim group).

The evaluation of tolerability was conducted in all the 114 randomized patients who received at least one dose of a study medication. There was a significant difference between the ocular discomfort scores of patients in the 2 treatment groups, with a greater percentage of patients in the Dorz/Tim group reporting mild, moderate, or severe ocular discomfort compared to the Brinz/Tim group. The most common ocular adverse reactions (incidence>1%) included blurred vision, eye irritation (characterized as a burning sensation), eye pain (characterized as a stinging sensation), and foreign body sensation. Ocular irritation, ocular pain, and foreign body sensation were reported at a significantly higher incidence by patients treated with Dorz/Tim than patients receiving Brinz/Tim (P=0.0001). In contrast, patients treated with Brinz/Tim reported a significantly higher incidence of blurred vision compared to patients treated with Dorz/Tim (P=0.0001). After 2 weeks of treatment, the reports of ocular discomfort were significantly higher in the Dorz/Tim group than the Brinz/Tim group (48/57 [84.2%] vs. 28/57 [49.1%], respectively; P=0.0001; Table 4).

Table 4.

Distribution of Ocular Discomfort Scores on the Week 2 Visit

Brinz/Tim						Dorz/Tim
	Mild n/(%)	Moderate n/(%)	Severe n/(%)	Very severe n/(%)	Total n/(%)	Mild n/(%)	Moderate n/(%)	Severe n/(%)	Very severe n/(%)	Total n/(%)	P-value
Blurred vision	8 (14%)	7 (12.2%)	3 (5.2%)	1 (1.7%)	19 (33.3%)	5 (8.7%)	1 (1.7%)	0	0	6 (10.5%)	0.001^a
Ocular irritation	3 (5.2%)	1 (1.7%)	0	0	4 (7.01)	9 (15.7%)	4 (7.01%)	4 (7.01%)	2 (3.5%)	19 (33.3%)	0.001^a
Eye pain	2 (3.5%)	0	0	0	2 (3.5%)	10 (17.5%)	5 (8.7%)	1 (1.7%)	1 (1.7%)	17 (29.8%)	0.001^a
Foreign body sensation	2 (3.5%)	0	0	0	3 (5.2%)	8 (14.03%)	5 (8.7%)	2 (3.5%)	1 (1.7%)	16 (28.07)	0.001^a

P-value from Paired Samples Test (^aP<0.01).

Discussion

This study demonstrated that IOP lowering effects of Brinz/Tim were similar to the Dorz/Tim fix combination, but the drug combination provides greater ocular comfort in patients, with open-angle glaucoma or ocular hypertension, who would benefit from therapy with a fixed combination product. The mean IOP reduction with Brinz/Tim ranged from 6.42 to 10 mmHg, representing a 26–37% reduction from baseline. This is equivalent to the results obtained using the established treatment of Dorz/Tim (8.16–12.41 mmHg; 31%–41%). The upper limits of the 95% confidence intervals for treatment group differences were below 1.0 mmHg at all 12 time points in this study, including measurements performed after 3 months of treatment.

Abnormal diurnal variation of IOP is a well-known characteristic in glaucoma patients, especially in cases of open-angle glaucoma and ocular hypertension.⁸ Therefore, it is imperative to reveal IOP variations by obtaining measurements at varying time points. Controlling IOP at these time points might be critical in the treatment of glaucoma.⁸ In our study, Brinz/Tim and Dorz/Tim provided meaningful IOP reductions throughout the day. Mean IOP reductions at 8 AM, 10 AM, and 4 PM ranged from 6.4 to 10 mmHg for Brinz/Tim and from 8.1 to 12.4 mmHg for Dorz/Tim when data from all visits were pooled. In accordance with our data, Manni et al.⁹ found that IOP reductions ranged from 7.2 to 9.2 mmHg for Brinz/Tim and from 7.4 to 8.9 mmHg for Dorz/Tim. Those authors concluded that there is no statistically significant difference between the formulations in terms of efficacy.

The IOP-lowering fixed combination drugs, such as topical beta blockers and carbonic anhydrase inhibitors, allow for a simplified treatment regimen, thereby increasing patient compliance and reducing preservative exposure at the ocular surface. Brinz/Tim eye drops and Dorz/Tim eye drops contain 0.01% and 0.0075% benzalconium chloride, respectively,^10,11 and this preservative has been associated with subclinical conjunctival inflammation^12,13 and aggravation of ocular surface disease.¹⁴

This clinical study demonstrates that the ocular irritation, eye pain, and foreign body sensation rates were significantly lower with Brinz/Tim ophthalmic suspension in patients with open-angle glaucoma or ocular hypertension. The difference may be explained by the higher pH values of the Brinz/Tim combination. Due to their inherent molecular structure, carbonic anhydrase inhibitors have poor water solubility in the physiologic pH range. To overcome this characteristic, the pH of Dorz/Tim ophthalmic solution is 5.6–5.7, thus increasing the aqueous solubility.¹⁵ On the other hand, the pH range of Brinz/Tim is 7.5–7.2, and therefore much closer to physiologic levels.¹⁶ The Brin/Tim fixed combination causes increased blurred vision due to its suspension formulation.¹⁷ The higher incidence of blurred vision in patients treated with Brin/Tim could be expected for a suspension formulation,¹⁷ and numerous studies have demonstrated greater comfort and higher patient preference rates for brinzolamide over Dorz/Tim.^18–23

In summary, this prospective, randomized, double-blinded clinical trial demonstrated that Brinz/Tim 0.5% eye drops produced a statistically significant reduction in IOP just as the Dorz/Tim eye drop solution when both were dosed twice daily. Moreover, patients with ocular hypertension or open-angle glaucoma may prefer the Brinz/Tim fixed combination over the Dorz/Tim fixed combination due to the greater ocular discomfort associated with Dorz/Tim. Since the active components are similar, the observed differences in preference and discomfort between these 2 drugs might be ascribed due to formulation differences. Moreover, greater ocular surface comfort seen in the Brinz/Tim treatment may provide a better patient experience and improve therapeutic compliance.

Footnotes

Author Disclosure Statement

None of the authors of the above manuscript has any conflict of interest or financial disclosure.

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