Current Medical Research and Opinion

ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20

Efficacy and safety of brimonidine and dorzolamide for intraocular pressure lowering in glaucoma and ocular hypertension

L. Jay Katz, Steven T. Simmons & E. Randy Craven

To cite this article: L. Jay Katz, Steven T. Simmons & E. Randy Craven (2007) Efficacy and safety of brimonidine and dorzolamide for intraocular pressure lowering in glaucoma and ocular hypertension, Current Medical Research and Opinion, 23:12, 2971-2983, DOI: 10.1185/030079907X242476 To link to this article: https://doi.org/10.1185/030079907X242476

Published online: 18 Oct 2007.

Submit your article to this journal

Article views: 97

View related articles

Citing articles: 10 View citing articles

Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=icmo20 Current Medical Research and Opinion® 0300-7995 Vol. 23, No. 12, 2007, 2971–2983 doi:10.1185/030079907X242476

© 2007 LibraPharm Limited All rights reserved: reproduction in whole or part not permitted

REVIEW Efficacy and safety of brimonidine and dorzolamide for intraocular pressure lowering in glaucoma and ocular hypertension L. Jay Katz a, Steven T. Simmons b and E. Randy Craven c a Glaucoma, Wills Eye Hospital, Philadelphia, PA, USA b Glaucoma Consultants of the Capital Region, Slingerlands, NY, USA c Glaucoma Consultants of Colorado, Littleton, CO, USA

Address for correspondence: L. Jay Katz, MD, Glaucoma Wills Eye Hospital, 840 Walnut St, Ste 1110, Philadelphia, PA 19107, USA. Tel.: +1 215 928 3197; Fax: +1 215 928 0166; [email protected] Key words: Adjunctive – Brimonidine – Dorzolamide – Glaucoma – Intraocular pressure

ABSTRACT

Background: Brimonidine and dorzolamide are by brimonidine and dorzolamide were more intraocular pressure (IOP)-lowering medications pronounced when the medica­tions were used most commonly used in second-line treatment of adjunctively with other classes of drugs. Six other glaucoma and ocular hypertension. trials showed similar efficacy, and one additional Scope: An evidence-based review of monotherapy study showed lower IOP with comparative clinical trials of brimonidine and dorzolamide treatment. Ocular burning was noted dorzolamide was under­taken to determine the with dorzolamide more than any other adverse relative efficacy and safety of these drugs in event with either drug. Trials ranged widely in reducing IOP. Using the keywords ‘brimonidine’ duration of therapy and the time of day IOP and ‘dorzolamide’, all articles describing such measurements were taken, and many were too trials from September 1966 to July 2007 were small for sufficient statistical power. found in MEDLINE and EMBASE. Conclusion: Brimonidine and dorzolamide are Findings: In all identified studies, brimonidine both efficacious and reasonably well tolerated. and dorzolamide were both found to provide Possible overall distinctions in efficacy were significant IOP reduction from treated or untreated obscured by differences in study designs and baseline levels. Results of eight trials reported to treatment regimens, but adjunctive therapy with date indicate that brimonidine produced either a brimonidine may reduce IOP as effectively or more lower treated IOP or greater pressure reduction effectively than adjunctive or fixed combination from baseline than dorzolamide at one or more dorzolamide therapy. In certain patients with measured timepoints, and provided comparable glaucoma and ocular hypertension brimonidine IOP lowering over all other measurements. may be a better choice than dorzolamide for Differences between the IOP reductions provided second-line treatment.

Introduction are representative members of two of these drug classes. Many classes of drugs are available to reduce intraocular Dorzolamide is a topical carbonic anhydrase pressure (IOP) in the treatment of glaucoma and ocular inhibitor that reduces IOP by suppressing aqueous hypertension (OHT). Dorzolamide and brimonidine humor pro­duction1,2. Dorzolamide hydrochloride

Paper 4023 2971 2.0% ophthalmic solution (Trusopt*), available in a IOP19,20, but they are sometimes used as monotherapy buffered isotonic solution of pH 5.6 preserved with and are frequently used as adjunctive therapy with benzalkonium chloride (BAK) 0.0075%, is indicated a prosta­glandin analogue or a beta-blocker such as in the treatment of elevated IOP in patients with timolol21,22. Both brimonidine and dorzolamide are OHT or open-angle glaucoma. It can be used safely in commonly considered drugs for second-line therapy23. pediatric patients between the ages of 2 and 6 years3–5. In choosing between these medications, it is important In its pivotal trials for drug approval, dorzolamide TID to consider their relative efficacy and safety profiles. reduced IOP by 3–5 mmHg3 but was less effective than A literature search of the MEDLINE database timolol in lowering IOP at both peak and afternoon from 1966 through July 2007 and EMBASE from trough effect6,7. Dorzolamide is labeled for TID dosing 1988 through July 2007 using the search terms but is often used BID in clinical practice. There is a ‘brimonidine’ and ‘dorzolamide’ revealed multiple warning on the label that dorzolamide is a sulfonamide studies that directly compared these drugs in the that is systemically absorbed after topical application, treatment of glaucoma and OHT. All reports of studies so adverse reactions attributable to sulfonamides, that compared the IOP-lowering efficacy and/or safety including fatal reactions, are theoretically possible but of these two medications were included in this review. have not been reported. Dorzolamide is contraindicated The most relevant reports of studies that used just in patients with hypersensitivity to any component of one of the medications were included as background the medication. Common side effects associated with information. References cited in articles elicited by the dorzolamide treatment include ocular burning and search were reviewed and included when appropriate. stinging, bitter taste, and allergy. Relevant articles in languages other than English were Brimonidine is a selective alpha2-adrenergic receptor translated. This review summarizes and discusses agonist that has a dual mechanism of IOP lowering: it the results of those comparison studies, which are both reduces aqueous production and stimulates uveo­ divided into three treatment situa­tions: brimonidine scleral outflow8. In its pivotal trials for drug approval, and dorzolamide monotherapy, brimonidine and topical brimonidine tartrate 0.2% (Alphagan†), reduced dorzolamide as adjunctive therapy, or brimonidine– IOP at least as well as timolol at peak effect (2 h after timolol and dorzolamide–timolol fixed combinations. dosing) but less effectively than timolol at morning trough9–11. Brimonidine is indicated for reducing IOP in patients with open-angle glaucoma or OHT. It is Brimonidine and dorzolamide contraindicated in patients with hypersensitivity to any as monotherapy component of the medication and in patients receiving monoamine oxidase inhibitor therapy, and it should Three separate prospective, randomized studies with not be used in children under the age of 3 years12,13. The crossover designs have evaluated the efficacy and safety label recommends TID dosing, but brimonidine is most of brimonidine compared with dorzolamide as mono­ commonly used BID in clinical practice. Common side therapy in glaucoma and OHT24–26. The results of these effects associated with brimon­idine treatment include studies, described below, suggest that there is no overall conjunctival hyperemia, allergic conjunctivitis, eye difference between the drugs in the frequency of side pruritus, lethargy, and dry mouth14. effects, but ocular stinging and burning are more often New formulations of brimonidine contain brimonidine associated with dorzolamide treatment. When used tartrate 0.1 or 0.15% in a buffered solution of pH as mono­therapy, brimonidine and dorzolamide show 6.6–7.4 preserved with Purite‡ 0.005%15. Although similar efficacy. the new formulations contain a reduced concentration A prospective, double-masked, randomized, crossover of brimonidine, they were shown in clinical trials study24 compared brimonidine 0.2% and dorzolamide to have the same IOP-lowering efficacy and better 2.0%, each dosed TID for 6 weeks, in 40 patients with tolerability compared with the brimonidine 0.2% glaucoma or OHT. The study design included a 2-week formulation because the change in pH provides better washout between treatment periods. IOP was measured bioavailability15,16. In contrast to the more commonly used at 8 a.m. and 10 a.m. at the study baseline and after preservative BAK, Purite has not been associated with 6 weeks of treatment. Mean baseline IOP for all patients ocular surface side effects after repeated exposure17,18. was 24.1 mmHg. After treatment, mean IOP was similar Both brimonidine and dorzolamide are less between groups at 8 a.m. (20.8 mmHg with brimonidine efficacious than the once-daily prostaglandin analogue and 20.7 mmHg with dorzolamide, p = 0.99). At drugs (latano­prost, bimatoprost, travoprost) in reducing 10 a.m. (peak effect), mean IOP was 17.8 mmHg with * Trusopt is a registered trade name of Merck & Co, Inc; Whitehouse Station, NJ, USA † Alphagan is a registered trade name of Allergan Inc; Irvine, CA, USA ‡ Purite is a registered trade name of Allergan Inc; Irvine, CA, USA

2972 Efficacy and safety of brimonidine compared with dorzolamide © 2007 LIBRAPHARM LTD – Curr Med Res Opin 2007; 23(12) brimonidine treatment and 18.6 mmHg with dorzol­ efficacy of both drugs in this study (8–12% mean IOP amide treatment ( p = 0.10). In safety analyses, there was reduction) and the lack of significant differences between no significant difference in incidence of ocular adverse drugs. The order effect had minimal impact on the IOP- events during treatment (18 on dorzolamide vs. 10 on lowering results at trough (without correction, the mean brimonidine, p = 0.10). The only individual adverse IOP reduction was 3.0 mmHg with both drugs; after event with a significant difference in incidence between correction for the order effect, the mean IOP reduction treatments was stinging/burning, which was reported for was 3.1 mmHg on brimonidine and 2.9 mmHg on 15 patients on dorzolamide (38%) and one patient on dorzolamide, p < 0.001). The true peak effect of the brimonidine (2.5%, p < 0.01). One patient discontinued medications may not have been measured at 9 a.m. (1 h from brimonidine treatment because of ocular adverse after dosing), but the uncorrected mean IOP reduction events and two did so because of systemic adverse at this time was 3.1 mmHg on brimonidine compared events not necessarily related to treatment. The results with 2.4 mmHg on dorzolamide. The order effect on of this industry-sponsored short-term study suggest that the 9 a.m. results was not reported. The most common brimonidine and dorzolamide are both well tolerated adverse event was ocular burning, reported for over when dosed thrice daily as monotherapy, and they 40% of patients during dorzolamide treatment but less provide similar IOP lowering. However, dorzolamide than 10% of brimonidine patients. Burning and stinging use was associated with a higher incidence of stinging/ were more frequent with dorzolamide ( p ≤ 0.017), burning. and dry eye was more frequent with brimonidine ( p = Whitson and associates25 reported a prospective, 0.04). Four patients dropped out of the study because double-masked, randomized, crossover comparison of adverse events not necessarily related to treatment of brimonidine 0.2% and dorzolamide 2% each given (one during dorzolamide treatment because of burning TID for 6 weeks in 43 glaucoma or OHT patients and three during brimonidine treatment because of with a 2-week washout between treatment periods. conjunctival hyperemia, lethargy, and a non-specified IOP was measured at 8 a.m. (morning trough), 9 a.m., adverse event). The results of this industry-sponsored and 11 a.m. at baseline before each treatment period study demonstrate that brimonidine and dorzolamide and at Week 6 of treatment. Over both baselines, dosed TID are both well tolerated and have similar IOP- mean IOP (8 a.m.) was 24.3 mmHg for patients on lowering efficacy. However, once again, dorzolamide dorzolamide, and 24.6 mmHg for those on brimonidine use was associated more frequently with ocular burning ( p = 0.9). Mean baseline IOP for the first treatment and stinging. period was 24.3 mmHg for the brimonidine group and Sharpe and associates26 performed a prospective, 26.1 mmHg for patients initially receiving dorzolamide double-masked, randomized, crossover comparison ( p = 0.1). Patients who received brimonidine in the of brimonidine–Purite 0.15% and dorzolamide 2%, second treatment period entered it with a mean IOP each given BID for 4 weeks in 33 glaucoma and OHT of 24.9 mmHg, and those in the dorzolamide group patients with a 4-week washout between treatment had a mean second baseline IOP of 22.1 mmHg periods. In this industry-sponsored study, IOP was ( p = 0.06). The mean IOP reductions from treatment measured at 8 a.m. (morning trough), 10 a.m. (peak), period baseline to Week 6 of brimonidine treatment at 6 p.m., and 8 p.m. (evening trough) at baseline before 8 a.m., 9 a.m., and 11 a.m. were 3.0 mmHg, 3.1 mmHg, each treat­ment period and at Week 4 of treatment. and 2.6 mmHg, respectively. The corresponding mean Mean baseline IOP before brimonidine treatment IOP reductions with dorzolamide treatment were was 22.9 mmHg and 22.2 mmHg before dorzolamide 3.0 mmHg, 2.4 mmHg, and 2.9 mmHg, respectively, treatment ( p = 0.46). The primary efficacy measure and none of the differences between treatment groups was mean IOP after 4 weeks of treatment. At 10 a.m. were statistically significant ( p ≥ 0.96). These results (peak effect), brimon­idine–Purite provided a mean should be interpreted with caution for several reasons, IOP of 18.1 mmHg while that for dorzolamide was primarily because the order of treatment periods effect 19.5 mmHg ( p = 0.10). With a difference in mean was statistically significant. Baseline IOP was reported IOP of 1.4 mmHg, statistical signif­icance could not for only the 8 a.m. measurements, but at this timepoint, be expected because the study was not powered to baseline mean IOP for patients initially treated with detect a difference of that magnitude. Mean IOP at brimonidine was 2.2 mmHg higher at the start of the other times of the day was similar between treatments: first period than at the start of the second treatment 21.0 mmHg with both treatments at 8 a.m. ( p = 0.9), period, and baseline mean IOP for patients initially 19.0 mmHg with brimonidine–Purite and 19.4 mmHg treated with dorzolamide was 1.2 mmHg higher. This with dorzolamide at 6 p.m. ( p = 0.59), and order effect might have been caused by an inadequate 19.0 mmHg with brimonidine–Purite and 19.2 mmHg washout period (2 weeks) between treatment periods with dorzolamide at 8 p.m. ( p = 0.69). Mean diurnal and could partially explain both the unexpectedly low IOP was 19.3 mmHg with brimonidine–Purite and

© 2007 LIBRAPHARM LTD – Curr Med Res Opin 2007; 23(12) Efficacy and safety of brimonidine compared with dorzolamide Katz et al. 2973 19.8 mmHg with dorzolamide ( p = 0.46). The mean ectropion28. Based on systematic drug discontinuation IOP reduction from treatment-period baseline was and rechallenge in 13 patients presenting with significantly­ greater with brimonidine–Purite than with ectropion, dorzolamide was found to be the cause in dorzolamide at peak (5.3 mmHg vs. 3.6 mmHg, p = seven of eight patients who were initially on the drug. 0.03) and at evening trough (3.3 mmHg vs. 1.7 mmHg, Of five patients that had been using brimonidine, three p = 0.04), as well as in the mean diurnal measurements ectropion cases were attributed to its use. Although (3.6 mmHg vs. 2.4 mmHg, p = 0.03). The mean this adverse effect has not been noted in a significant reduction from baseline IOP results should be inter­ number of treated patients, this study suggests that preted with caution, however, because there was a certain patients may be susceptible to eyelid ectropion possible effect of treatment order on baseline IOP with use of either dorzolamide or brimonidine. associated with dorzolamide treatment, and the authors suggested that the 4-week washout used between treatment periods may have been inadequate26. All Brimonidine and dorzolamide enrolled patients completed the study as planned. The as adjunctive therapy only significant difference in adverse events between treatments was a much higher incidence of burning Several head-to-head randomized controlled trials29–33 upon instillation with dorzolamide (24%) than with have compared the efficacy and safety of brimonidine brimonidine (3%, p = 0.02). The results of this study and dorzolamide as adjunctive therapy with beta- indicate that brimonidine–Purite and dorzolamide blockers or other pre-existing therapy (Table 1). With dosed BID are comparable in effectiveness and both adjunctive brimonidine providing IOP reductions were generally well tolerated, although the degree of similar to or greater than those provided by adjunctive discomfort was substantially greater with dorzolamide. dorzolamide in each study (Table 1), efficacy results Recently, Quaranta and associates27 reported a study from the studies tended to favor brimonidine. comparing the effects of brimonidine, dorzolamide, timolol, and latanoprost on blood pressure and 24- Adjunctive therapy with beta-blockers h IOP control in 27 treatment-naïve patients with newly diagnosed moderate or advanced glaucoma. This Because beta-blockers reduce IOP by inhibiting was a prospective, investigator-masked, randomized, aqueous humor production34, it has been deemed crossover comparison with 6-week treatment periods important to determine whether medications that and a 4-week washout between treatments. Mean lower IOP in whole or in part by suppressing aqueous baseline IOP was 24.2 mmHg (24-h mean). Mean production, such as dorzolamide and brimonidine, IOP across 24 h was 18.3 mmHg with brimonidine have additive effects with beta-blockers. A short- and 17.4 mmHg with dorzolamide. Dorzolamide term study in normal subjects showed that combined produced lower IOP than brimonidine from 10 p.m. to treatment with brimonidine and timolol caused a 6 a.m. ( p ≤ 0.003), but the treatments did not differ further inhibition of aqueous flow and decrease in significantly from 6 a.m. to 8 p.m. It is possible that IOP compared to treatment with brimon­idine or the different dosing schedules used for the two drugs timolol (15.4%, p < 0.001) alone35. Similarly, in a – dorzolamide 2% was dosed three times daily, whereas study reported by Toris and associates, aqueous flow brimonidine 0.2% was dosed twice daily – can account and IOP were reduced more by combined treatment for the difference in IOP level. Of note, although mean with dorzolamide and timolol than by treatment with changes in blood pressure were small and not clinically either dorzolamide ( p < 0.04) or timolol ( p = 0.001) significant in the pivotal trials of brimonidine11, alone36. Further, many longer-term clinical studies in brimonidine treatment was associated with consistently patients with glaucoma or OHT have confirmed that lower blood pressure compared with both baseline and both brimonidine22,30,37,38 and dorzolamide30,38–45 provide the other treatments in the 24-h study ( p < 0.0001)27. significant additional mean decreases in IOP when Mean baseline systolic blood pressure was 125.1 mmHg added to ongoing beta-blocker therapy. and diastolic pressure was 73.6 mmHg. With Stewart and associates21 reported a retrospective brimonidine treatment, mean systolic pressure was study of brimonidine (n = 24), dorzolamide (n = 67), reduced to 116.8 mmHg and diastolic to 64.5 mmHg. and latanoprost (n = 50) given as adjunctive therapy The clinical significance of these findings is not clear with a beta-blocker in patients with glaucoma or OHT. and the investigators suggested that longer-term studies Baseline patient characteristics were similar between will be needed to evaluate effects of the treatments on the treat­ment groups, with brimonidine patients at nocturnal hypotension and ocular perfusion pressure27. 21.7 mmHg, dorzolamide patients at 23.0 mmHg In a recent study, a connection was noted between and latanoprost patients at 22.9 mmHg (stated non- dorzolamide or brimonidine use and induction of significant). Almost all of the patients on brimonidine

2974 Efficacy and safety of brimonidine compared with dorzolamide © 2007 LIBRAPHARM LTD – Curr Med Res Opin 2007; 23(12)

= 0.74 ≥ 0.101 for unoprostone vs brim or ≤ 0.018 brim vs dorz; lat dorz = 0.007 (peak) = 0.12 (trough) p Statistical significance (brim vs dorz) p -value not reported for brim vs dorz p dorz p p p p < 0.05

mmHg mmHg

mmHg mmHg

mmHg mmHg mmHg mmHg mmHg mmHg mmHg

2 2.2 (Month 1) Peak: 6.0 Trough: 2.9 Trough: 1.9 30.8% 27.3% 30.6% 3.3 3.1 2.7 2. Peak: 4.1 (Month 1 peak) 4.4 (8-h diurnal Week 12) 2.8 IOP reduction (24-h circadian Week 6) p -value 0.52 0.284 0.31 0.96 NA Mean baseline IOP (mm Hg) 19.0 19.0 21.56 20.89 22.8 22.7 23.2 22.37 22.38 NA D

Adjunctive therapy Brim P 0.15% BI Dorz 2% BID Brim 0.2% BID Dorz 2% TID Brim 0.2% BID Dorz 2% BID Latanoprost QD Brim 0.2% BID Dorz 2% BID Brim 0.2% BID Dorz 2% BID Unoprostone BID Randomized controlled trials of brimonidine and dorzolamide in adjunctive therapy

Table 1. Table Beta-blocker Beta-blocker Timolol Pre-existing therapy Various regimens Latanoprost

weeks 3 months 12 weeks 6 3 months 1 year Treatment duration 33 92 106 146 272 N Reference 32 33 30 31 29

© 2007 LIBRAPHARM LTD – Curr Med Res Opin 2007; 23(12) Efficacy and safety of brimonidine compared with dorzolamide Katz et al. 2975 (92%) used the adjunctive drug BID, and most of the have the potential to produce IOP lowering additive to patients on dorzolamide also used their adjunctive that achieved with timolol. therapy BID (81%) rather than TID. The study results In a prospective, randomized, parallel-group clinical showed significantly lower mean IOP values after comparison, brimonidine or dorzolamide was given 3 months with adjunctive brimonidine (17.4 mmHg) twice daily for 1 month as adjunctive therapy with a compared with adjunctive dorzolamide (20.1 mmHg, beta-blocker in 180 eyes of 92 patients with glaucoma p = 0.03), but no between-group difference in the or OHT who had IOP uncontrolled on beta-blocker reduction from beta-blocker treated baseline (4.2 mmHg therapy alone29. Treatment success was determined for brimonidine vs. 3.1 mmHg for dorzolamide, by the achievement of at least a 15% IOP reduction stated non-significant). Treatment was successfully from beta-blocker-treated baseline. Patients who were maintained for 3 months in 58% of brimonidine successfully treated at Month 1 were continued on their patients versus 40% of dorzolamide patients (among- therapy for another 2 months, while those who did not group p < 0.005; pairwise between-group p-value not demonstrate at least 15% IOP lowering were switched reported); the higher success rate with brimonidine to the other treatment arm and seen at visits after 1 occurred primarily because many more dorzolamide and 3 months of crossover therapy. IOP was measured patients (49%) than brimonidine patients (21%) had at study visits in the morning 1.5–2 h after instillation a change in medical regimen or had surgery prior to of dorzolamide or brimonidine. Mean baseline beta- Month 3 because their IOP was not low enough. The blocker-treated IOP was 22.4 mmHg in each treatment percentage of patients who discontinued treatment group. After 1 month of treatment, significantly more because of adverse events did not vary significantly brimonidine-treated eyes (78.3%) demonstrated at least among the treatment groups (21% for brimonidine vs. a 15% reduction from baseline IOP compared with 13% for dorzolamide, p > 0.05). This study had several dorzolamide-treated eyes (71%, p = 0.05). Moreover, limitations: patients were not randomized to treatment, of the nine patients (19.6%) on brimonidine who had there was a 1.3 mmHg mean difference between less than a 15% IOP reduction, five were crossed over brimon­idine and dorzolamide treatment groups in to dorzolamide, and none of these five patients had a baseline IOP which was not accounted for in overall successful IOP lowering response on dorzolamide either. statistical comparisons, there was no control for diurnal In contrast, 13 patients (28.3%) had inadequate IOP IOP, and Month 3 efficacy data were not available for lowering on dorzolamide, and five were crossed over a large percentage of patients. Nonetheless, the results to brimonidine treatment where all five subsequently of this industry-sponsored study suggest that IOP showed at least a 15% reduction from baseline IOP. lowering with brimonidine is as or more effective than Six patients on dorzolamide and seven on brimonidine with dorzolamide, and may be associated with higher discontinued treatment because of adverse effects not success rates as an adjunctive with a beta-blocker. necessarily related to treatment. It should be noted that A prospective, randomized, crossover comparison patients who failed treatment on one medication at study was initiated to investigate the capacity for Month 1 and crossed over to the other treatment arm adjunctive brimonidine or dorzolamide to acutely lower were included in the Month 1 mean IOP evaluation of IOP46. A single drop of brimonidine or dorzolamide both drugs. The mean IOP reduction at Month 1 was was given to 28 advanced glaucoma patients who had significantly greater in patients treated with adjunctive uncontrolled IOP after at least 2 weeks of beta-blocker brimonidine (4.4 mmHg) than in patients treated with therapy. The washout period between treatment adjunctive dorzolamide (3.3 mmHg, p < 0.05). In this periods was 1 month. IOP was measured at 2, 4, 6, and study, brimonidine provided an additional 15% IOP 8 h after the administration of adjunctive medication. reduction in a higher percentage of patients than did Each of the study medications reduced IOP significantly dorzolamide, and a greater mean IOP reduction from from baseline at every timepoint. At two of the four baseline at peak effect when used as adjunctive therapy timepoints (4 and 8 h after dosing), the mean IOP for 1 month with a beta-blocker. At Month 3, there reduction was significantly larger with brimonidine was no significant difference in mean IOP between (5.6–7.0 mmHg) than with dorzolamide (3.5– patients treated with adjunctive brimon­idine and 4.1 mmHg, p = 0.04). At the other two timepoints, the patients treated with adjunctive dorzolamide. Although mean IOP reduction was comparable between drugs the number of patients who dropped out of the study (3.0–4.0 mmHg with dorzolamide and 2.9–4.4 mmHg between Month 1 and Month 3 was not reported, with brimonidine, stated non-significant). This study the crossover study design and the discontinua­tion was limited because it was a single drop study and of patients from treatment at Month 1 because of an the run-in on timolol therapy may not have been long inadequate IOP-lowering response may account for enough for timolol to achieve maximal effects. The the lack of difference between treatments in mean IOP results show that both brimonidine and dorzolamide reduction from baseline to Month 3.

2976 Efficacy and safety of brimonidine compared with dorzolamide © 2007 LIBRAPHARM LTD – Curr Med Res Opin 2007; 23(12) A prospective, investigator-masked, randomized, but brimonidine provides greater IOP-lowering parallel-group, 3-month trial compared brimonidine efficacy. Furthermore, patients are more likely to BID (n = 54) with dorzolamide TID (n = 52) as achieve a clinically relevant additional IOP reduction adjunctive therapy with beta-blockers in patients with brimonidine adjunctive treatment. with glaucoma or OHT who had IOP uncontrolled on Hommer et al.31 reported a prospective, double- beta-blocker therapy30. IOP was measured at 8 a.m. masked, randomized, parallel-group comparison of (trough effect, just prior to study drug instillation) brimonidine (n = 48), dorzolamide (n = 48), and and 10 a.m. (peak effect) at baseline, Month 1, and unoprostone (n = 50) each given as adjunctive therapy Month 3 in this industry-sponsored study. Patients BID for 12 weeks to glaucoma and OHT patients who who failed to achieve at least a 15% reduction from had uncontrolled IOP after a 2-week run-in on timolol. beta-blocker-treated baseline IOP at 10 a.m., Month The main outcome measure was the change from timolol- 1 or who failed to tolerate treatment were switched treated baseline IOP measured over 8 h at Week 12. No to the other treatment arm. The efficacy results in the significant differences in the mean diurnal IOP reduction trial favored brimonidine over dorzolamide. Baseline from baseline were found between unoprostone and mean IOP was comparable between treatment brimonidine ( p = 0.154) or between unoprostone and groups (21.6 mmHg for brimonidine and 20.9 mmHg dorzolamide ( p = 0.101). Statistical comparisons were not for dorzolamide, p = 0.284), but at Month 1, the made between brimonidine and dorzolamide treatment mean IOP reduction from beta-blocker-treated groups directly. The mean diurnal IOP reduction at baseline was significantly larger in the brimonidine Week 12 was 2.7 mmHg (12.3%) in the unoprostone group than in the dorzolamide group at peak effect group, 2.8 mmHg (12.5%) in the brimonidine group, (6.0 mmHg vs. 4.1 mmHg, p = 0.007). The mean and 3.1 mmHg (14.4%) in the dorzolamide group. The IOP reduction from baseline at trough effect was overall incidence of treatment-related adverse events was 2.9 mmHg with brimonidine versus 1.9 mmHg with 23% in the brimonidine group compared with 29% in the dorzolamide ( p = 0.120). More patients achieved dorzolamide group and 22% in the unoprostone group. the target 15% additional IOP reduction at 10 a.m. The most common adverse event was burning/stinging, Month 1 with brimonidine adjunctive therapy than which was reported by 14.6% of patients receiving with dorzolamide adjunctive therapy (86% vs. 62%, dorzolamide, versus 4.2% of brimonidine patients p = 0.005). However, at Month 3 in this study, and 4.0% of unoprostone patients. The study results significantly more brimonidine patients (78%) suggest similar IOP-lowering efficacy and tolerability of achieved the target IOP reduction at 10 a.m. than brimonidine and dorzolamide as adjunctive therapy with did dorzolamide patients (44%, p = 0.007). Even timolol. These results should be interpreted with caution, after patients who had inadequate IOP lowering at however, because baseline IOP was not reported, and it is Month 1 had been switched to the other treatment unclear whether baseline diurnal IOP was similar among arm, brimonidine continued to provide a larger mean the treatment groups. A further limitation of the study is IOP reduction compared with dorzolamide at peak that the 2-week washout of previous medications and 2- effect (6.4 mmHg vs. 4.1 mmHg, p = 0.059). After week run-in on timolol before baseline IOP measurements 3 months, trough IOP reductions were comparable may have been inadequate in duration. between the treatment groups, with brimonidine A randomized, double-masked, 1-year clinical providing a mean reduction of 2.82 mmHg, and compar­ison of brimonidine BID (n = 90), dorzolamide dorzolamide a mean of 2.40 mmHg ( p = 0.54). Of BID (n = 91), and latanoprost QD (n = 91) added to five unsuccessful patients on brimonidine who were pre-existing therapy was performed in Indian patients crossed over to dorzolamide and returned for follow- with primary open-angle glaucoma and uncontrolled up 1 month later, none achieved the target 15% IOP IOP32. Baseline IOP was 22.8 mmHg for brimonidine reduction with dorzolamide therapy. In contrast, patients, 22.7 mmHg for dorzolamide patients, and of 13 unsuccessful patients on dorzolamide who 23.2 mmHg for latanoprost patients ( p = 0.31). The were switched to brimonidine, six (46%) achieved authors reported that IOP lowering from baseline at the target 15% IOP reduction on brimonidine. Few Year 1 was significantly greater in patients treated with adverse events were reported in either treatment brimonidine than in those treated with dorzolamide group. Five patients discontinued each therapy (9.2% (mean IOP reduction of 30.8% vs. 27.3%, p = 0.018), of brimonidine patients and 9.8% of dorzolamide based on a model that adjusted for pretreatment IOP, patients) and were crossed over to the other study fundus changes, visual field changes, laser treatment, arm or exited early from the study because of and surgery. By comparison, latanoprost QD provided adverse events. The results of this trial suggest that an adjusted mean IOP reduction of 30.6% ( p = 0.76 brimonidine and dorzolamide are both well tolerated vs. brimonidine and p = 0.002 vs. dorzolamide). Data when used as adjunctive therapy with a beta-blocker, were not available for the five or six patients in each

© 2007 LIBRAPHARM LTD – Curr Med Res Opin 2007; 23(12) Efficacy and safety of brimonidine compared with dorzolamide Katz et al. 2977 group who discontinued from the study prior to Year ( p ≤ 0.001). This study was limited because patients 1, but none of these patients exited the study early were excluded if they discontinued therapy before the because of poor IOP control. The overall incidence end of the year because of lack of efficacy or adverse of side effects was similar between the brimonidine events. Also, no information was provided on baseline (36.6%) and dorzolamide (24.1%) treatment groups characteristics of the treatment groups other than IOP ( p = 0.067); the most common side effects were ocular (such as demographics, diagnosis, or treatment history), stinging and burning in the brimonidine group (11.9%) and treatment was not assigned randomly, so it is and bitter taste in the dorzolamide group (9.4%). This likely that patient selection bias might have influenced study was limited because the pre-existing therapy the comparative efficacy of the medications that was was not required to be a beta-blocker, or indeed, to observed. Nonetheless, the results of the study suggest be limited to medical therapy. Although most patients that brimonidine, dorzolamide, and beta-blockers may in each group were treated with a beta-blocker, all effectively reduce IOP when used as adjunctive some were treated with pilocarpine or dipivefrine therapy with latanoprost. alone or in multiple-drug therapy, and it is possible Konstas and associates33 recently reported a prospect­ that some patients had received only laser or surgical ive, double-masked, randomized, crossover comparison therapy when they were randomized to brimonidine, of brimonidine–Purite 0.15% and dorzolamide as dorzolamide, or latanoprost treatment. This limitation adjunctive therapy in 33 glaucoma patients who had in the study design makes it difficult to draw strong uncontrolled IOP after at least a 3-week run-in on conclusions, but the results are supportive of other latanoprost monotherapy. Each study drug was given studies that suggest better adjunctive IOP lowering twice daily as adjunctive therapy with latanoprost for with brimonidine compared with dorzolamide. 6 weeks, with a 6-week washout between treatment periods. The primary outcome measure was circadian

Adjunctive therapy with latanoprost IOP, measured at seven timepoints over 24 h after 6 weeks of adjunctive therapy. Of the 33 enrolled Only two reports of studies comparing brimonidine and patients, one discontinued early because of an allergic dorzolamide as adjunctive therapy with medications reaction while on dorzolamide, and one was not included other than beta-blockers were identified, and both dealt in the analysis because of protocol violations. Of the 31 with the use of these drugs as adjunctive therapy with patients who had data available, one (3.2%) had the the prostaglandin prodrug latanoprost33,47. Latanoprost, same circadian IOP (average of all seven measurements) available since 1996, reduces IOP more effectively on both drugs, 19 (61.3%) had lower circadian IOP with than timolol when used as monotherapy48 and in 2002 brimonidine–Purite, and 11 (35.5%) had lower circadian received FDA approval for first-line use in glaucoma IOP with dorzolamide. There were no statistically and OHT. Other once-daily prostaglandin analogues significant differences in mean IOP reduction from (bimatoprost and travoprost) are as efficacious or more baseline between brimonidine–Purite and dorzolamide efficacious than latanoprost49–51 and bimatoprost received at any individual timepoint or in the circadian curve a first line indication in 2006 when long-term safety ( p ≥ 0.05). The mean circadian IOP was 16.9 mmHg data became available. The once-daily prostaglandin with brimonidine–Purite and 16.8 mmHg with analogues lower IOP by improving aqueous outflow: dorzolamide. At the 8 a.m. timepoint when IOP reached latanoprost and travoprost reduce IOP by increasing its highest levels, mean IOP was 18.4 mmHg with uveoscleral outflow52,53 and bimatoprost has been brimonidine–Purite and 18.9 mmHg with dorzolamide. demonstrated to reduce IOP by increasing trabecular The results of this industry-sponsored study suggest that meshwork as well as uveoscleral outflow54,55. brimonidine–Purite is at least as effective as dorzolamide O’Conner and associates47 reported a retrospective in providing 24-h IOP control when used as adjunctive study of brimonidine, dorzolamide, and beta-blockers therapy with latanoprost. The only significant difference used as adjunctive therapy with latanoprost in 73 eyes between treatments in the incidence of adverse events of 73 glaucoma patients with IOP uncontrolled on was a statistically higher incidence of bitter taste with latanoprost alone. This chart review included patients dorzolamide treatment (24% vs. 0% with brimonidine, who were treated for 1 year with no change in medical p = 0.01). regimen or surgical intervention within that period. The average IOP reductions reported from latanoprost- treated baseline after 1 year of adjunctive treatment Fixed combinations with were 3.9 mmHg with dorzolamide BID or TID (n = 25), timolol 2.0 mmHg with brimonidine (n = 25), and 2.5 mmHg with beta-blockers (n = 23). Each of these mean IOP A fixed combination of dorzolamide 2.0%/timolol reductions was significantly different from baseline 0.5% (Cosopt, Merck & Co, Inc.; Whitehouse Station,

2978 Efficacy and safety of brimonidine compared with dorzolamide © 2007 LIBRAPHARM LTD – Curr Med Res Opin 2007; 23(12) NJ, USA) has been available since the late 1990s for for this industry-sponsored study. Baseline mean IOP reducing IOP in patients who do not respond adequately on timolol was similar between the treatment groups to beta-blockers alone. In clinical studies, twice-daily (24.44 mmHg for fixed combination dorzolamide/ fixed-combination dorzolamide/timolol has been timolol vs. 24.29 mmHg, p = 0.659). Adjusted more effective than monotherapy with its component mean IOP reductions took treatment group, study medications timolol BID or dorzolamide TID56,57. The site, and baseline IOP into account using analysis of fixed combination is less effective by approximately covariance models. In the modified intent-to-treat 1 mmHg than concomitant dorzolamide TID and patient population, the adjusted mean IOP reduction timolol BID overall (confidence level > 0.96)45,58, but over follow-up ranged from 3.7 to 5.5 mmHg with it is equivalent in efficacy to concomitant dorzolamide brimonidine plus timolol and 3.1 to 5.0 mmHg with and timolol when each medication is dosed twice dorzolamide/timolol, but none of the between-group daily43. differences were statistically significant ( p ≥ 0.062). In some countries, a fixed combination of In the per-protocol patient population, the primary brimonidine 0.2%/timolol 0.5% (Combigan, Allergan efficacy endpoint (mean IOP reduction from baseline Inc; Irvine CA, USA) is also available. In a controlled at 11 a.m. at Month 3) was statistically significant in 3-month clinical study in patients with glaucoma or favor of concomitant brimonidine and timolol therapy OHT, the fixed combination of brimonidine/timolol (an adjusted mean IOP reduction of 5.77 mmHg BID (n = 385) reduced IOP significantly more than did with brimonidine and timolol vs. 4.87 mmHg with either timolol BID (n = 392, p ≤ 0.026) or brimonidine dorzolamide/timolol, p = 0.046). The overall incidence TID (n = 382, p < 0.001) alone59. These findings of treatment-related adverse events was 64% for were verified in a 12-month trial60 in which mean fixed combination dorzolamide/timolol and 60% for IOP reductions were greater with fixed brimonidine/ concomitant brimonidine plus timolol (stated non- timolol than timolol 0.5% BID alone at all measured significant). Ocular burning, ocular stinging, and taste timepoints ( p ≤ 0.002), and greater than brimonidine perversion occurred at significantly different rates 0.2% TID alone at all but one measured timepoint between treatment groups; each of these adverse ( p < 0.001). In another randomized controlled trial events was more common in the dorzolamide/timolol in 371 glaucoma and OHT patients with inadequate group: ocular burning was reported by 41% of dorzol­ IOP control after at least 3 weeks run-in on any amide/timolol patients versus 20% of brimonidine plus monotherapy, the fixed combination of brimonidine/­ timolol patients ( p < 0.001), stinging was reported by timolol BID was as effective as concomitant therapy 22% in the dorzolamide/timolol group and 12% on with timolol BID and brimonidine BID in reducing brimonidine plus timolol ( p = 0.024), taste perversion IOP61. Differences between the fixed combina­tion and was noted by 26% of dorzolamide/timolol patients concomitant therapy were ≤ 0.35 mmHg for mean and by 10% of patients using brimonidine plus timolol IOP and ≤ 0.30 mmHg for mean change from baseline ( p < 0.001). Five percent of patients in each group IOP at all timepoints over the 12-month study, and discontinued from the study because of adverse events. none of the differences were statistically significant The results of this study suggest that concomitant ( p ≥ 0.274). treatment with brimonidine and timolol is associated with less stinging, burning, and taste perversion than the Brimonidine plus timolol versus dorzolamide/timolol fixed combination over 6 months dorzolamide/timolol fixed combination and may provide better efficacy at peak effect. A prospective, investigator-masked, randomized, Two studies that compared the fixed combination of parallel-group, industry-sponsored 3-month dorzolamide/timolol with brimonidine plus timolol comparison trial of concomitant brimonidine BID concomitant therapy were found38,62. Following similar and timolol BID (n = 250) versus fixed-combination designs, these studies showed that the two treatments dorzolamide/timolol BID (n = 242) was performed in have comparable tolerability and efficacy. glaucoma and OHT patients with IOP uncontrolled Sall and associates reported a prospective, after a 3-week run-in on timolol38. IOP was measured investigator-masked, randomized, parallel-group at 8:30 a.m. (trough) and 10:30 a.m. (peak) at 6-month compar­ison study of concomitant brimonidine baseline, Month 1, and Month 3. Patient convenience 0.2% BID and timolol 0.5% BID (n = 149) versus and satisfaction were also evaluated at Month 1 and fixed-combination dorzolamide 2%/timolol 0.5% BID Month 3 using a survey. Baseline mean IOP on timolol (n = 144) in glaucoma and OHT patients with IOP was 24.1 mmHg for both treatment groups ( p-value uncontrolled after a 3-week run-in on timolol62. IOP not given). The primary efficacy outcome measure was measured at 9 a.m. (trough, just before dosing) (mean IOP reduction from baseline at 10:30 a.m. and 11 a.m. (peak) at baseline and Months 1, 3, and 6 at Month 3) was statistically significant in favor of

© 2007 LIBRAPHARM LTD – Curr Med Res Opin 2007; 23(12) Efficacy and safety of brimonidine compared with dorzolamide Katz et al. 2979 concomitant brimonidine and timolol therapy (mean instillation (30%) than fixed combination brimonidine/ IOP reduction of 5.3 mmHg with brimonidine and timolol (3.3%; p = 0.027). Both fixed combinations timolol vs. 4.3 mmHg with dorzolamide/timolol, effectively reduce IOP, but brimonidine/timolol may p < 0.001). The mean IOP reduction at 8:30 a.m. be more comfortable to use. at the Month 3 visit was similar between treatment groups (3.5 mmHg with brimonidine and timolol vs. 3.3 mmHg with dorzolamide/timolol). There were Discussion no significant differences between treatment groups in the overall incidence of treatment-related adverse Comparison studies of brimonidine and dorzolamide events (21% with brimonidine and timolol vs. 28% cover a range of treatment combinations, durations of with dorzol­amide/timolol, stated non-significant) therapy, and measurement timepoints. Many are too or in discontinua­tions because of adverse events not small for statistical power. On the whole, however, the necessarily related to treatment (7% with brimonidine studies show that when used either as monotherapy or and timolol vs. 5% with dorzolamide/timolol). Burning as adjunctive therapy, brimonidine tends to reduce IOP was reported by 14% of the dorzolamide/timolol group more than dorzolamide at peak effect, and brimonidine versus 2.4% of the brimonidine plus timolol group, and dorzolamide show similar IOP-lowering efficacy stinging occurred at a rate of 4.9% for dorzolamide/ at trough effect. The overall incidence of adverse timolol versus 1.6% for brimonidine plus timolol, events was similar between drugs; however, burning, and taste distortion occurred in 4.5% of dorzolamide/ stinging and bitter taste were often more common timolol patients versus 0% of those on brimonidine plus with dorzolamide than with brimonidine in the timolol, but none of these means were significantly studies reviewed here. There was no difference in the different. There were no significant differences between incidence of treatment-related ocular allergy between treatment groups in patient-reported convenience or brimonidine and dorzolamide, even in the longer-term satisfaction with treatment after either 1 or 3 months (6-month) study62. ( p ≥ 0.056). The results of this study suggest that both Efficacy findings are consistent with a meta- treatments are well tolerated, and that concomitant analysis of these drugs when used as monotherapy20. therapy with brimonidine and timolol provides better The meta-analysis included data from randomized efficacy at peak effect and similar efficacy at trough controlled trials published through December 2003. effect compared with fixed-combination dorzolamide/ The average percentage reduction of IOP from baseline timolol therapy. after 1 month of treatment was 25% (95% confidence interval (CI): 28–22%) for brimonidine 0.2% and 22% Brimonidine/timolol fixed combination (95%CI: 24–20%) for dorzolamide 2% at peak effect versus dorzolamide/timolol fixed (2 h after morning dosing) and 18% (95%CI: 21–14%) combination for brimonidine and 17% (95%CI: 19–15%) for dorzolamide at morning trough (just prior to dosing). One study that compared fixed combination dorzol­ The reason for the greater IOP reduction with brimon­ amide/timolol with fixed combination brimonidine/­ idine at peak effect might involve the physiological timolol was identified63. In this prospective, multicenter, mechanism of the actions of the drugs. Dorzolamide masked-observer, crossover comparison, 30 primary reduces IOP by inhibiting aqueous production64; there open-angle glaucoma or OHT patients were washed are no reports in the literature that it affects outflow65. out from their previous medication for 4 weeks. On the other hand, brimonidine reduces IOP by a They were next randomized to begin the first 4-week dual mechanism involving both inhibition of aqueous treatment period on either fixed combination brimon­ production (the predominant effect with short-term idine/timolol BID or fixed combination dorzol­amide/ treatment) and stimulation of aqueous outflow through timolol BID. After a second 4-week wash-out period, the uveoscleral pathway (the predominant effect with they were switched to the second medication for a chronic treatment)8,66. The ability of brimonidine to final 4-week period. Baseline mean diurnal IOP was increase aqueous outflow might confer better additivity 22.9 mmHg, and both fixed combinations significantly with aqueous suppressants such as beta-blockers. reduced IOP relative to baseline ( p < 0.00001). Both Data directly comparing the effects of brimonidine the mean diurnal IOP ( p = 0.510) and mean diurnal and dorzolamide on aqueous dynamics are limited. reduction from baseline ( p = 0.430) were comparable In a randomized, double-masked, placebo-controlled for the fixed combinations. The incidence of reported study in 20 normal subjects dosed BID with each ocular adverse events was the same for each drug drug, aqueous flow was measured after three doses of ( p = 0.359), but fixed combination dorzolamide/ drug1. The study was limited because brimonidine was timolol was associ­ated with more ocular stinging upon compared to placebo in the fellow eye, and dorzolamide

2980 Efficacy and safety of brimonidine compared with dorzolamide © 2007 LIBRAPHARM LTD – Curr Med Res Opin 2007; 23(12) was compared to prior placebo treatment of the same likely go undetected. Additional studies are needed eye while the fellow eye was treated with brimonidine to determine the relative efficacy of brimonidine and and dorzolamide, making a contralateral eye effect dorzolamide as adjunctive therapy with prostaglandin possible. The results of the study, nonetheless, showed analogues. a trend for greater reduction of aqueous flow with Fixed-combination therapy offers several potential brimonidine (28.2%) compared with placebo than advantages over concomitant therapy with two drugs70. with dorzolamide (19.3%; p < 0.09). The fixed-combination regimen is more convenient, Larger IOP variation, as well as higher IOP, and this simpler regimen might enhance compliance. is associ­ated with increased risk of glaucoma Use of fixed combinations might also be associated progression67,68. None of the comparison studies with de­creased corneal exposure to preservatives discussed in this review evaluated IOP variation or and decreased costs. Studies have demonstrated the ability of dorzolamide and brimonidine to provide that concomitant treatment with brimonidine and stable IOP over time or protect against glaucomatous timolol lowers IOP significantly more than fixed progression. However, in a study in which glaucoma combination dorzol­amide/timolol at peak effect patients on monotherapy were given a water drinking and is as well tolerated as the dorzolamide/timolol test, patients treated with brimonidine BID showed a combination over 6 months of treatment38,62. A recent significant elevation in IOP over baseline ( p ≤ 0.05) study showed that the fixed combinations are at least for only 45 min after drinking 1 L of water, and their equally effective63, and overall findings reviewed IOP levels peaked at 20% over the baseline value. here suggest that replacement of the dorzolamide/ In contrast, patients treated with dorzolamide TID timolol combination with the brimon­idine/timolol showed a significant elevation in IOP ( p ≤ 0.05) combination may provide better efficacy. Over for at least 105 min after drinking the water, and longer periods of use, allergic blepharocon­junctivitis their IOPs peaked at 29% over the baseline value65. associated with chronic brimonidine treatment may Although the study was limited in that patients were become an additional concern71,72. Interestingly, the not randomized to treatment, the results suggest that combination of brimonidine and timolol is associated brimonidine may be more effective than dorzolamide with lower incidence of allergy than brimonidine in stabilizing IOP in particular stress conditions, and alone60,73. Long-term direct comparison studies of the authors suggested that the effect of brimonidine dorzolamide/timolol and brimonidine/timolol will on aqueous outflow explains its ability to stabilize IOP be needed to determine the relative efficacy and better than aqueous inhibitors such as dorzolamide65. tolerability of these fixed combinations for chronic Because the once-daily prostaglandin analogues and treatment. non-selective beta-blockers reduce IOP more effectively as primary agents, dorzolamide and brimonidine are not usually used as first-line therapy. However, many Conclusions patients receive adjunctive therapy with these drugs, and alpha agonists and carbonic anhydrase inhibitors Brimonidine and dorzolamide are both good choices for may be preferred second-line therapy23. It is important second-line therapy in glaucoma. With studies showing to choose an effective medication when adding to comparable or greater efficacy in reducing IOP, and ongoing therapy, because if IOP is not low enough on a less incidence of discomfort, brimonidine may prove to 2-drug regimen, the long-term success rates associated be a more effective choice for many patients. with the addition of a third or fourth medication are not high69. Almost all comparative studies of brimonidine and dorzolamide in adjunctive therapy have added Acknowledgments them to a beta-blocker. The results have generally shown better peak IOP lowering with brimonidine and Declaration of interest: Financial support for the similar IOP lowering with the drugs at trough, even development of this manuscript was provided by when brimonidine was dosed BID and dorzolamide Allergan, Inc (Irvine, CA). The views expressed are was dosed TID. Only one randomized controlled trial33 those of the authors, and the manuscript was neither evaluated brimonidine and dorzolamide as adjunctive reviewed nor approved by Allergan, Inc. LJK is on therapy with a prostaglandin analogue (latanoprost). Speakers Bureaus for Allergan, Alcon, Merck, Pfizer In that study, no significant differences were found and Ista and has received research support from between the drugs33. However, the study was small, Allergan, Alcon, Merck and Pfizer. STS is a consultant with sample sizes chosen to give a power of 80% to for Allergan, Inc., is on the Speakers Bureau for Merck, detect a 1.5 mmHg difference between treatment and has received research support from Alcon and groups, and differences on the order of 1 mmHg would Merck. ERC is on Speakers Bureaus for Allergan,

© 2007 LIBRAPHARM LTD – Curr Med Res Opin 2007; 23(12) Efficacy and safety of brimonidine compared with dorzolamide Katz et al. 2981 Alcon, and Merck. The authors thank Kate Ivins, PhD, 22. Simmons ST, Earl ML. Three-month comparison of brimonidine and latanoprost as adjunctive therapy in glaucoma and ocular Aron Ross, PhD, and Elizabeth Davis, PhD, for writing hypertension patients uncontrolled on beta-blockers: tolerance and editorial support, and Remy Kachadourian, PhD and peak intraocular pressure lowering. Ophthalmology for translation services. 2002;109:307-14 23. Lee DA, Higginbotham EJ. Glaucoma and its treatment: a review. Am J Health-Syst Pharm 2005;62:691-9 24. Stewart WC, Sharpe ED, Harbin Jr TS, et al. Brimonidine 0.2% References versus dorzolamide 2% each given three times daily to reduce intraocular pressure. Am J Ophthalmol 2000;129:723-7 1. Tsukamoto H, Larsson LI. Aqueous humor flow in normal 25. Whitson JT, Henry C, Hughes B, et al. Comparison of the human eyes treated with brimonidine and dorzolamide, alone safety and efficacy of dorzolamide 2% and brimonidine 0.2% and in combination. Arch Ophthalmol 2004;122:190-3 in patients with glaucoma or ocular hypertension. J Glaucoma 2. Wang RF, Serle JB, Podos SM, Sugrue MF. MK-507 (L-671,152), 2004;13:168-73 a topically active carbonic anhydrase inhibitor, reduces 26. Sharpe ED, Day DG, Beischel CJ, et al. Brimonidine purite aqueous humor production in monkeys. Arch Ophthalmol 0.15% versus dorzolamide 2% each given twice daily to reduce 1991;109:1297-9 intraocular pressure in subjects with open angle glaucoma or 3. Trusopt [package insert]. Whitehouse Station (NJ): Merck & ocular hypertension. Br J Ophthalmol 2004;88:953-6 Co, Inc; 1998 27. Quaranta L, Gandolfo F, Turano R, et al. Effects of topical 4. Ott EZ, Mills MD, Arango S, et al. A randomized trial assessing hypotensive drugs on circadian IOP, blood pressure, and dorzolamide in patients with glaucoma who are younger than calculated diastolic ocular perfusion pressure in patients with 6 years. Arch Ophthalmol 2005;123:1177-86 glaucoma. Invest Ophthalmol Vis Sci 2006;47:2917-23 5. Portellos M, Buckley EG, Freedman SF. Topical versus oral 28. Hegde V, Robinson R, Dean F, et al. Drug-induced ectropion: carbonic anhydrase inhibitor therapy for pediatric glaucoma. what is best practice? Ophthalmology 2007;114:362-6 J AAPOS 1998;2:43-7 29. Carrasco Font C, Arias Puente A, Garcia Saenz MC, et 6. Heijl A, Strahlman E, Sverrisson T, et al. A comparison of al. Efficiency of brimonidine 0.2% and dorzolamide 2% as dorzolamide and timolol in patients with pseudoexfoliation adjunctive therapy to beta-blockers. Arch Soc Esp Oftalmol and glaucoma or ocular hypertension. Ophthalmology 2004;79:163-8 1997;104:137-42 30. Simmons ST. Efficacy of brimonidine 0.2% and dorzolamide 7. Strahlman E, Tipping R Vogel R; International Dorzolamide 2% as adjunctive therapy to beta-blockers in adult patients with Study Group. A double-masked, randomized 1-year study glaucoma or ocular hypertension. Clin Ther 2001;23:604-19 comparing dorzolamide (Trusopt), timolol, and betaxolol. Arch 31. Hommer A, Kapik B, Shams N. Unoprostone as adjunctive Ophthalmol 1995;113:1009-16 therapy to timolol: a double masked randomised study 8. Toris CB, Camras CB Yablonski ME. Acute versus chronic versus brimonidine and dorzolamide. Br J Ophthalmol effects of brimonidine on aqueous humor dynamics in ocular 2003;87:592-8 hypertensive patients. Am J Ophthalmol 1999;128:8-14 32. Sodhi PK, Pandey RM, Ratan SK. Efficacy and safety of 9. Schuman JS. Clinical experience with brimonidine 0.2% and brimonidine, dorzolamide and latanoprost as adjunctive therapy timolol 0.5% in glaucoma and ocular hypertension. Surv in primary open angle glaucoma. Int J Clin Pract 2003;57: Ophthalmol 1996;41(Suppl):S27-S37 875-8 10. LeBlanc RP; Brimonidine Study Group 2. Twelve-month results 33. Konstas AG, Karabatsas CH, Lallos N, et al. 24-hour intraocular of an ongoing randomized trial comparing brimonidine tartrate pressures with brimonidine purite versus dorzolamide added 0.2% and timolol 0.5% given twice daily in patients with glaucoma to latanoprost in primary open-angle glaucoma subjects. or ocular hypertension. Ophthalmology 1998;105:1960-7 Ophthalmology 2005;112:603-8 11. Katz LJ; Brimonidine Study Group. Brimonidine tartrate 34. Dailey RA, Brubaker RF, Bourne WM. The effects of timolol 0.2% twice daily vs timolol 0.5% twice daily: 1-year results in maleate and acetazolamide on the rate of aqueous formation in glaucoma patients. Am J Ophthalmol 1999;127:20-6 normal human subjects. Am J Ophthalmol 1982;93:232-7 12. Bowman RJC, Cope J, Nischal KK. Ocular and systemic side 35. Larsson LI. Aqueous humor flow in normal human eyes treated effects of brimonidine 0.2% eye drops (Alphagan) in children. with brimonidine and timolol, alone and in combination. Arch Eye 2004;18:24-6 Ophthalmol 2001;119:492-5 13. Enyedi LB, Freedman SF. Safety and efficacy of brimonidine in children with glaucoma. J AAPOS 2001;5:281-4 36. Toris CB, Zhan GL, Yablonski ME, et al. Effects on aqueous flow 14. Alphagan [package insert]. Irvine (CA):Allergan, Inc.; 2001 of dorzolamide combined with either timolol or acetazolamide. 15. Katz LJ. Twelve-month evaluation of brimonidine–purite versus J Glaucoma 2004;13:210-5 brimonidine in patients with glaucoma or ocular hypertension. 37. Lee DA, Gornbein JA. Effectiveness and safety of brimonidine J Glaucoma 2002;11:119-26 as adjunctive therapy for patients with elevated intraocular 16. Dong JQ, Babusis DM, Welty DF, et al. Effects of the preservative pressure in a large, open-label community trial. J Glaucoma purite on the bioavailability of brimonidine in the aqueous humor 2001;10:220-6 of rabbits. J Ocul Pharmacol Ther 2004;20:285-92 38. Solish AM, DeLucca PT, Cassel DA, et al. Dorzolamide/ 17. Noecker R. Effects of common ophthalmic preservatives on timolol fixed combination versus concomitant administration ocular health. Adv Ther 2001;18:205-15 of brimonidine and timolol in patients with elevated intraocular 18. Noecker RJ, Herrygers LA, Anwaruddin R. Corneal and pressure: a 3-month comparison of efficacy, tolerability, and conjunctival changes caused by commonly used glaucoma patient-reported measures. J Glaucoma 2004;13:149-57 medications. Cornea 2004;23:490-6 39. Adamsons I, Clineschmidt C, Polis A, et al.; Additivity Study 19. Camras CB, Sheu W-P. Latanoprost or brimonidine as treatment Group. The efficacy and safety of dorzolamide as adjunctive for elevated intraocular pressure: multicenter trial in the United therapy to timolol maleate gellan solution in patients with States. J Glaucoma 2005:14:161-7 elevated intraocular pressure. J Glaucoma 1998;7:253-60 20. van der Valk R, Webers CA, Schouten JS, et al. Intraocular 40. Hartenbaum D, Maloney S, Vaccarelli L, et al. Comparison of pressure-lowering effects of all commonly used glaucoma drugs: dorzolamide and pilocarpine as adjunctive therapy in patients a meta-analysis of randomized clinical trials. Ophthalmology with open-angle glaucoma and ocular hypertension. Clin Ther 2005;112:1177-85 1999;21:1533-8 21. Stewart WC, Sharpe ED, Day DG, et al. Comparison of 41. Petounis A, Mylopoulos N, Kandarakis A, et al. Comparison of the efficacy and safety of latanoprost 0.005% compared to the additive intraocular pressure-lowering effect of latanoprost brimonidine 0.2% or dorzolamide 2% when added to a topical and dorzolamide when added to timolol in patients with beta-adrenergic blocker in patients with primary open-angle open-angle glaucoma or ocular hypertension: a randomized, glaucoma or ocular hypertension. J Ocul Pharmacol Ther open-label, multicenter study in Greece. J Glaucoma 2001;10: 2000;16:251-9 316-24

2982 Efficacy and safety of brimonidine compared with dorzolamide © 2007 LIBRAPHARM LTD – Curr Med Res Opin 2007; 23(12) 42. Garcia-Sanchez J; Spanish Latanoprost Study Group. Efficacy patients inadequately controlled with timolol alone comparing and side effects of latanoprost monotherapy compared to the dorzolamide–timolol combination to monotherapy with adding dorzolamide to timolol in patients with glaucoma and timolol or dorzolamide. Ophthalmology 1998;105:1952-9 ocular hypertension – a three-month randomised study. Eur J 58. Cosopt [package insert]. Whitehouse Station (NJ): Merck & Ophthalmol 2000;10:198-204 Co, Inc.; 2006 43. Hutzelmann J, Owens S, Shedden A, et al.; International 59. Craven ER, Walters TR, Williams R, et al. Brimonidine and Clinical Equivalence Study Group. Comparison of the safety timolol fixed-combination therapy versus monotherapy: a and efficacy of the fixed combination of dorzolamide/timolol 3-month randomized trial in patients with glaucoma or ocular and the concomitant administration of dorzolamide and hypertension. J Ocul Pharmacol Ther 2005;21:337-48 timolol: a clinical equivalence study. Br J Ophthalmol 1998;82: 60. Sherwood MB, Craven ER, Chou C, et al. Twice-daily 0.2% 1249-53 brimonidine-0.5% timolol fixed-combination therapy vs 44. Emmerich KH. Comparison of latanoprost monotherapy to monotherapy with timolol or brimonidine in patients with dorzolamide combined with timolol in patients with glaucoma glaucoma or ocular hypertension: a 12-month randomized trial. and ocular hypertension: a 3-month randomised study. Graefes Arch Ophthalmol 2006;124:1230-8 Arch Clin Exp Ophthalmol 2000;238:19-23 61. Goñi FJ; Brimonidine/Timolol Fixed Combination Study 45. Strohmaier K, Snyder E, DuBiner H, et al.; Dorzolamide-Timolol Group. 12-week study comparing the fixed combination of Study Group. The efficacy and safety of the dorzolamide– brimonidine and timolol with concomitant use of the individual timolol combination versus the concomitant administration of components in patients with glaucoma and ocular hypertension. its components. Ophthalmology 1998;105:1936-44 Eur J Ophthalmol 2005;15:581-90 46. Centofanti M, Manni G, Gregori D, et al. Comparative 62. Sall KN, Greff LJ, Johnson-Pratt LR, et al. Dorzolamide/timolol acute effects of brimonidine 0.2% versus dorzolamide 2% combination versus concomitant administration of brimonidine combined with beta-blockers in glaucoma. Graefes Arch Clin and timolol: six-month comparison of efficacy and tolerability. Exp Ophthalmol 2000;238:302-5 Ophthalmology 2003;110:615-24 47. O’Connor DJ, Martone JF, Mead A. Additive intraocular 63. Arcieri ES, Arcieri RS, Pereira AC, et al. Comparing the fixed pressure lowering effect of various medications with latanoprost. combination brimonidine-timolol versus fixed combination Am J Ophthalmol 2002;133:836-7 dorzolamide-timolol in patients with elevated intraocular 48. Hedman K, Alm A. A pooled-data analysis of three randomized, pressure. Curr Med Res Opin 2007:23:683-9 double-masked, six-month clinical studies comparing the 64. Wayman L, Larsson LI, Maus T, et al. Comparison of intraocular pressure reducing effect of latanoprost and timolol. dorzolamide and timolol as suppressors of aqueous humor flow Eur J Ophthalmol 2000;10:95-104 in humans. Arch Ophthalmol 1997;115:1368-71 49. Netland PA, Landry T, Sullivan EK, et al. Travoprost 65. Vetrugno M, Sisto D, Trabucco T, et al. Water-drinking test compared with latanoprost and timolol in patients with open- in patients with primary open-angle glaucoma while treated angle glaucoma or ocular hypertension. Am J Ophthalmol with different topical medications. J Ocul Pharmacol Ther 2001;132:472-84 2005;21:250-7 50. Parrish R, Palmberg P, Sheu W-P, et al. A comparison of 66. Toris CB, Gleason ML, Camras CB, et al. Effects of brimonidine latanoprost, bimatoprost, and travoprost in patients with on aqueous humor dynamics in human eyes. Arch Ophthalmol elevated intraocular pressure: a 12-week, randomized, masked- 1995;113:1514-7 evaluator, multicenter study. Am J Ophthalmol 2003;135: 67. Asrani S, Zeimer R, Wilensky J, et al. Large diurnal 688-703 fluctuations in intraocular pressure are an independent 51. Simmons ST, Dirks MS, Noecker RJ. Bimatoprost versus risk factor in patients with glaucoma. J Glaucoma 2000;9: latanoprost in lowering intraocular pressure in glaucoma and 134-42 ocular hypertension: results from parallel-group comparison 68. Nouri-Mahdavi K, Hoffman D, Coleman AL, et al. Predictive trials. Adv Ther 2004;21:247-62 factors for glaucomatous visual field progression in the Advanced 52. Toris CB, Camras CB, Yablonski ME. Effects of PhXA41, a new Glaucoma Intervention Study. Ophthalmology 2004;111: prostaglandin F2 alpha analog, on aqueous humor dynamics in 1627-35 human eyes. Ophthalmology 1993;100:1297-304 69. Neelakantan A, Vaishnav HD, Iyer SA, et al. Is addition of a 53. Travatan [package insert]. Fort Worth (TX): Alcon Laboratories, third or fourth antiglaucoma medication effective? J Glaucoma Inc.; 2001 2004;13:130-6 54. Brubaker RF. Targeting outflow facility in glaucoma management. 70. Fechtner RD, Realini T. Fixed combinations of topical glaucoma Surv Ophthalmol 2003;48(Suppl):S17-S20 medications. Curr Opin Ophthalmol 2004;15:132-5 55. Christiansen GA, Nau CB, McLaren JW, et al. Mechanism 71. Osborne SA, Montgomery DMI, Morris D, McKay IC. Alphagan of ocular hypotensive action of bimatoprost (Lumigan) in allergy may increase the propensity for multiple eye-drop patients with ocular hypertension or glaucoma. Ophthalmology allergy. Eye 2005;19:129-37 2004;111:1658-62 72. Manni G, Centofanti M, Sacchetti M, et al. Demographic and 56. Boyle JE, Ghosh K, Gieser DK, et al.; Dorzolamide-Timolol clinical factors associated with development of brimonidine Study Group. A randomized trial comparing the dorzolamide- tartrate 0.2%-induced ocular allergy. J Glaucoma 2004;13: timolol combination given twice daily to monotherapy with 163-7 timolol and dorzolamide. Ophthalmology 1998;105:1945-51 73. Alvarado JA. Reduced ocular allergy with fixed-combination 57. Clineschmidt CM, Williams RD, Snyder E, et al.; Dorzolamide- 0.2% brimonidine–0.5% timolol. Arch Ophthalmol 2007; Timolol Combination Study Group. A randomized trial in 125:717

CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com Paper CMRO-4023_5, Accepted for publication: 10 September 2007 Published Online: 18 October 2007 doi:10.1185/030079907X242476

© 2007 LIBRAPHARM LTD – Curr Med Res Opin 2007; 23(12) Efficacy and safety of brimonidine compared with dorzolamide Katz et al. 2983