Selecting Adjunctive Therapy in the Management of Glaucoma Patients

Use of fixed-combination agents does not necessarily double a patient’s safety risk.

By Nathan M. Radcliffe, MD

An impressive array of intraocular pressure (IOP)-lowering agents are available for treating glaucoma patients. About two-thirds of patients with glaucoma can be maintained at an acceptable IOP with a single medication, usually a prostaglandin analog, the most-often used first-line therapy category.1 Indeed, in the Ocular Hypertension Treatment Study (OHTS), 40% of patients in whom the objective was to lower the IOP by 20% required more than one medication to reach that target.2

One challenge of managing glaucoma is how to treat patients requiring additional IOP lowering. Is it best to change agents or add an additional one? If an agent is to be added, what criteria should be used to select the adjunctive therapy? In 2002, Fetcher and Realini published an article revealing that there were 56,000 possible combinations of agents that could hypothetically be used.3 That study has not been replicated, but in the ensuing decade plus, new agents have come to market, others have fallen out of favor but are still available, and generic formulations have been introduced—meaning that today, there are likely even more potential options.

It would be impractical to try every combination of agents for each patient, so it is prudent to rely on drugs with proven efficacy and tolerability. What do the data tell us? The Covert and Robin data cited previously found that using travoprost or bimatoprost as a primary therapy resulted in a 7% to 8% lower need for an adjunct agent than latanoprost.1 Using a potent monotherapy can decrease the need for an adjunctive agent.


When making a decision regarding an adjunctive agent, the first major choice is whether to add a single or fixed-combination agent. One of the biggest changes in glaucoma medications over the past decade has been the advent and popularization of fixed-combination agents. These offer several advantages, but also potential drawbacks.

When a single medication is added—be it a beta-blocker, a carbonic anhydrase inhibitor, or brimonidine (an alpha-andrenergic receptor agonist)—the safety and efficacy implications should be readily apparent. That is, if the IOP suddenly goes down, it is likely due to the addition of the new agent, and if any new safety signals appear, we know the new agent is likely responsible. As well, a single adjunctive agent may be sufficient to achieve the desired IOP target, and so a fixed-combination agent may be overkill—and if a fixed-combination agent is used, there is no way of telling which agent led to the desired effect. Another argument for single-agent adjunctive therapy is that many of them are available in generic formulations, and so there is an option to offer a potentially lower-cost option if it is appropriate for the patient.

It would seem as though introducing a patients to single agents exposes them to only one set of potential side effects; as a result, single agents are perceived as safer than using a fixed combination, which introduces exposure to two molecules. The idea that fixed-combination agents are less safe, however, may require some additional exploration.


Fixed-combination agents are quickly growing in popularity for adjunctive therapy. There are a number of reasons why these options are being selected with increasing frequency. The primary reason is that fixed-combination agents offer potentially greater IOP-lowering efficacy than their individual ingredients. In clinical trials, each of the fixed-combination agents approved by the US Food and Drug Administration (FDA) lowered IOP by at least 1 mm Hg more than its contributing agents—and in some cases, the additional effect was much greater than 1 mm Hg. Therefore, if a patient on a prostaglandin analog requires more than 2 to 4 mm Hg of IOP lowering to reach the target pressure, it may make sense to add a fixed-combination agent, as a single agent may fall short. An additional benefit of this strategy is that patients who do not respond to this aggressive approach are easily identified as needing an alternative strategy, such as laser or surgery.

But are fixed-combination agents at least as safe as their component ingredients? Or does the presence of two drugs, each with known safety risks, increase the odds patients will experience an untoward event?

Although it is true that patients using fixed-combination medications are being exposed to two active molecules, it is not the case that the use of a fixed-combination agent doubles the safety risk. On one hand, all of the fixed-combination agents exemplified good tolerability and safety in clinical trials. For instance, in the phase 3 trial comparing brimonidine 0.2% three times a day and timolol maleate 0.5% twice daily versus twice-daily use of fixed-combination brimonidine 0.2%/timolol maleate 0.5% (Combigan; Allergan), the incidence of treatment-related adverse events was statistically significantly lower in the fixed-combination group compared with the brimonidine group but higher than in the timolol group. The discontinuation rate was highest in the brimonidine monotherapy group, followed by the fixed agent, and the timolol group.4 It is likely that in the study, the beta-blocker component of the fixed agent (ie, timolol) effectively decreased allergic conjunctivitis caused by brimonidine. In a review of clinical trial data looking at fixed-combination agents compared with their individual ingredients, I showed that timolol positively affects the safety profile of other medications; in particular, use of timolol reduced the risk of common side effects, such as conjunctival hyperemia and ocular allergy, with the effect most pronounced for latanoprost 0.005%, bimatoprost 0.03%, and brimonidine 0.2%.5


There are three fixed-combination agents available for use in the United States: dorzolamide HCl 2.0%/timolol 0.5%; brimonidine 0.2%/timolol 0.5%; and brinzolamide 1%/brimonidine 0.2% (Simbrinza; Alcon). Each of these agents was proven safe and effective in rigorous FDA clinical trials; however, there may be important differences among the agents that are worth noting.

The most recent entrant to the fixed-combination market is brinzolamide 1%/brimonidine 0.2%. Because it does not contain timolol, this medication may be a good option for patients with known cardiac issues, who are taking systemic beta-blocker therapy, or who otherwise cannot tolerate a beta-blocker.

Timolol has long been a cornerstone in the management of glaucoma as an effective agent for adjunctive therapy. Both dorzolamide HCl 2.0%/timolol 0.5% and brimonidine 0.2%/timolol 0.5% contain a beta-blocker component, but the presence of the other ingredient is significant. As noted earlier, timolol may abate some of the conjunctival implications of brimonidine, but it has no such effect on dorzolamide. The most prevalent side effect of dorzolamide, a carbonic anhydrase inhibitor, is burning and stinging likely due to a high acidity.

I do not frequently use dorzolamide as a single agent in the management of glaucoma in my practice. In fact, in the European Glaucoma Prevention Study, which compared patients randomized to dorzolamide or placebo, dorzolamide lowered IOP by 22%, placebo by 19%, and visual field progression was similar in both groups.6 I am not confident using a fixed-combination medication containing an ingredient that demonstrated a similar effect as a placebo in a randomized trial.

Furthermore, there may be variability in the pH levels of different generic formulations of dorzolamide HCl 2.0%/timolol 0.5%, meaning that some formulations may be more likely to induce stinging. The original generic formulation of this drug, Cosopt, was approved in 1998, and a preservative-free option, Cosopt PF, was introduced in 2012. Although these drugs contain the same ingredients in the same concentrations, the pH balance is different; the FDA considers these two offerings therapeutically equivalent, yet from a safety standpoint, they may induce differing levels of stinging upon instillation.

Although the terms Cosopt and Cosopt PF are still loosely associated with this fixed-combination agent, when it became a generic medication, the official name became timolol maleate 0.5% and dorzolamide HCl 2%—which is quite a mouthful for patients to remember. In my practice, I have noted that many patients cannot remember the name of this medication, and on several occasions, I have had a patient remember only half the ingredients and incorrectly report to my technician or staff what he or she is currently taking. As well, generic fixed-combination agents are often given unfavorable tier status on formularies, and so they may be expensive.


We are fortunate to have several agents at our disposal to treat patients with glaucoma, as it is important to get patients’ IOP under control as quickly as possible. There may be a benefit in using fixed combinations early—and in some cases aggressively—to achieve control of patients’ glaucoma and to identify those patients who cannot be controlled so they can be moved on to other options, such as laser or surgery.

There are numerous options for adjunctive therapy in the management of glaucoma. If an additional 2 to 4 mm Hg of IOP lowering is needed to achieve the target pressure, a single agent is a reasonable option. The safety and efficacy profiles of the various classes (beta-blockers, carbonic anhydrase inhibitors, and brimonidine) have been delineated in several clinical trials. Fixed-combination agents are growing in popularity, especially for patients in whom higher levels of IOP lowering are needed. Currently, three options for fixed-combination agents are available. Clinicians may wish to carefully weigh the available evidence regarding their safety and efficacy and consider how the ingredients in the formulation may interact with one another to affect the safety profile. n

1. 1. Covert D, Robin AL. Adjunctive glaucoma therapy use associated with travoprost, bimatoprost, and latanoprost. Curr Med Res Opin. 2006 May;22(5):971-6. Study

2. Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120(6):701-713;discussion 829-830.

3. Realini T, Fechtner RD 6,000 ways to treat glaucoma. Ophthalmology. 2002;109(11):1955-1956.

4. Sherwood MB, Craven ER, Chou C, et al. Twice-daily 0.2% brimonidine-0.5% timolol fixed-combination therapy vs monotherapy with timolol or brimonidine in patients with glaucoma or ocular hypertension: a 12-month randomized trial. Arch Ophthalmol. 2006;124(9):1230-1238.

5. Radcliffe NM. The impact of timolol maleate on the ocular tolerability of fixed-combination glaucoma therapies. Clin Ophthalmol. 2014 12;8:2541-2549.

6. Miglior S, Zeyen T, Pfeiffer N,et al; European Glaucoma Prevention Study (EGPS) Group. Results of the European Glaucoma Prevention Study. Ophthalmology. 2005;112(3):366-375.

Nathan M. Radcliffe, MD
• Director of the Glaucoma Service at NYU Langone Ophthalmology Associates in New York, New York
• (212) 263-2573; fax: (212) 263-2574;
• Financial disclosure: consultant to Allergan