The Role of Combination Therapy in Glaucoma Management

Individualizing therapy decisions will help patients achieve maximal benefit.

By Mark R. Parsons, OD, and Walter Whitley, OD, MBA

The diagnosis and treatment of glaucoma presents several challenges for clinical decision making. A number of factors such as age, family history, race, central corneal thickness, optic nerve damage, and intraocular pressure (IOP) influence how to manage glaucoma suspects, ocular hypertensives, and glaucoma patients. Every patient requires individualized therapy to achieve maximal benefit. Once the diagnosis is made, the decision to initiate therapy and which medication to use has traditionally been straightforward. For many glaucoma patients, the safety and efficacy profile of medical monotherapy is appropriate; however, for some patients, monotherapy may be inadequate. In the Ocular Hypertension Treatment Study (OHTS), 40% of medically treated patients required two or more medications to reach a 20% IOP reduction after 5 years.1

Decisions regarding modifying the treatment protocol over the course of the patient’s disease can be equally challenging. A thorough understanding of the benefits of adjunctive therapies such as additional medications or surgical approaches (ie, laser therapy, minimally invasive glaucoma procedures, trabeculectomies, or shunts) will help determine which treatment or treatments may be appropriate. The focus of this article is to review the role of topical combination agents in the management of glaucoma patients.


Glaucoma is not a single clinical entity but rather a group of ocular diseases with various causes that ultimately ultimately are associated with a progressive optic neuropathy leading to a loss of visual function.2 Glaucomatous optic neuropathy is described as progressive rim loss to the optic nerve over time with associated retinal nerve fiber layer dropout and eventual correlating visual field loss. Because IOP is currently the only modifiable risk factor in glaucomatous eyes,3 the physician’s goal is to slow the disease process by using medical or surgical IOP-lowering therapy.

The current standard of care for the majority of newly diagnosed glaucoma patients is to start nighttime monotherapy with prostaglandin analogues (PGAs). PGAs have the ability to lower IOP by approximately 30% to 35%.4 Once initiated, a follow-up visit is scheduled after 3 to 4 weeks to monitor the PGAs initial efficacy and to provide baseline information for future therapeutic modifications. If the PGA is ineffective or not well tolerated, an immediate change is warranted.

The choice of a new agent is somewhat complicated. Anecdotally, many practitioners have had success switching to another PGA. According to the XLT Study Group, who compared the currently available PGAs, there is no statistically significant difference in IOP-lowering efficacy between latanoprost, bimatoprost, and travoprost.4 Additionally, PGA use has been associated with conjunctival injection, iris color change, increase in eyelash length, and periorbital skin darkening and fat atrophy.5 Patients taking latanoprost may be at a higher risk for a recurrence of herpes simplex keratitis.6 Thus, if switching a patient to another brand of PGAs will not likely change the therapeutic outcome, and/or if tolerability is an issue, then the consideration of other adjunct therapies is warranted.

Adding therapies raises several questions: (1) What medication should be added to the current therapy? (2) If the PGA is to be replaced, what class of medication should be used? (3) When would initiating combination therapy be warranted? Although many options are available, combination drop therapy might be an ideal replacement therapy. The FDA indication for currently available combination drops is the reduction of elevated IOP in patients with glaucoma or ocular hypertension who require adjunctive or replacement therapy due to inadequately controlled IOP.7


Adjunct Therapy Considerations

If monotherapy alone is not sufficient, there are several medication classes from which to choose for additional therapy including beta-blockers, alpha-adrenergic agonists, carbonic anhydrase inhibitors, and pilocarpine, all of which complement PGAs mechanisms of action, but differ in dosage, efficacy, and side effects. The severity of the patient’s glaucoma and history of compliance are important to consider. An increase in the frequency or dosage of medication often leads to a decrease in compliance.8 In cases of more severe disease warranting maximal IOP lowering, combination therapy may be a more suitable choice than adding single agents to the monotherapy regimen.

Replacing Current Therapy

Common reasons for replacing the current therapeutic agent include ocular side effects, adverse effects, and compliance. Poor tolerance of the PGA may warrant a trial of the preservative-free PGA tafluprost (Zioptan; Merck). Although this switch may reduce any additive ocular irritation caused by preservatives, the drug itself is most likely the main reason for the adverse reactions. If poor efficacy was the reason for the change, alternative treatments could include replacing the PGA with a different class of medication or laser therapy. Some patients may respond better to one therapeutic class over another. In the scenario where alternative monotherapy cannot consistently control IOP alone, considering two adjunctive monotherapies or starting combination therapy would be appropriate. Clinicians should choose the agent to switch to after evaluating the patient’s medical status and ruling out the medications’ contraindications. Even though many patients are risk averse to any type of surgery, laser treatment may be a viable alternative, and invasive or minimally invasive surgical intervention may be considered in certain circumstances.


There are several combination therapies available for adjunct or replacement therapy. These include dorzolamide 2%/timolol 0.5% (Cosopt; Merck and generic formulations are available), brimonidine 0.2%/ timolol 0.5% (Combigan; Allergan and generic formulations are available), and the newest addition to the market, brinzolamide 1%/brimonidine 0.2% (Simbrinza; Alcon). In the pivotal studies for Combigan, there was consistent IOP lowering at 12 months with twice-a-day dosing.9 As for Simbrinza, the addition of brinzolamide introduces a fixed-combination treatment alternative without the side effects commonly seen with beta blockers.10 Although the systemic safety profile may be improved in a drug that is beta-blocker free, ocular side effects of brinzolamide 1%/ brimonidine 0.2% have been measured around 25% in a 3-month trial.11 In the study, 11.3% of brinzolamide/brimonidine recipients discontinued the medication due to nonserious treatment-related adverse effects. This is compared to 2.1% brinzolamide patients and 9.4% of brimonidine patients. As with any medication, monitoring patients for efficacy and side effects will be important.

There are instances when combination drops may be considered for front-line therapy. A patient newly diagnosed with advanced glaucoma might be started on a PGA and combination drop after the first visit. There is no sense delaying the inevitable need to lower IOP 50% for these patients. Steroid responders, or those with an increase in IOP due to topical steroids, are great candidates for combination therapy because their spike in IOP usually warrants a drop that can combat this spike quickly.1,12 Any immediate need to lower IOP, such as in angle closure, justifies the use of combination therapy in addition to oral acetazolamide and pilocarpine. With the availability of selective laser trabeculoplasty (SLT), patients who are noncompliant and/or have shown poor control in their glaucoma with drops alone can be managed more aggressively.13 An SLT procedure, at first, should usually not be used to replace topical therapy, but to add to it. SLT’s effect on IOP lowering should be assessed before the decision to discontinue topical therapy can be made.


There are several factors to consider in deciding when to use combination therapy. These include an immediate need to drastically lower IOP, steroid responders, if progression is detected and appropriate target IOP cannot be reached with current therapy, or the patient’s intolerance to prior noncombination medications. The current armamentarium of glaucoma therapies makes it possible to deliver world-class care to patients and help preserve their sight.

Mark R. Parsons, OD, is a resident at the Wilmington VAMC, Elsmere, Delaware. He acknowledged no financial interest in the product or companies mentioned herein. Dr. Parsons may be reached at

Walter Whitley, OD, MBA, is the director of optometric services at Virginia Eye Consultants, Norfolk. He is a consultant to and a speaker for Allergan. Dr. Whitley may be reached at

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