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Combination can reduce burden


Simplification of the therapeutic regimen to enable compliance is the primary rationale for using a fixed-combination product in the management of glaucoma, but IOP-lowering efficacy along with safety and tolerability cannot be overlooked.

Key Points

Indianapolis, IN-Simplification of the therapeutic regimen to enable compliance is the primary rationale for using a fixed-combination product in the management of glaucoma, but IOP-lowering efficacy along with safety and tolerability cannot be overlooked, said Louis B. Cantor, MD.

The case of an elderly patient with glaucoma who achieved IOP control after treatment was switched from quadruple topical therapy to the fixed combination of brimonidine tartrate 0.2%/timolol maleate 0.5% ophthalmic solution (Combigan, Allergan) highlights how this dual product fulfills all of these goals, he said.

In December 2009, an African-American woman with a long history of glaucoma and poor compliance with her prescribed topical medications presented for a follow-up visit. Her medications included a prostaglandin analogue (PGA) agent at bedtime along with a beta-blocker, alpha-adrenergic agonist, and carbonic anhydrase inhibitor, each used twice daily. Despite the polypharmacy regimen, the patient had bilateral IOPs of about 22 mm Hg, which was too high considering the severity of her glaucoma.

When queried about how well she was doing using the four medications, the patient admitted that the regimen was incredibly confusing. In considering alternate options, laser trabeculoplasty was ruled out because the patient had minimal response to a procedure performed several years prior. Surgery was discussed, but the patient was opposed to it.

Taking into account that the patient also had conjunctival hyperemia and ocular irritation that was thought to be associated with her PGA agent, Dr. Cantor decided to discontinue all topical medications and "start over" by switching to the fixed combination of brimonidine/timolol. The patient was instructed to place one drop in each eye twice daily, once in the morning and once in the evening at an interval of about every 12 hours.

At her next visit 1 month later, the patient's eyes were no longer red, she reported improved ocular comfort with the ability to maintain good compliance, and IOP was 15 mm Hg in both eyes.

Potential power shown

"Admittedly, this case represents an extreme situation and not all patients [taking] maximal medical therapy may be adequately treated by switching to this single fixed combination," said Dr. Cantor, who also is director, glaucoma service, Department of Ophthalmology, Indiana University School of Medicine.

"However, her situation demonstrates the potential power of fixed-combination treatment with [brimonidine/timolol], which is well-tolerated and, most importantly, greatly reduces the drop burden so that patients may be more compliant with effective IOP-reducing medication," he added.

The dramatic response of the patient's glaucoma most likely is due to better medication compliance, he said. However, various studies have demonstrated the IOP-lowering efficacy of the fixed combination of brimonidine/timolol and show that, on average, it offers IOP-reducing activity roughly equivalent to that achieved with a PGA agent, ~30%.

"Timolol and brimonidine lower IOP via complementary mechanisms of action, working both to decrease inflow and increase outflow, so that whether using the two medications separately or in the fixed combination, there is additive efficacy," Dr. Cantor said.

Excellent tolerability and a favorable safety profile are additional features of the fixed combination of brimonidine/timolol, he said.

Dr. Cantor observed that although allergic conjunctivitis is one of the most important side effects of brimonidine, the incidence of this problem has decreased with newer formulations of brimonidine that contain a lower concentration of the active ingredient. However, experience from both clinical trials and clinical practice indicates that the rate of allergy associated with its use is lower than that expected considering it contains brimonidine 0.2%.

"The incidence of allergic conjunctivitis with the fixed combination of brimonidine/timolol is approximately similar to that occurring with the 0.1% formulation of brimonidine with a preservative [Alphagan P 0.1% with Purite, Allergan]. The reasons for this phenomenon are not well understood," Dr. Cantor said. "However, as postulated by Jorge Alvarado, MD, timolol might be providing some protective effect, acting to block reactive intermediates associated with the alpha-adrenergic agonist from reaching the immune processing cells in the conjunctiva."

The fixed combination of brimonidine/timolol also is very comfortable on instillation and has a low incidence of other side effects. In this regard, Dr. Cantor said, it stands in contrast to the fixed combination of dorzolamide 2%/timolol 0.5% (Cosopt, Merck), which, because of the pH of the formulation and/or the presence of the carbonic anhydrase inhibitor, is associated with significant burning and stinging on instillation, as well as a higher rate of taste perversion.


Louis B. Cantor, MDE-mail: lcantor@iupui.edu

Dr. Cantor receives research support from Allergan. He is a consultant and a member of the speakers' bureau as well. He also has received research support from Alcon Laboratories, Merck, and Pfizer.

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