Brimonidine/timolol combination fares well in study

January 15, 2009

The fixed combination of brimonidine and timolol (Combigan, Allergan) provided greater overall patient comfort, and IOP decreased significantly, compared with the fixed combination of dorzolamide and timolol (Cosopt, Merck & Co.) in patients with primary open-angle glaucoma.

Key Points

Atlanta-The fixed combination of brimonidine and timolol (Combigan, Allergan) provided greater overall patient comfort and significant IOP reduction compared with the fixed combination of dorzolamide and timolol (Cosopt, Merck & Co.) in patients with primary open-angle glaucoma (POAG). David B. Yan, MD, MSc, FRCS, and Jacqueline V. Freudenthal, MD, reported their results at the annual meeting of the American Academy of Ophthalmology.

Dr. Yan explained that although alpha-agonists are effective treatment for patients with ocular hypertension and chronic open-angle glaucoma (COAG), clinical studies also have reported that alpha-agonist agents are highly effective as adjunctive therapy to primary treatment with beta-blockers for COAG.

"Currently, the most widely used fixed combination glaucoma therapy is a combination of a beta-blocker and a carbonic anhydrase inhibitor, i.e., the fixed combination of dorzolamide/timolol," he said. "Previous studies have shown that fixed combinations of beta-blockers with alpha-agonists may be better tolerated by patients while being equal to or more effective in reducing IOP than fixed combinations with topical carbonic anhydrase inhibitors."

In light of the previous studies' findings, the authors conducted an investigator-masked study of the tolerability and efficacy of the combination therapies when patients were switched from 2% dorzolamide and 0.5% timolol to 0.2% brimonidine and 0.5% timolol.

Fifty patients (16 women) were randomly assigned in the study. Either ocular hypertension or POAG had been diagnosed in all of them. Twenty-five patients were randomly assigned to treatment with dorzolamide/timolol, and the remainder were randomly assigned to receive treatment with brimonidine/timolol. The patients were included if their IOP control was considered borderline, which was defined as at or up to 15% above the target IOP and greater than 15 mm Hg on dorzolamide/timolol alone or combined with a prostaglandin analogue.

Eleven patients entered the study on treatment with dorzolamide/timolol alone, whereas 39 patients had been treated with the dorzolamide/timolol as adjunctive therapy in combination with a prostaglandin analogue. IOP was measured at 2 hours after the administration of the study medications.

Assessments

The tolerability of the drugs was assessed and the IOP was measured during screening at week –4, baseline at week 0, and at weeks 8 and 12. Tolerability was assessed at those time points based on the results of a patient questionnaire that measured stinging, blurred vision, bitter taste, and overall patient discomfort. The questionnaire used a linear grading scale that measured the patients' subjective responses in which 0 indicated none, 1 mild, 2 moderate, and 3 severe.

The patients who were randomly assigned to receive the dorzolamide/timolol took it through week 8 and then were switched to brimonidine/timolol from week 8 to week 12.

The patients who were randomly assigned to receive brimonidine/timolol were switched at baseline from dorzolamide/timolol to brimonidine/timolol twice daily, and they remained with the treatment through week 12.

Forty-eight patients completed the study; one patient withdrew because of a non-serious side effect, and one patient was lost to follow-up for the last visit.

Treatment phases

Dr. Yan reported that in the treatment phases from baseline to week 12, the patients experienced less stinging with brimonidine/timolol compared with dorzolamide/timolol (0.54 versus 1.46, p = 0.0001), less blurring (0.67 versus 1.13, p = 0.02), less bitter taste (0.13 versus 0.88, p = 0.002), and less overall discomfort (0.46 versus 1.13, p = 0.0001). In the run-in phase from week –4 to week 0 (baseline), brimonidine/timolol showed significantly less stinging compared with dorzolamide/timolol (linear score scale 0.57 versus 1.46, p = 0.0002), he said.

No significant difference was found between the two treatments for blurring (0.75 versus 1.13, p = 0.10), bitter taste (0.68 versus 0.88, p = 0.48), or overall discomfort (0.95 versus 1.13, p = 0.40). The authors speculated that poor adherence with the dorzolamide/timolol therapy at the initial screening visit (week –4) might have resulted in the different findings between the run-in and treatment phases.

The mean difference in IOP during the treatment phase was a –1.6 mm Hg decrease in favor of brimonidine/timolol fixed combination compared with dorzolamide/timolol (p = 0.001), Dr. Yan said.

"Interestingly, the mean decrease in IOP when switching from dorzolamide/timolol to brimonidine/timolol was significantly greater [p = 0.01] during the open run-in phase [–2.4 mm Hg, p = 0.0001] compared with the treatment phase [–0.8 mm Hg, p = 0.02]," he said. "Poorer compliance with initial dorzolamide/timolol therapy at screening may have affected the IOP results much like the tolerability results."

No clinically significant differences were observed in the blood pressure and heart rate measurements when the patients were switched from the combination of dorzolamide and timolol to brimonidine and timolol, Dr. Yan added.

Based on these results, he said, he was able to conclude that the patients had a greater reduction in IOP 2 hours after treatment with brimonidine/timolol than they had with dorzolamide/timolol (p = 0.001).

In addition to the greater decrease in IOP, brimonidine/timolol also afforded greater overall patient comfort with reduced stinging, blurring of vision, and bitter taste, Dr. Yan said.

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