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Fixed combinations: Canadian studies

ByMichael A. Motolko, MD, FRCSC, FACS

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Michael A. Motolko, MD, FRCSC, FACS

For years ophthalmologists had only one fixed combination glaucoma medication, dorzolamide and timolol. Ophthalmologists can now add the fixed combination of brimonidine and timolol to their armamentarium.

The Combigan Early Experience Data (CEED) II study is a phase-4, open-label, prospective 2-month surveillance study evaluating the efficacy, tolerability and safety of the fixed combination brimonidine and timolol.¹ Patients included in the study required lower intraocular pressure (IOP) in addition to their current medical therapy. The exclusion criterion was a person having allergy to either of the two components: the alpha-2 agonist or the beta blocker.

Patients were examined at baseline, at 1 month and at 2 months. The fixed combination of brimonidine and timolol was used across the board as monotherapy, as replacement therapy or as adjunctive therapies. The study took place in 123 centers across Canada with more than 2000 patients enrolled representing 3000 eyes.

Results

IOP was lowered nearly 18% over the baseline (4 mm Hg) in the 2000 patients.¹ In terms of target pressure, the Advanced Glaucoma Intervention Study created the benchmark of 18 mm Hg IOP for ophthalmologists to look for when determining the effectiveness of glaucoma treatment.² Forty-one percent of patients in the CEED II study had IOP under 18 mm Hg with initial therapy. This number was not satisfactory. When adding or switching to the fixed combination brimonidine and timolol, 77% of patients reached the target pressure of 18 mm Hg or lower.¹

Fifty-four percent of eyes treated with brimonidine and timolol had a 15% reduction in pressure from baseline. Fifteen percent represents the ideal minimum IOP lowering that ophthalmologists seek when a glaucoma medication is added. That number was chosen to eliminate the errors in tonometry. The variability of tonometry was ±10%, or 2 mm Hg in a 20-mm Hg pressure range.

It should be noted that patients’ responsiveness to medications is highly variable. Some of the patients had increased IOP when they were switched to brimonidine and timolol.

Head to head comparison

In the CEED II study, a group of patients were treated with dorzolamide and timolol, and then switched to brimonidine and timolol. The additional pressure lowering after the switch was approximately 11% (2.6 mm Hg).¹

In terms of target pressures, 74% of patients were at 18 mm Hg or less by the end of the study in this subgroup analysis, compared to 52% at baseline. Forty-four percent of all eyes achieved additional pressure reductions of greater than 15%.

Additional studies

In a parallel, randomized 3-month comparison study by Donald R. Nixon, MD, of the effect of fixed combination medication on lowering IOP, patients were placed in one of two groups.³ The first group of patients had not received any medication and were treated with a fixed combination medication, either brimonide and timolol or dorzolamide and timolol. The second group of patients had received initial treatment with the prostaglandin latanoprost, and they were randomized to receive either brimonidine and timolol or dorzolamide and timolol in addition to latanoprost.

Results of the study showed that, when added to latanoprost, both brimonidine/timolol and dorzolamide/timolol were efficacious. There was an IOP reduction of nearly 7.8 mm Hg for patients receiving brimonidine and timolol when added to the prostaglandin, and an IOP drop of nearly 6.7 mm Hg for patients receiving dorzolamide and timolol when added to the prostaglandin. The only statistical significance in the study was that the absolute value of brimonidine and timolol was 15.6 mm Hg, a better result than dorzolamide and timolol at 17.3 mm Hg.

When both groups of medication are added to a prostaglandin, the results are efficacious. There is a trend toward slightly better IOP lowering with brimonidine and timolol as compared to dorzolamide and timolol, but the difference is not statistically significant.

References

1. Ahmed I. Combigan Early Experience Data. Clin Surg J Ophthalmol. 2007;25:50-54.
2. The AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol. 2000 Oct;130(4):429-440.
3. Nixon DR. Evaluation of the safety and efficacy of brimonidine tartrate-timolol maleate ophthalmic solution and dorzolamide hydrochloride-timolol maleate ophthalmic solution in patients with open-angle glaucoma or ocular hypertension. Poster presented at: Annual Meeting of the Association for Research in Vision and Ophthalmology; April 30-May 4, 2006; Fort Lauderdale, FL.