Glaucoma: Latest brimonidine formulation shows improved safety, tolerability

September 1, 2009

A meta-analysis based on data from 12-month trials including patients treated with brimonidine 0.1% with a preservative (Alphagan P 0.1% with Purite, Allergan) and patients using brimonidine 0.15% (Alphagan P 0.15%, Allergan) showed better systemic safety and tolerability with the lower-concentration product.

Key Points

Indianapolis-The newest ophthalmic formulation of brimonidine tartrate (Alphagan P 0.1%, Allergan), containing 0.1% of the active ingredient and a preservative (Purite, Allergan), offers benefits of improved systemic safety and tolerability compared with an older formuation with the preservative that contains brimonidine 0.15% (Alphagan P 0.15%, Allergan), according to the findings of a recently published meta-analysis.

"Brimonidine has been available as an IOP-lowering treatment for more than a decade, and it has a very good track record for efficacy and safety," said Louis B. Cantor, MD. "The meta-analysis data show that the series of formulation modifications introduced over time have successfully improved this treatment modality by enhancing its safety and tolerability. IOP data from various clinical trials show these benefits occur without compromising IOP-lowering efficacy."

Dr. Cantor is chairman and professor of ophthalmology, as well as the Jay C. and Lucile L. Kahn Professor of Glaucoma Research and Education and director of glaucoma service, at the Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis. He was the lead author of the meta-analysis (Curr Med Res Opin. 2009;25:1615–1620).

Although the efficacy and safety of thrice-daily dosing of brimonidine 0.1% and brimonidine 0.15% had been demonstrated in clinical trials using the original brimonidine formulation (brimonidine 0.2% with benzalkonium chloride [Alphagan 0.2%, Allergan]) as the control, no head-to-head studies directly compared the 0.1% and 0.15% formulations of brimonidine administered on a three-times-daily administration schedule. Brimonidine 0.1% had been shown to be similar to brimonidine 0.15% in its IOP-lowering efficacy and safety profile in a previous study, but that study had a noninferiority design, enrolled patients already using brimonidine, and the medications were administered just twice daily, Dr. Cantor said.

"The goal for using any medication in clinical practice is to identify the lowest dose needed to provide the desired therapeutic effect in order to optimize safety," he said. "This was the motivation for developing the 0.1% formulation of brimonidine, and the meta-analysis offered an opportunity to compare it with brimonidine 0.15% in lieu of a prospective clinical trial."

Two previous studies

The meta-analysis included data from two previously reported studies that had similar patient entry criteria and methodology. Both were multicenter, prospective, randomized, double-masked, parallel-group, 12-month trials in which patients used brimonidine 0.1% or 0.15% according to the recommended three-times-daily dosing schedule.

In one study, which pooled data from the two pivotal trials, 1,187 patients with glaucoma or ocular hypertension underwent washout of existing medications and were randomly assigned 1:1:1 to brimonidine 0.15%, brimonidine 0.2%, or brimonidine 0.2%. The other study included 433 patients who were randomly assigned after medication washout to brimonidine 0.1% or brimonidine 0.2%. Patient demographic and baseline characteristics were similar in the two studies.

Comparisons between the two newer brimonidine formulations showed that brimonidine 0.1% had a significantly lower incidence of treatment-related adverse events compared with brimonidine 0.15% (41.4% versus 49.7%; p = 0.050) and a numerically lower rate of treatment-related ocular adverse events (39.5% versus 42.6%; p = 0.461).

"The difference between groups in incidence of ocular adverse events was not statistically significant," Dr. Cantor said. "They may be clinically significant, although there was no significant difference between groups in the rate of discontinuation for ocular adverse events."

Adverse events

Analyses of treatment-related systemic adverse events showed that they occurred significantly less often among patients treated with brimonidine 0.1% compared with those using brimonidine 0.15% (4.7% versus 14.2%; p < 0.001). Rates of discontinuations due to systemic adverse events also were significantly lower in the brimonidine 0.1% group compared with brimonidine 0.15% (0.9% versus 4.2%; p = 0.025).

"Lower systemic absorption with the lower concentration formulation likely explains the difference in systemic adverse events," he said. "This hypothesis is supported by animal pharmacokinetics studies comparing plasma levels of brimonidine after topical administration of 0.1% or 0.15% brimonidine, although in clinical trials, levels of brimonidine have not been detected in blood."

Dr. Cantor added that the difference in rates of discontinuation for systemic adverse events is noteworthy, considering that ocular hypertension and glaucoma are lifelong diseases requiring adherence to long-term therapy.

The meta-analysis reaffirmed the safety benefits of both brimonidine 0.15% and brimonidine 0.1% versus brimonidine 0.2% for significantly reducing the incidence of treatment-related adverse events and ocular adverse events, although only brimonidine 0.1% had a significantly lower rate of systemic adverse events compared with brimonidine 0.2%.

Dr. Canton acknowledged that, as a limitation, the meta-analysis included only two studies.

"By pooling data from different studies, a meta-analysis can provide greater statistical power and allow comparisons between treatments that were not made directly in a single trial," Dr. Cantor said. "Some meta-analyses will be based on large numbers of studies, but ours included only two. Therefore, we believe additional studies are warranted to further evaluate the relative safety and tolerability of the two [newer] formulations of brimonidine."