Although edged out by prostaglandin analogs as the preferred first-line medication for glaucoma therapy, beta-blockers, including a once-a-day formulation of timolol maleate (Istalol, ISTA Pharmaceuticals) remain an acceptable choice for first-line or additive therapy, according to one ophthalmologist. Timolol generally is well tolerated and may be a cost-effective choice for some patients.
San Francisco-Prostaglandin analogs have become the first-line therapy of choice for most glaucoma specialists, yet topical beta-blockers remain a safe and effective alternative for monotherapy or adjunctive therapy in many situations, according to Jason Bacharach, MD, associate professor of ophthalmology and director, glaucoma clinic, California Pacific Medical Center, San Francisco.
One beta-blocker in particular has advantages that merit inclusion in the glaucoma specialist's armamentarium (such as once-a-day dosing), a formula built on a molecule with a long track record and a low cost compared with other glaucoma therapies, said Dr. Bacharach. Timolol maleate ophthalmic solution 0.5% (Istalol, ISTA Pharmaceuticals, also known as timolol long acting, or TLA) is a nonselective beta-blocker that received FDA approval in 2004 after being developed by Senju Pharmaceutical Co. of Japan and being licensed to ISTA.
"[TLA] is my beta-blocker of choice," Dr. Bacharach said. "I'm having excellent results with it. It's well tolerated, and it has good efficacy. I have a really great tool in my arsenal to treat patients."
Formulations of timolol have been available for more than 20 years, Dr. Bacharach said, and have been shown to be effective at lowering IOP and flattening the diurnal curve.
A liquid formulation initially was approved in the 1980s for twice-a-day dosing. In the 1990s, Merck introduced a new formulation containing gellan gum, which received once-a-day dosing approval from the FDA. It was believed that the gel formulation would allow the drug to remain in the eye longer, lowering the risk of systemic side effects.
The gel may cause blurring, however, and some patients dislike the gummy feel of the medication in their eye, Dr. Bacharach said.
From then until a few years ago, no further evolution occurred involving the pharmacokinetic properties of the timolol molecule, according to Dr. Bacharach. Then, Senju devised a new solution in which timolol maleate, a cationic molecule, was combined with sorbic acid, an anionic compound, to create an ion pair formation that produced greater corneal permeability due to the increased lipophilicity of the molecule. This product attribute and the resultant higher concentrations of the drug in the anterior chamber of the eye helped gain FDA authorization of once-daily dosing for this liquid formulation.
"Studies in albino rabbit models have demonstrated quite nicely that [TLA] not only attains early high concentrations in the anterior chamber but that it obtains significantly higher concentrations in the anterior chamber throughout the dosing period in relation to generic timolol maleate," he commented.
"With the TLA once-a-day compound, I find that it is a drug with a potentially better safety profile than the generic timolol maleate solutions. The theory is that if there are higher concentrations in the anterior chamber, then less of it will be available to be absorbed systemically," he continued.
Clinical trials data
To illustrate the effectiveness of beta-blockers, and particularly those with the timolol maleate molecule, Dr. Bacharach referred to a meta-analysis of 28 randomized clinical trials by van der Valk et al. [Ophthalmology. 2005;112:1177-1185] that estimated the IOP reduction achieved by the most frequently prescribed glaucoma drugs. In the analysis of absolute and relative change from baseline at peak and trough, timolol was judged to be one of the four most effective pressure-reducing agents in patients with primary open-angle glaucoma and ocular hypertension. Timolol was ranked slightly behind the three prostaglandin analogs and better than alpha-adrenergic agonists and carbonic anhydrase inhibitors in sustaining diurnal control.
The ability to achieve diurnal control is an important factor in glaucoma management, said Dr. Bacharach, noting that Asrani et al. [J Glaucoma. 2000;9:134-142] concluded that large fluctuations in IOP are a significant risk factor in progression.
"Clinically we have a drug that lowers the IOP, it flattens the diurnal curve, and we believe it limits systemic absorption," he said.