Rx perspective
Preservative-free Travoprost Debuts
New formulation reduces the incidence of ocular surface disease.
By John R. Samples, M.D.

Preservatives are ubiquitous in foods and pharmaceutical products. The most common ophthalmic preservative, benzalkonium chloride (BAK), can provoke allergy in some patients. This chemical is a detergent that is effective in preventing the growth of bacteria and fungi in containers, ultimately preserving the ophthalmic solutions we prescribe.  

Dangerous Allergic Reactions

Occasionally the allergy is insidious and hard to detect. Often it only becomes evident after trying a number of medications, only to have the patient return with a red eye after taking the prescribed medication. BAK can also be responsible for toxicity to ocular cells, including corneal and conjunctival epithelial cells.

BAK effects can be seen inside the eye on corneal endothelial cells, which are responsible for controlling the hydration of the corneal stroma and the trabecular cells along the beams of the trabecular meshwork.1 BAK can only reach these cells when an eye is very inflamed or after glaucoma surgery, when a thin layer of conjunctiva is the only barrier between the aqueous humor filling the anterior chamber and the outside world.

In addition to allergy and cellular toxicity, another concern with BAK is its role in and contribution to dry eye conditions. This is a concern because dry eye conditions and ocular surface disease are particularly common in glaucoma patients. This phenomenon has been much underappreciated until recently.

The recognition of the toxic effects of BAK has come from many ophthalmic pharmaceutical firms in the form of alternative preservative or no-preservative artificial tear products. Such products are beneficial for most patients who require chronic therapy. For patients who require topical IOP-lowering medication without BAK or similar compounds, recent choices have included a preservative-free beta blocker, timolol, which is available in single unit doses from Merck. Also available is an alpha adrenergic agonist, brimonidine (Alphagan) preserved with Purite, which is currently available in two strengths of 0.10% and 0.15% from Allergan. These medications effectively lower pressure but have to be used more than once a day.

In contrast, the most desirable agents for lowering IOP are prostaglandin analogues. Their ability to flatten the all-day pressure curve in glaucoma and once-daily dosing regimens make them ideal for the treatment of glaucoma; at present the majority of ophthalmologists in the United States use them as first-line medications.

A New Preservative System

To date, all three of the prostaglandins have been preserved with BAK. On Sept. 21, Alcon received FDA approval for the BAK-free formulation of their prostaglandin, travoprost. The new formulation will be available in 2.5 mL and 5 mL multidose containers and will be marketed as Travatan Z. Although the exact details of the preservation method remain proprietary, the new preservative system, known as sofZia, is similar to an already marketed Alcon product, Systane Free. A specific combination of ions and butters are used to achieve the preservative state. SofZia exceeds all USP requirements for preservative efficacy testing; hence it seems to be tough on bugs but gentle to the eye.  

The initial indication is that Travatan Z will not cost any more than the Travatan currently on the market. Travatan is an effective pressure-lowering agent that works through tight binding of the F-prostanoid receptor,2 resulting in a long duration of action.3-5

Work in our clinic has suggested that BAK may enhance or increase the topical-adverse reactions seen with other classes of medications such as alpha adrenergic agonists and topical carbonic anhydrase inhibitors. Ultimately, it may be desirable to get rid of this preservative in all medications.

In addition to single agents that do not contain BAK, other strategies in the future may include the use of combined agents. A single dose of a combined agent includes only half of the exposure to a preservative that two drops contain, a highly desirable feature of combined beta blocker-prostaglandins that are approved in many countries outside of the United States.

Early clinical information on Travatan Z suggests that it is equivalent in efficacy to original Travatan and is well tolerated, with few patients reporting hyperemia.2 However, the real value of this type of medicine is more subtle.

It is desirable to eliminate anything that contributes to ocular surface disease in the glaucoma patient. Furthermore, eliminating agents with demonstrated adverse effects upon the conjunctiva may enhance the success of surgical procedures for glaucoma. Some ophthalmologists have opined that patients treated with chronic medications simply do not do as well with filtering surgery as patients who have not been medically treated. The removal of BAK from chronic glaucoma drops may eliminate this perceived difference. For these reasons, it is highly recommended.

John R. Samples, M.D., is professor of ophthalmology at the Casey Eye Institute of Oregon Health and Science University.

References

1. Samples JR, Binder PS, Nayak S. The effect of epinephrine and benzalkonium chloride on cultured corneal endothelial and trabecular meshwork cells. Exp Eye Res. 1989;49:1-12.

2. Lewis RA, Weiss MJ, Landry TA, et al. Travoprost 0.004% with and without benzalkonium chloride: a comparison of safety and efficacy. J Glaucoma. In press.

3. Sharif NA, Davis TL, Williams GW. [3H]AL-5848 ([3H] 9‚-(+)Fluprostenol). Carboxylic acid of travoprost (AL-6221), a novel FP prostaglandin to study the pharmacology and autoradiographic localization of the FP receptor. J Pharm Pharmacol. 1999;51:685-694.

4. Davis TL, Sharif NA. Quantitative autoradiographic visualization and pharmacology of FP-prostaglandin receptors in human eyes using the novel phosphor-imaging technology. J Ocul Pharmacol Ther. 1999;15:323-336.

5. Hellberg MR, Sallee VL, McLaughlin MA, et al. Preclinical efficacy of travoprost, a potent and selective FP prostaglandin agonist. J Ocul Pharmacol Ther. 2001;17:421-432.