therapeutic insights
A Truly New Dry Eye Concept
Restasis claims to improve tear production.
Grant Vorster, O.D.

The dry eye industry has blossomed into a multi-million dollar market in recent years. To date, 14 pharmaceutical companies have launched more than 35 dry eye-related products in the United States alone. Practitioners are able to treat their patients' symptoms with eye drops, ointments, gels, sprays and nutritional supplements. The majority of these products are aimed at increasing the amount of moisture in the eye by supplementing the tear film or by reducing evaporation.

Taking a new approach

The latest product touted to revolutionize the current dry eye market treats the underlying inflammation on the ocular surface and lacrimal tissue, thereby improving tear production. Restasis (cyclosporine ophthalmic emulsion, 0.05%), developed and manufactured by Allergan, Inc., received approval for distribution last year on December 23 from the U.S. Food and Drug Administration (FDA). In 1999, the FDA's Ophthalmic Drugs Subcommittee unanimously rejected an initial finding after concluding that clinical trials involving 877 patients didn't show efficacy. According to Allergan, the addition of further confirmatory studies and aggressive research have enabled it to relaunch its bid successfully.

Allergan is marketing Restasis as the first and only prescription medication indicated to increase tear production in patients who don't produce the correct amount of tears. This deficiency is presumably caused by ocular inflammation associated with keratoconjunctivitis sicca (chronic dry eye disease [CDED]).

Restasis's engine

The active ingredient in Restasis is cyclosporine 0.05%, which is an immunosuppressive agent that has a number of important medical uses when administered systemically. However, it's also toxic to the kidneys, which places limitations on its dosage. The safety profile of cyclosporine ophthalmic emulsion 0.05% and 0.1% instilled twice daily over a 12-month period into patients' eyes has been investigated in a recent Phase III study. Results showed that the long-term use of topical cyclosporine ophthalmic solutions at doses clinically efficacious for treating dry eye will not cause systemic side effects.

How does it work?

The exact mechanism of action of Restasis isn't known, although two theories exist.

The first suggests that Restasis acts as a partial immunomodulator and thereby regulates the influx of inflammatory agents (T-cells) into the cornea.

The second theory states that Restasis acts as an anti-inflammatory and inhibits the T-cells from releasing cytokines that initiate the inflammatory cascade. Topical cyclosporine ophthalmic emulsion has also been shown to increase the number of goblet cells in patients who have keratoconjunctivitis sicca. By reducing ocular surface inflammation, the proliferative activity of the epithelium may be enhanced.

Castor oil is the vehicle

The inactive ingredients of Restasis are castor oil, glycerin, polysorbate 80, carbomer 1342, purified water and sodium hydroxide to adjust the pH.

Interestingly, the castor oil that acts as a soluble vehicle has also been shown to improve patient's symptoms in dry eye studies. The report states that the improved symptoms may be attributed to greater tear stability as a result of lipid spreading, prevention of tear evaporation and the lubricating effect of the oil eye drops. A comparison between Restasis and a topical, castor oil-based emulsion over a six-month period showed that significantly more patients responded favorably to the Restasis.

Every rose has its thorns

The most common adverse reaction to Restasis in the clinical trials was ocular burning, noted in 17% of patients. Other side effects reported in 1% to 5% of patients included conjunctival hyperemia, discharge, epiphora, eye pain, foreign body sensation, pruritus, stinging and blurred vision. Patients should not use Restasis concomitantly with contact lenses (although this may be a moot point as contact lenses are contraindicated in most patients who have chronic dry eye disease).

Restasis particulars

Restasis is packaged in single-use, 0.4-ml vials that patients should discard after each use. Allergan recommends that patients invert the vial a few times to obtain a uniform, white opaque emulsion before instilling the drops.

Patients can use Restasis concomitantly with artificial tears, but should allow a 15-minute interval between instilling the two products.

Restasis provides a new alternative for treating refractory cases of moderate to severe keratoconjunctivitis sicca. With the launch date set for this month, many eyecare practitioners around the country are eagerly awaiting the chance to see the results in their own clinical settings. Time (and patient responses) will tell if Restasis truly brings about a revolutionary change in managing chronic dry eye.

References available upon request.

Dr. Vorster is currently an optometry resident at the Bascom Palmer Eye Institute in Miami. You can reach him at gvorster@med.miami.edu.

Dr. Christensen has a partnership practice in Midwest City, Okla. He's a diplomate in the Cornea and Contact Lens Section of the American Academy of Optometry. He's also a member of National Academies of Practice.