Loteprednol etabonate provides multiple benefits for those initiating topical cyclosporine

May 1, 2008

When initiating treatment with topical cyclosporine ophthalmic emulsion 0.05% (Restasis, Allergan), adjunctive use of loteprednol etabonate ophthalmic suspension 0.5% (Lotemax, Bausch & Lomb) hastens and increases relief of dry eye signs and symptoms and reduces cyclosporine-associated burning and stinging without adding safety concerns, according to the results of a multicenter, randomized, controlled, masked trial comparing the combination regimen with cyclosporine plus artificial tears.

Key Points

When initiating treatment with topical cyclosporine ophthalmic emulsion 0.05% (Restasis, Allergan), adjunctive use of loteprednol etabonate ophthalmic suspension 0.5% (Lotemax, Bausch & Lomb) hastens and increases relief of dry eye signs and symptoms and reduces cyclosporine-associated burning and stinging without adding safety concerns, according to the results of a multicenter, randomized, controlled, masked trial comparing the combination regimen with cyclosporine plus artificial tears.

The study included 118 patients with dry eye disease who were assigned randomly to initial monotherapy using loteprednol etabonate or an artificial tear four times a day for 2 weeks. Thereafter, patients continued using their assigned study agent twice daily and began concomitant twice-daily treatment with topical cyclosporine. Additional use of artificial tears was allowed for all patients as needed and treatment continued through day 60.

At the end of the study, both treatment groups demonstrated improvements from baseline in central corneal (fluorescein) staining, conjunctival (lissamine green) staining, tear production, and the Ocular Surface Disease Index (OSDI). Treatment efficacy, however, was consistently greater in patients using loteprednol with cyclosporine compared with the controls. Safety evaluations showed treatment with loteprednol significantly reduced stinging with cyclosporine initiation without causing any significant increases in IOP after long-term use.

"Our study shows adding loteprednol as initiation therapy to cyclosporine addresses these drawbacks to increase patient compliance and satisfaction with cyclosporine treatment of dry eye disease," he added. "With this dual regimen, patients benefit from combination immunomodulatory treatment that reduces the inflammation associated with dry eye disease in two different ways. As our study demonstrated, adding loteprednol to cyclosporine as initiation therapy resulted in more rapid resolution of dry eye disease while dramatically reducing the burning associated with cyclosporine and without adversely affecting IOP."

John D. Sheppard, MD, MMSc, president, Virginia Eye Consultants, and associate professor of ophthalmology, microbiology and molecular biology, Eastern Virginia Medical School, Norfolk, said, "We were pleased to find in this study that initiating dry eye treatment with loteprednol etabonate reduced the stinging that can occur with cyclosporine initiation as well as accelerating improvement in the signs and symptoms of dry eye without causing additional side effects.

"These findings demonstrate that the individual relative strengths and weaknesses of topical cyclosporine and lote-prednol etabonate are highly complementary and create a synergistic combination," he continued. "Loteprednol helps to minimize cyclosporine-associated stinging and addresses its delayed onset of action, while cyclosporine covers concerns about the benzalkonium chloride content of loteprednol and long-term continuous use."

Baseline measures

At baseline, mean central fluorescein corneal staining score was 0.30 in the loteprednol group and 0.28 in the artificial tears group. At day 60, central fluorescein corneal staining was eliminated in patients using loteprednol with cyclosporine (mean score 0.0), whereas the mean score in the artificial tears group was 0.10. The change from baseline was significantly different in each treatment group, but a between-group comparison also showed a significant difference favoring loteprednol.

Across both treatment groups, mean baseline conjunctival staining scores for the temporal and nasal regions of the right and left eyes ranged from 0.9 to 1.4. For all four measures, treatment with loteprednol plus cyclosporine was associated with significant improvements from baseline at day 60. Mean conjunctival staining scores in patients using the artificial tears with cyclosporine also were improved, but none of the changes from baseline achieved statistical significance.

Mean Schirmer test scores were similar in the two study groups at baseline. Both treatment regimens resulted in a significant increase in tear production after 60 days. The change from baseline, however, was greater among patients using loteprednol with cyclosporine compared with the group using artificial tears (28% versus 17%).

Data also were collected on the frequency of adjunctive artificial tear use. Analyses showed that both treatment groups were able to decrease their reliance on additional artificial tears.

Mean OSDI score was about 33 in both treatment groups at baseline. At day 14 after completion of the induction course, patients using loteprednol etabonate already benefited with a significant improvement in OSDI score, whereas minimal change was seen in patients using artificial tears. The mean OSDI score continued to improve in both treatment groups after the addition of cyclosporine, but when assessed at days 30 and 60, the improvement from baseline was significantly greater in patients using loteprednol with cyclosporine compared with the control group.

Consistent with the site-active mechanism of action of the corticosteroid ester, mean IOP values at days 14, 30, and 60 showed no significant adverse effect of ongoing treatment with loteprednol.

"The loteprednol etabonate molecule is retro-engineered to produce a highly active anti-inflammatory molecule with glucocorticoid receptor binding affinity 4.5 times stronger than dexamethasone," Dr. Sheppard said. "The substitution of an ester for a ketone group at the 20 position on the steroid core allows for degradation of unbound loteprednol by tissue esterase enzymes. As a result, the steroid either is acting to reduce inflammation while bound to the glucocorticoid receptor or is metabolized by tissue esterases into an inactive form that does not affect IOP or cause cataract."