Safety and Tolerability of Two Percent Cyclosporine (Sandimmune®) Ophthalmic Ointment in Normal Volunteers

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Abstract
Thirty-six healthy male volunteers were enrolled in two sequential double-masked, placebo-controlled trials with the objective of assessing the safety and local tolerability of 2% cyclosporine ophthalmic ointment. Subjects were randomly assigned to active or placebo groups and dosed once, twice, or thrice daily for 14 days. Safety and tolerability were assessed through patient interviews, ophthalmologic examinations, routine laboratory testing, and blood cyclosporine assays. Relative to placebo, cyclosporine ointment was associated with higher frequencies of ocular burning, tearing, redness, itching, and headache. These intolerances were dose-related and reported predominantly in the TID group; QD and BID cyclosporine ophthalmic ointment were better tolerated than the placebo control. Symptoms were usually mild, were reported only once beyond Day 2 in the QD-BID groups, and never required interruption of the study. Transitory, asymptomatic, and unexplained elevations of serum transaminases were seen in five subjects in the first study, but were not confirmed in the second and are not felt to be drug-related. Cyclosporine blood levels were uniformly below the limits of detection. We conclude that the tolerability profile of 2% cyclosporine ointment, dosed once or twice daily in normal volunteers, is acceptable and supportive of trials in patient populations.