Frequent Dosing of Topical Cyclosporine A for Severe Ocular Surface Disease Anisa I. Gire, Sezen Karakus, Shanna M. Ingrodi, and Esen Karamursel Akpek Abstract Purpose: To study the systemic safety and patient tolerability of frequent dosing of cyclosporine A (CsA) 0.05% eyedrops in the treatment of ocular surface disease. This is a retrospective case series. Patients with significant ocular surface diseases who were treated using topical CsA higher than the usual twice daily dosing (3–8 times daily and over a treatment period of 1–70 months). The main outcome measures are plasma levels of CsA and local tolerability. Methods: Symptom assessment, corneal staining using fluorescein, conjunctival staining using lissamine green, tear film breakup time, and other signs according to the disease process were monitored. Discontinuation of treatment due to intolerability was recorded. CsA levels were measured in the plasma at a clinical laboratory. Results: Plasma levels of CsA were below the level of detection (7 ng/mL) in all the 41 patients included. All patients tolerated the treatment well with none discontinuing due to any treatment-related local adverse effects. Conclusions: This study demonstrates that CsA 0.05% ophthalmic emulsion applied more frequently than the usual twice daily dosing was safe and well tolerated in patients with significant ocular surface diseases. Introduction D ry eye affects an estimated 5 million Americans aged 50 years and older. 1 It has been defined as a ‘‘multi- factorial disease that is caused by a decrease in tear pro- duction and/or an increase in tear evaporation and is associated with elevated tear osmolarity, symptoms of oc- ular irritation, and signs of ocular surface inflammation.’’ 2 Dry eye has a significant impact on affected patients’ quality of life due to ocular discomfort and visual dysfunction. 3–6 It also has a large economic impact not only due to cost of therapy but also its consequent effects on workplace pro- ductivity. 3,7 The combination of its high prevalence and detrimental effects on the affected patients’ quality of life underscores the importance of effective treatment strategies for dry eye. Irrespective of the presence of any identifiable under- lying local or systemic inflammatory disorder, dry eye is invariably associated with chronic inflammation of the ocular surface mediated by lymphocytes. 8,9 Cyclosporine A (CsA) 0.05% ophthalmic emulsion (Restasis; Allergan, Inc., Irvine, CA) has been widely used in patients with dry eye since the U.S. Food and Drug Administration (FDA) approved it in 2003. CsA is an immunomodulator that in- hibits T-lymphocyte activation and function and apoptosis of conjunctival epithelial cells. 10,11 Systemically adminis- tered CsA is known to cause serious side effects, including nephrotoxicity, hypertension, increased risk of opportu- nistic infections, and hepatotoxicity. 10,12 In phase 3 clini- cal trials, topical CsA at concentrations of 0.05% or 0.1% CsA had negligible plasma levels after 3 years of contin- uous use at the recommended twice daily dosing. However, local side effects such as burning, stinging, discharge, foreign body sensation, and hyperemia were commonly reported. 13 Topical CsA has also been used off-label in the treatment of a variety of other ocular surface conditions, including ocular rosacea, graft-versus-host disease (GvHD), atopic keratoconjunctivitis, and posterior blepharitis. 10,11,14–16 It has been the main treatment of severe vernal keratocon- junctivitis in children since 1980s. 17 A few studies reported on its use at more frequent doses ranging from 3 to 8 times a day in patients with some of these severe ocular surface diseases. 18–20 Currently, whether frequent dosing of topical CsA 0.05% could cause systemic side effects is not known and has been a concern particularly in the pediatric age group. Therefore, we sought to examine the plasma con- centration of CsA in patients who received high-frequency topical application of CsA for the treatment of various ocular surface diseases. We also recorded local side effects and the dropout rate due to intolerability to treatment. Ocular Surface Diseases and Dry Eye Clinic, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland. JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS Volume 32, Number 3, 2016 ª Mary Ann Liebert, Inc. DOI: 10.1089/jop.2015.0078 150 Downloaded by Johns Hopkins Univ e-journal package from www.liebertpub.com at 04/24/18. For personal use only.