Corneal edema: an underrecognized safety risk of amantadine

To characterize a large case series of corneal edema associated with amantadine and to disseminate the information on that safety risk.

For this retrospective pharmacovigilance case series, we searched the FDA Adverse Event Reporting System (FAERS) and the medical literature for case reports of corneal edema associated with amantadine. After the application of corneal edema case definition criteria, case reports were assessed for a drug-event causal association between amantadine and corneal edema development.

We identified 54 cases of corneal edema reported or published since the 1990s with reasonable evidence of a causal association with amantadine prescribed for Parkinson's disease or other neuropsychiatric indications. The median amantadine total daily dose was 200 mg (range, 100-400 mg). Corneal edema developed after a median exposure of 12 months (range, 0.6-120 months) with most cases occurring within 24 months of amantadine initiation. There was no apparent relationship between reported total daily dose or exposure duration and corneal edema frequency or severity. The median age at corneal edema development was 61 (IQR, 50.0-64.5; range, 8-82). Corneal edema was bilateral in all cases. In eight cases, corneal grafts were either performed (n = 6) or planned (n = 2). Amantadine was permanently discontinued in all but two cases where the amantadine dose was reduced, and topical corticosteroid treatment was initiated.

Corneal edema is an important yet underrecognized safety risk associated with chronic amantadine use, particularly among patients with Parkinson's disease. Based on our findings, the Warnings and Precautions section of the United States Prescribing Information of all amantadine products was amended.