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Executive Summary

The uncertain effect of ophthalmic fluoromethalone on intraocular pressure should be reflected in labeling for the corticosteriod, FDA's Anti-Infective Drugs Ophthalmic Drugs Advisory Subcommittee concurred at its Oct. 26 meeting. Subcommittee member Michael Cobo, MD, Duke University Medical Center, commented: "I think the labeling should be changed.... I would change the description of the drug -- where it says that fluorometholone 'demonstrated' a lower propensity to increase intraocular pressure -- to 'suggests,' and even then, to 'suggests inconclusively.'" Cobo continued: "If anything I would make the description more stringent because of the underlying suggestion that because [fluorometholone has] a somewhat lesser effect in some statistical analysis that this may be a more trivial drug" than other ophthalmic corticosteroid products. "I think it is a very dangerous drug if used injudiciously," Cobo remarked. The subcommittee was asked by FDA whether fluorometholone products significantly differ from other ophthalmic topical corticosteroid products in their propensity to increase intraocular pressure and whether the products should be relabeled to reflect the subcommittee's conclusions. Fluorometholone, a progesterone derivative, was cleared 20 years ago under the DESI program for pre-1962 drugs. The product is marketed for the treatment of corticosteroid-responsive inflammation of the eye by Allergan under the tradenames FML and FML Forte, and by Alcon, which licenses its fluorometholone acetate product from Upjohn, under the tradename Flarex. "The fluorometholone products have been promoted as having a lower tendency to increase intraocular pressure versus other corticosteroid drugs," FDA Medical Reviewer Emma Knight, MD, told the committee. "There have been implied claims of superiority made for fluorometholone regarding this lower rate of intraocular pressure incidence [and] because of the question of safety for long-term use, the promotion and claims of superiority, we decided to look at the studies regarding fluorometholone and intraocular pressure," Knight said. The agency is understood to have contacted Allergan cautioning the company about superiority claims for its fluorometholone products. FDA apparently is concerned that such promotions might lead to more indiscriminant use of fluorometholone products by physicians without a demonstrated improved safety profile. "There have been adverse experiences reported of increased intraocular pressure with fluorometholone drugs," FDA's Knight noted. There have been two cases in the last three years of visual loss in patients receiving fluorometholone .1% solution, she reported. The subcommittee considered data from seven published studies on fluorometholone products that were presented by both Allergan and FDA. A number of the studies showed that fluorometholone increased intraocular pressure in patients, but the increases in pressure were generally less than half as much as those produced by dexamethasone or betamethasone treatment. However, near the end of the six-week studies, differences between the treatments seemed to diminish. FDA contended that while fluorometholone demonstrated a trend toward lower increase in intraocular pressure, the published studies are inconclusive because they were open-label in design with small patient numbers, had inconsistent end-points and were only six weeks in duration. Subcommittee consultant Claude Cowan, MD, Howard University College of Medicine, observed that "the data seem to suggest that there may be a difference" between fluorometholone and dexamethasone; however, because of the inadequacy of the studies, he could not conclude "that this drug is, in fact, less likely to raise intraocular pressure." Noting that "the only reason that fluorometholone exists is because it is marketed as having a lower propensity of raising intraocular pressure," committee consultant Michael Belin, MD, Albany Medical College, remarked: "I am not comfortable with the data that exists currently." The subcommittee stopped short, however, of recommending that FDA remove the reference to lower incidence of intraocular hypertension entirely from fluorometholone labeling. "The labeling should reflect exactly what has been done and not be more broadly taken," subcommittee consultant Barbara Klein, MD, University of Wisconsin, said. When it was pointed out to the committee by FDA that any mention of lower propensity in labeling could be exploited in advertising, Cowan said that advertising then should include "some mention of the caveats that we have noted." The subcommittee also recommended that differences in the pharmacokinetics of fluorometholone alcohol and acetate products be described in labeling. Such a labeling change could benefit Allergan in distinguishing FML from Alcon's Flarex acetate product. Data presented to the committee by Allergan consultant John Polansky, PhD, University of California-San Francisco, showed that the acetate form degrades more slowly than the alcohol form. The slower rate of degradation may pose a greater risk of intraocular pressure increase, Polansky maintained.

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