ASCRS alert: beware of NSAIDs postoperatively

Some U.S. patients receive generics by law. NSAID makers say the confusion has tarred all drugs.

WASHINGTON — The American Society of Cataract and Refractive Surgery (ASCRS) has issued an alert based on individual physician reports and a preliminary survey it conducted among its members that topical ophthalmic nonsteroidal anti-inflammatory drugs (NSAIDs) may be causing corneal melts.

The cautionary statement said, “A surprising number of respondents have experienced severe complications, including corneal melting leading to perforation. Additional reports indicate the occurrence of conjunctival and scleral melting and severe punctate keratopathy.

“While ASCRS plans to research the problem further, at this time it appears wisest to avoid the routine use of NSAIDs after anterior segment surgery and to monitor current post-surgical cases carefully,” the statement continued. “Topical corticosteroids without NSAIDs have not been implicated at this time.”

Although physicians were urged to discontinue use of all topical NSAIDs, a preponderance of cases occurred with the use of generic diclofenac, ASCRS said. These cases occurred with or without concomitant use of topical corticosteroids. In addition, patients with dry eye syndrome seem to be at greater risk for complications.

Drug makers contacted by Ocular Surgery News have criticized the survey as anecdotal and unscientific. Some fear that their branded drugs have been unfairly associated with the generics. Falcon, an Alcon affiliate that makes generic diclofenac, said aggressive use may be part of the problem.

Meanwhile, the U.S. Food and Drug Administration (FDA) is preparing a report about NSAIDs and the adverse events monitored by the agency.

How it all started

ASCRS sent out its caution Aug. 3 after surveying its U.S. membership about the link between NSAIDs and corneal melting. A few physicians had brought the issue to the group’s attention after noticing cases of severe corneal complication beginning around December 1998.

Executive director David Karcher said ASCRS sent out 5,500 surveys and received 1,100 responses, 105 of which reported corneal melts in patients who had been placed on topical ophthalmic NSAIDs. The group is now trying to determine which brands were prescribed and which were actually dispensed.

In the states of Florida and Georgia, patients under the Medicare program automatically get generic drugs, Mr. Karcher said. “When doctors responded ‘Acular’ [in the survey], they may have prescribed Acular but the patient may have received something else.”

It remains to be established whether there is any epidemiological or statistical significance to the preliminary and anecdotal reports, Mr. Karcher said. ASCRS has sent a follow-up survey to the 105 doctors who saw patients with corneal melting.

“We want to know dosages and make sure of the physicians’ follow-up on what was dispensed,” Mr. Karcher said. “We want to find out if they pretreated and when these corneal problems first presented postoperatively.”

According to Manus C. Kraff, MD, the one common denominator seems to be the generic form of diclofenac. However, he added, the survey is not statistical but rather anecdotal. ASCRS may consult with an epidemiologist to further examine the issue. In the meantime, the organization feels its blanket warning is appropriate.

“Any good clinician has to observe, and from the observation make their decisions long before total scientific method comes into play,” Dr. Kraff said. ASCRS has historically served as an early warning system for drug- and device-related complications, particularly during the development of modern IOLs.

FDA prepares report

While ASCRS begins its own study, the FDA has been following these adverse events and is preparing a report for its own regulatory officials.

According to Wiley Chambers, MD, the FDA’s deputy director for anti-inflammatory, analgesic and ophthalmic drug products, epidemiologists monitor the adverse event reporting program, called Med Watch. Those agents have prepared a consultative report.

Although Dr. Chambers could not cite specific elements of the report, he did say that there have not been an undue number of cases reported to the agency to date, and no clear pattern has formed.

Dr. Chambers said reports to Med Watch about corneal melting have not always identified specifically which NSAID was prescribed or dispensed. Adverse events are not always clearly defined, and the term “corneal melt” might be applied to any kind of keratitis, whether it perforates or not.

“NSAIDs, along with steroids, are known to delay wound healing,” Dr. Chambers said. “Some of the events that have been reported are not unlike what has been reported in the past with steroids and are consistent with current labeling.”

Current labeling for NSAIDs and steroidals alike notes a greater likelihood of keratitis and other corneal problems postoperatively. The definition of a corneal problem is one issue under discussion.

Drug companies respond

ASCRS’s caution to physicians said that a preponderance of cases occurred with the use of generic diclofenac. Alcon, the parent company of the generic drug affiliate Falcon, began to distribute that drug to market in August 1998 and has distributed 410,000 units.

Alcon has received reports by physicians of corneal adverse events associated with diclofenac sodium ophthalmic solution 0.1% and profenal ophthalmic solution 1%. Alcon also noted that adverse corneal events occur with other topical NSAID products when used similarly for post-cataract inflammation.

“It is not surprising, as noted in the ASCRS letter, that more reports have been made for the generic diclofenac solution given the prevalence of its use in cataract surgery,” Alcon said in a written response to questions from Ocular Surgery News.

The company said it has investigated all adverse events reported, and communicated with ASCRS and the FDA.

“The results of our investigations to date suggest that a preponderance of the reported adverse events occur in cataract surgery where topical and/or intraoperative NSAIDs are being aggressively used,” Alcon wrote. “This often includes use both before and during surgery, as well as extended use beyond the indicated 2-week post-surgical period, and at times in conjunction with a topical corticosteroid.”

Comparing generic and brand

Alcon has conducted two clinical studies comparing diclofenac sodium solution with the CIBA Vision Ophthalmics brand Voltaren for control of post-cataract surgery inflammation. These studies, in which the NSAIDs were dosed postoperatively four times daily for 14 days beginning the day after surgery, demonstrated no difference between Voltaren and generic diclofenac in the occurrence or severity of adverse events, Alcon stated.

In the United States, class labeling for topical NSAIDs contains a precautionary statement that use “may slow or delay healing.” Product labeling identifies corneal lesions and ulcers as possible adverse events.

Alcon strongly recommended all topical NSAIDs be used according to their labeled instructions.

Although ASCRS only mentioned diclofenac by name, it cautioned against the postoperative use of all nonsteroidals. Makers of brand-name drugs argue that their products have been inappropriately indicted with the generics.

Millions of NSAID prescriptions have been written since the drugs launched in the early 1990s, according to the companies. Physicians have written 5.5 million prescriptions for Acular (ketorolac tromethamine, Allergan) since 1992, and 3.2 million for Voltaren (diclofenac sodium, CIBA Vision Ophthalmics) in the past 9 years.

According to Allison Parham of CIBA Vision Ophthalmics, physicians reported to sales representatives as early as January that their patients were experiencing corneal melting from NSAIDs.

“This has been an issue that has gone on since January, when doctors first started to alert us that they were experiencing corneal melting,” she said. However, this adverse event was not found in patients who had been receiving brand-name Voltaren. “They were starting to uncover that they were getting generics from the pharmacy.”

Although the initial reports could hurt all NSAIDs, Ms. Parham said that ASCRS is doing what is needed to ensure patient safety.

Head of CIBA Vision Ophthalmics North America C. Daniel Myers added that Voltaren and generic diclofenac are formulated with different preservatives and emollients.

The company sent a letter to ASCRS asking the group to reconsider the issue as one of generic substitution, marketplace confusion and limitations created by governmental agencies of what doctors can prescribe, Mr. Myers said.

Database search

According to Allergan, the company’s pharmaceutical research division searched internal databases for adverse event reports, particularly for corneal melts. They found only two, from 1995. Neither of these events were in post-surgical cases, and both were associated with underlying corneal disease.

According to Janet Cheetham, PharmD, director of clinical research, Acular was tested in about 1,500 patients in clinical trials for allergic conjunctivitis, postop inflammation and other conditions. In these trials there were no corneal melts. In light of the clinical trial and safety surveillance data, Allergan officials said they were surprised by and strongly disagree with the ASCRS recommendation to the extent that it could be interpreted to apply to Acular.

“We do not believe that the recommendation is in the patient’s best interests,” said John R. Gibson, MD, senior vice president of product development. “Acular is safe and we do not believe according to everything that we’ve garnered that corticosteroids can be represented as a better alternative.”