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True extent of NSAID problems now becoming clearer
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An August 1999 warning about corneal problems with topical ophthalmic nonsteroidal anti-inflammatory drugs (NSAIDs) kicked off a chain reaction of statements, rebuttals and clarifications by physicians, manufacturers and the American Society of Cataract and Refractive Surgery (ASCRS), and within 90 days a multimillion-dollar-a-year drug was withdrawn from the market.
The true number and nature of the clinical cases reported in the survey conducted by ASCRS that led to the warning — and all that followed — will remain unclear until Oliver Schein, MD, of the Wilmer Eye Institute, issues his detailed report on the survey data. In the meantime, many experts say that the topical NSAIDs still available to clinicians are perfectly safe to use as indicated. Does all this leave you confused? Here is what Primary Care Optometry News could find out about the safety of these drugs.
Doing the numbers
When anecdotal reports of postoperative corneal melts associated with NSAIDs started to circulate early in 1999, it was no consolation to patients or their eye doctors that it was an exceedingly rare phenomenon. According to data from the health-care market research firm Scott Levin Associates, there were 1,083,000 prescriptions written for Acular (ketorolac tromethamine, Allergan), 557,000 for Voltaren (diclofenac sodium, CIBA Vision) and 61,000 for DSOS (diclofenac sodium ophthalmic solution, Falcon) in 1998. (DSOS was not available on the U.S. market until August 1998.) ASCRS said that according to the manufacturers, there were approximately 1 million units of Acular, 500,000 units of Voltaren and 500,000 units of DSOS sold in the 12 months preceding the survey the society conducted asking about adverse corneal events. The survey found only about 200 cases with adverse events, and there were few details on those.
It is hard to know what to say about the survey results today because a number of conflicting statements about the data have been released.
The initial Aug. 3 ASCRS statement did not number or describe in any detail the cases of postoperative corneal complications, but it did say that “all currently used topical NSAIDs were implicated.” None should be used postoperatively, the statement said flatly, until the nature of the problem could be determined.
Eight days later, after a review of the survey responses and discussions with doctors and manufacturers, ASCRS revised its position and released some figures.
The Aug. 11 “NSAID Update” was ambiguous, however. The warning against using any postoperative NSAIDs was gone, but not specifically revoked. On the one hand, ASCRS wanted to “reiterate our significant concerns.” On the other, “we are also aware of the otherwise excellent and long track record of NSAIDs.” Sometimes there were three hands: “the majority of cases have been associated with generic diclofenac” (that is, the Falcon brand DSOS), but “Voltaren has been mentioned” – but then again, maybe those patients did not get Voltaren at all. There had not yet been any attempt to verify which drug was dispensed.
At least the statement on Acular seemed clear enough: “eight cases of varying degrees of keratitis have been reported” and “No cases of corneal melts.”
But then 4 weeks later, Kenneth Rosenthal, MD, speaking on behalf of the Cataract Special Interest Group of the ASCRS, told the annual meeting of the European Society of Cataract and Refractive Surgeons (ESCRS) that the ASCRS survey found eight corneal melts associated with Acular (two of which required major intervention or resulted in permanent and severe loss of vision) and 16 cases of keratitis. Those figures, based on the initial tabulation of the ASCRS survey, were repeated in several published news reports and in an article Dr. Rosenthal wrote for Ophthalmology Times.
So what did the ASCRS survey find out about Acular?
Acular record clarified
Peter C. Bartlett of Allergan’s department of scientific information and medical compliance wrote in a letter responding to written questions that “upon investigation of these reports, they [ASCRS] found that there were no corneal melts associated with use of Acular after cataract or refractive surgery.”
According to David Garbe, director of the department, when he and his colleagues at Allergan investigated the eight reported cases of “corneal melt” in the ASCRS survey, they found that some cases were not a corneal melt as the survey had defined it.
“Some doctors saw corneal thinning,” Mr. Garbe said, “but not what most people would consider a corneal melt.” One case of “corneal melt” was in fact a neurotrophic ulcer in a very ill cancer patient.
“Allergan has not received, to date, any post-marketing reports of corneal melt which are associated with use of Acular after cataract or refractive surgery,” Mr. Bartlett told us in his letter.
It is even less clear what the ASCRS survey said about diclofenac. The story has been told in several different ways.
First we need to clarify the two products involved. There were two brands of topical ophthalmic diclofenac available in the U.S. at the time of the ASCRS survey. One was CIBA Vision’s Voltaren, introduced to the market in 1991 and still available today. The other was DSOS, introduced in August 1998 by Alcon subsidiary Falcon and withdrawn from the market in September 1999.
DSOS was not a generic drug. Diclofenac was the active ingredient in both Voltaren and DSOS, but the formulations were different. DSOS came to market only after the FDA reviewed a New Drug Application and Alcon and CIBA Vision agreed to settle a patent dispute. An approvable letter for DSOS was issued based on a clinical study demonstrating safety and efficacy in control of post-cataract surgery inflammation equivalent to Voltaren.
Now, what did the ASCRS survey say about each of these two drugs?
The Aug. 11 “NSAID Update” from ASCRS said that “at least 200 cases of corneal toxicity” ranging in severity from superficial punctate keratitis to “full corneal melts” had been reported, that “the majority of cases have been associated with generic diclofenac,” but that “we have yet to determine what agent was actually dispensed.”
In his ESCRS presentation on the survey, Dr. Rosenthal said that there were 21 cases of corneal melt associated with Voltaren, none of which required intervention. In his later article, however, he wrote that “patients in this group with severe reactions who had been treated with Voltaren or Acular all had underlying rheumatological disease, which may have contributed to the clinical picture.”
Dr. Rosenthal also wrote that severe corneal problems associated with NSAID use began appearing only after the introduction of DSOS and seemed to occur exclusively in the U.S. — the only market in which DSOS was available.
But ASCRS placed a different emphasis in a Sept. 27 “NSAIDs Update.”
Clarifications, qualifications
“Following discussions with Alcon (Falcon) and further investigations, members of both the ASCRS Executive Committee and the Cataract Special Interest Group unanimously share the view that corneal complications can result from the use of any of the topical NSAIDs now on the market in the United States.” Here again there was a qualifier: “The majority of the most severe corneal melts occurred following the use of generic diclofenac.”
Soon thereafter, DSOS was voluntarily taken off the U.S. market by Alcon.
“The FDA classified this as a product withdrawal, not a recall,” said Fred Pettinato, Alcon’s vice president and general manager for pharmaceuticals, in an interview. “We have worked closely with the ASCRS throughout this process and have developed a better working relationship with the ASCRS as a result. We still believe that this is a class of drug issue,” he added, noting the ASCRS statement that all ophthalmic NSAIDs were implicated.
“We know the incidence of corneal adverse events is very low,” Mr. Pettinato continued. Controlled clinical trials revealed similar safety profiles and resulted in identical approved labeling for all ophthalmic NSAIDs.
“Unfortunately,” he added, “this is not how NSAIDs are currently used in today’s cataract practices. Furthermore, the conditions now ascribed to increasing patient susceptibility to NSAID-related corneal events — such as diabetes, rheumatic disease and a history of dry eye — were exclusion criteria for entry into the clinical trials.”
So where does that leave Voltaren users? According to Dan Myers, the president of North American ophthalmics for CIBA Vision, it leaves them most of all with a better understanding of how to use NSAIDs properly.
“Maybe this has raised awareness of problems that might not have been reported otherwise,” Mr. Myers said. “For all the cases that ASCRS sent to us, we contacted every one of the doctors.” That review found great variations in the severity of the conditions being described.
“The wording matters,” Mr. Myers said. “What some call corneal melt versus thinning versus keratitis is somewhat subjective. We would suggest that surgical intervention should be the boundary between serious problems and other corneal adverse events.”
CIBA Vision investigated all the reports in the ASCRS survey that identified Voltaren as the drug being used and found only three eyes in two patients that had corneal melt requiring surgical intervention. One case was a patient with rheumatoid arthritis.
“I think we all know now that is probably a population that is predisposed to this,” Mr. Myers said, “and you should be cautious using NSAIDs if you use them at all” in those patients.
Even before Alcon, Allergan and CIBA Vision started investigating the ASCRS case reports, the FDA had already received some reports of serious corneal conditions that physicians thought were caused by topical ophthalmic diclofenac.
MedWatch protocols
The database of MedWatch — the Adverse Event Reporting System (AERS) maintained by the Office of Postmarketing Drug Risk Assessment (OPDRA) of the FDA — includes all adverse events with medical products on the U.S. market that were reported to the FDA since the system was activated on Nov. 1, 1997. Reports made before that date are also on file but are much more difficult to search.
According to OPDRA, 90% of the reports received by the FDA still come from drug manufacturers, which are required to notify the FDA of any adverse events reported to them. The other 10% are from health care professionals and consumers, who may report directly to the FDA but are under no obligation to do so. The MedWatch program has been designed to make it easy to report adverse events associated with drugs or medical devices. (See “For Your Information” at the end of this article for MedWatch contact information.)
MedWatch on diclofenac
Primary Care Optometry News requested and obtained the AERS data on adverse events reported for diclofenac or ketorolac. No adverse events involving ophthalmic ketorolac were found.
By searching for key words in an electronic document containing more than 1,100 AERS Individual Safety Reports on diclofenac, we identified 52 in which the ophthalmic form was listed as the primary suspected agent in adverse events reported between Nov. 1, 1997, and Oct. 18, 1999 (the latest date for which reports were available at the time we made our request). Those reports were all dated after March 1999. In 41 of those cases, an outcome of “Required Intervention to Prevent Permanent Impairment/Damage” was noted.
Although AERS emphasizes that “the information contained in the reports has not been scientifically or otherwise verified” and that “accumulated case reports cannot be used to calculate incidence or estimates of drug risk,” the data do document the recent history of ophthalmic diclofenac.
The story in brief
For 16 months, from the time the database begins in November 1997 until March 1999, there were no adverse event reports mentioning topical ophthalmic diclofenac. For most of that time, the only brand of ophthalmic diclofenac was Voltaren.
According to several independent sources and published news reports, surgeons started noticing unexplained corneal melts in some of their postoperative cataract and refractive surgery patients in January 1999. Alcon had introduced DSOS to the U.S. market in August 1998, and several doctors became convinced that the corneal problems were related to that drug.
Some surgeons notified the drug manufacturers, who then investigated each case and filed the required FDA reports.
The first one to reach the FDA is dated March 31, 1999. It lists corneal erosion as an adverse event in a male patient receiving diclofenac, with Alcon named as the manufacturer. No outcome was specified in that case, but on April 2 there was another report of corneal erosion, this time accompanied by postoperative wound breakdown. This report classified the problem as one requiring intervention to prevent damage. In May, there were two cases requiring intervention.
While MedWatch logged another 10 serious cornea cases in June and eight in July, the ASCRS was gathering information in its member survey. Three more case reports came in to the FDA in August, and ASCRS issued its first warnings. Nine more reports came in September and eight more in October. By then, DSOS was withdrawn from the market. By the end of the year, however, Allergan and CIBA Vision had launched educational and promotional efforts encouraging clinicians to continue using Acular and Voltaren at the right dosage in the right patients.
Throughout the debate on the issue, Alcon maintained that improper dosing of NSAIDs and poor patient selection were responsible for the corneal complications. There were clearly cases where diclofenac or ketorolac use had gone far beyond the four-times-daily maximum in the approved product labeling.
Ophthalmologists who have studied NSAIDs agree that overdosing will cause corneal complications and that certain classes of patient are at significantly greater risk for problems. They emphasize, however, that the boundaries of safe practice are clearly marked.
According to cornea specialist and anterior segment surgeon Richard L. Lindstrom, MD, “I use both [steroidals and NSAIDs] and I’ve never had a melt of any kind.” He does acknowledge that there is a logical reason why such problems could occur.
Melts explained
When surgeons create an incision, Dr. Lindstrom said, the cornea responds by cleaning up dead cells from the trauma of surgery and then rebuilding the tissue by bringing in new collagen. NSAIDs shut down the arachidonic acid pathway to prostaglandins and allow leukotrienes to fill those receptors. This brings in white blood cells, which carry lytic enzymes and coagulases.
This throws off the balance between cleaning out dead cells and building new ones, which can trigger corneal erosions and melting.
“It does appear that the NSAIDs, by bringing in too many white cells, can get out of balance,” Dr. Lindstrom said. “You are overloaded with white cells and have too much of the lytic side faster than the rebuilding side can happen.”
Although this potential exists, experienced clinicians say that the record of ophthalmic NSAIDs shows them to be very safe. At the 1999 American Academy of Ophthalmology meeting, Allergan hosted an “Ask the Experts” panel on ophthalmic NSAIDs at their booth.
“There’s a perception that maybe nonsteroidals are not as safe as we thought,” said panel moderator Kerry Solomon, MD, in opening the discussion. “Maybe we should be rethinking how we’re dosing and using nonsteroidals.”
“Is there a safety issue to the use of nonsteroidals?” Calvin Roberts, MD, asked rhetorically. “There’s a safety issue with every medication we use, and no medicine is 100% safe. However, we learn to raise the safety profile and apply medicine to our patients judiciously.”
Dr. Solomon asked panelists, “Is starting the drops immediately at the end of your cataract surgery or dosing them preoperatively being too aggressive?”
“Let’s start with on-label use,” Dr. Roberts replied. “On-label use for nonsteroidals in cataract surgery is four times a day starting 24 hours after surgery for a period of 2 weeks. My experience has been with nonsteroidals four times a day beginning 3 days prior to surgery. The study published in the September 1996 issue of Ophthalmology showed that patients who were treated 3 days prior to surgery had a statistically significant decrease in the amount of inflammation that was present on the first postoperative day. I always continue my patients on nonsteroidals for at least a month.”
“I also use nonsteroidals to prevent not only inflammation but cystoid macular edema,” said Michael B. Raizman, MD. “I start the drops at least 2 days, sometimes 3 days before surgery. I continue the drops for at least 4 weeks after surgery. I think patients who have lost vitreous should be on NSAIDs for 12 weeks, maybe longer.
“We have very good data that show this does in fact prevent cystoid macular edema. And in my studies and all the studies of CME prevention that I’ve read in the literature, there have been no problems with corneal toxicity.”
Posterior segment specialist Jeffrey S. Heier, MD, agreed. “It is not uncommon to have CME patients on NSAIDs for upwards of 4 or 5 months,” he said, “often with complicated eyes. Some patients have been on them for 6 months to a year, and I have never seen a corneal melt.”
These surgeons have continued to use Voltaren as well as Acular in their postoperative patients, and they encourage their colleagues to use the NSAID class with care but not fear.
For Your Information:
- MedWatch reports can be made by telephone to (800) FDA-1088, by fax to (800) FDA-0178 or at the FDA Web page http://www.fda.gov/medwatch/ report/hcp.htm. If you have a question about submitting a report about an adverse event associated with a drug, call the FDA Reports Evaluation Branch at (301) 827-3170. Adverse event reporting forms (FDA Form 3500) can be obtained from Consolidated Forms and Publication Distribution Center, Washington Commerce Center, 3222 Hubbard Road, Landover, MD 20785.