Bristol-Myers Squibb cites FDA monograph review in defending Excedrin safety.

BRISTOL-MYERS CITES OTC MONOGRAPH REVIEW IN SUPPORT OF EXCEDRIN SAFETY in responding to a position paper presented by the National Kidney Foundation at an OTC "feedback" meeting in Rockville, Md. on March 8. In a prepared statement delivered at the meeting, Bristol-Myers Squibb Executive Medical Director-Worldwide Consumer Medicines Howard Hoffman, MD, alluded to FDA's recently completed review of caffeine as an analgesic adjuvant when he said the agency has "corroborated" the company's position that Excedrin and combination analgesics are safe.

In support of the continued marketing of combination analgesics, Hoffman said FDA has "concluded there was no evidence of increased risk of renal toxicity when combination analgesics such as Excedrin were used according to product labeling."

In an April 18, 1995 letter sent to the company reflecting FDA's decision to grant caffeine monograph status as an analgesic adjuvant, the agency said it determined "that caffeine at a dose of 65 mg can be generally recognized as safe and effective...when combined with aspirin or with a combination of aspirin and acetaminophen" ("The Tan Sheet" May 8, 1995, pp. 1-5). Responding to data submitted by McNeil, including a retrospective case-control study on analgesic use and end-stage renal disease, FDA concluded that "the data...are not sufficient to demonstrate an increased risk of renal toxicity from OTC analgesic drug products containing caffeine when used according to monograph directions."

The National Kidney Foundation requested the "feedback" session with FDA in order to present a position paper on the safety of OTC analgesics that was developed by an expert panel that met last June and was published in the January issue of the American Journal of Kidney Diseases ("The Tan Sheet" March 11, p. 7). The foundation recommended to FDA that the "availability of [OTC] analgesic mixtures...should cease."

Speaking on behalf of the foundation, William Henrich, MD, Medical College of Ohio, declared that "a positive and direct relationship exists" between the sale of combination analgesics and "the prevalence of classic analgesic nephropathy." Henrich cited epidemiology data for Sweden and Australia that found that removing combination OTC analgesics from the market reduced the incidence of end-stage renal disease in those countries.

Hoffman acknowledged the higher rates of end-stage renal disease in Belgium, but noted the different analgesic ingredients available in that country. "In the 30 years of marketing of Excedrin with over 30 bil. tablets, there have been no specific reports of chronic kidney disease reported to us," he said.

The foundation is not limiting its recommendation to acetaminophen-aspirin-caffeine combinations, such as Excedrin. The group also included any OTC analgesics containing more than one active analgesic ingredient or an active ingredient and caffeine as an analgesic adjuvant.

Hoffman maintained that the issue has "been thoroughly reviewed by independent medical experts" and that "none of these authorities agree with the committee's conclusions."

FDA's Internal Analgesic Panel decided to allow combinations of acetaminophen and aspirin in OTC analgesic products in the OTC review panel's advanced notice of proposed rulemaking published in the July 8, 1977 Federal Register. However, the panel recommended that combinations include only two effective ingredients at their minimum effective doses.

FDA subsequently outlined its general policy on combination products in a September 1978 guideline, which states: "Category I [safe and effective] active ingredients from the same therapeutic category that have different mechanisms of action may be combined to treat the same symptoms or condition if the combination meets the OTC combination policy in all respects and the combination is on a benefit-risk basis, equal to or better than each of the active ingredients used alone at its therapeutic dose."

However, an NIH consensus panel concluded in February 1984 that "considerable evidence indicates that combinations of antipyretic analgesics, taken in large doses over a long period of time, cause a specific form of kidney disease and chronic renal failure." The panel recommended that "serious consideration...be given to limiting over-the-counter products to those containing a single antipyretic analgesic agent."

The panel found "no evidence" that occasional use of OTC analgesics for headaches or general pains resulted in an increased risk of analgesic nephropathy. In addition, the recommendation that combinations be removed from the OTC market was based on the assumption that there is no additional benefit from having such products available to consumers to justify the risk of nephropathy. Also, the higher rate of kidney damage in some regions mirrored higher use of phenacetin-containing analgesics. Phenacetin was removed from the OTC market in 1968.

FDA addressed the consensus conference report in the Nov. 16, 1988 internal analgesics tentative final monograph, which adopted the recommendations of the OTC review panel regarding combination products. In the preamble to the TFM, FDA said it was including the conference report in the administrative record of the analgesic rulemaking and that the agency would consider comments on the consensus panel's recommendations in the internal analgesics final rule.

Bristol-Myers Squibb said it has worked with independent medical experts to investigate and monitor the issue since the consensus conference report in 1984. "At that time," Hoffman said, "company scientists and these independent experts concluded that there was no convincing epidemiological evidence to link specific analgesics or combination analgesics other than phenacetin...to chronic kidney disease." Hoffman added that Bristol-Myers has "continued to monitor the literature on this subject and has not uncovered any additional information that would alter these conclusions."

He also reported that the company "thoroughly reviewed the extensive references" provided by the National Kidney Foundation and concluded that the "studies cited by the [foundation's expert panel] either did not appropriately reflect the possible influence of phenacetin on the subjects or failed to reflect potential regional differences in medical practice or dosing and other confounding factors."

In a letter to the National Kidney Foundation in December, Bristol-Myers Squibb questioned the manner in which the foundation released its report. The company said it was "disappointed...that the NKF would release its recommendations without first entering into a dialogue with us." Bristol-Myers met with the foundation to present the company's data as well as its analysis of the data considered by the National Kidney Foundation expert panel on March 15.