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McNEIL IS NOT PROMOTING SUPROL TO PHYSICIANS; FDA's ADVISORY COMMITTEE RECOMMENDS BOXED LABEL WARNING FOR FLANK PAIN SYNDROME, TWO-YEAR PATIENT FOLLOW-UP

Executive Summary

McNeil has halted promotion of its nonsteroidal anti-inflammatory Suprol (suprofen). The company's Director of Clinical Research Carol Ellis, MD, noted at FDA's Arthritis Drugs Advisory Committee meeting Dec. 2 that McNeil does not plan to advertise the drug in any way. Advertisements have not appeared in medical journals since September. The committee concluded at its meeting that Suprol should be relabeled to include a boxed warning highlighting the adverse reaction of flank pain. The committee also recommended that physicians be advised in the labeling as well as in a "Dear Doctor" letter that patients receiving Suprol should be followed up for at least two years. In addition, the committee said FDA and McNeil should "work out an acceptable system for follow-up . . . to assess permanent kidney function." Committee member designate Gerald Arnoff was alone in recommending that the drug be withdrawn from the market. However, Arnoff's membership has not yet been cleared through FDA and he was not considered a voting member at the Dec. 2 meeting. Arnoff said that until the risks with Suprol are in range with other nonsteroidal anti-inflammatories he would recommend removing it from the market. FDA Office of Drug Research & Review Director Robert Temple, MD, asked Arnoff if he would change his mind if it could be shown that hydration of the patient reversed the adverse effects. Arnoff responded that this would change his mind. Committee member Norman Gottlieb, MD, University of Miami, said he was "loath to have a drug removed" from the market that might help some people. Temple commented that FDA is accustomed "to the idea that when you're talking about rheumatoid arthritis, maybe osteoarthritis, that there is enough individuality of response that almost any number of drugs is worthwhile and almost any drug, almost no matter what its side effects, is acceptable as a last resort kind of agent." He added: "I guess I don't know how far one could push that, but there's a strong feeling that people respond individually to drugs." Temple said "its very important to try to figure out whether" there is a real patient population that would benefit from suprofen use. Ellis stated that use of Suprol "has dropped off dramatically" since McNeil sent out its third "Dear Doctor" letter in October, updating physicians about adverse reactions and pointing out labeling changes that limit use of suprofen to second line therapy. "One could argue that the risk/benefit ratio has come into line in light of that and that [Suprol] is being reserved for people who are not getting a response on any other drug," Ellis said. "From there you could argue that this risk might be quite acceptable." Describing the company's understanding of the pathophysiology of the flank pain syndrome, Ellis said. "We believe that suprofen causes an increase in urinary uric acid excretion and a decrease in urine flow. . . . The result of this is an increase in urine uric acid concentration which is very pH dependent." She explained that "in the presence of a low pH, it is very possible that uric acid crystals could form; and, if this occurs in a massive amount, there is plugging of the tubular with crystals" which results in pain as well as changes in renal function. Ellis added that the syndrome "will resolve spontaneously as the urine pH changes during the course of the day." Ellis maintained that patient variables such as the degree of hydration and serum uric acid levels will influence the flank pain reaction. Drug variables such as the degree of uricosuria and use pattern are also factors in the reaction, Ellis said. FDAer John Harter, MD, provided the committee with a handout listing 55 flank pain adverse reactions that have occurred with other NSAIDs. He explained that the data includes adverse reactions reported to FDA within the first three years of a drug's initial marketing. The list does not include indomethacin or phenylbutazone since the drugs were approved more than four years before FDA's system was implemented. McNeil's withdrawn Zomax (zomepirac) had 25 reported cases of flank pain, according to Harter's printout. That put Zomax second after suprofen in terms of adverse reactions. There were three cases with ibuprofen, two with piroxicam, one with meclomen and one with diflunazol. As of the end of November, FDA had received 301 reports of flank pain from suprofen use. The committee also discussed the possibility of residual effects from suprofen use. Temple stated that "we can't, with the available data and available follow-up, guarantee that there's no long-term residual effects." Temple said "what you can say is that so far" renal function returns to the way it was before a patient was treated with suprofen. He asked rhetorically: "Does that preclude a long-term effect of a subtle nature? Of course not. We can't know that." McNeil said it is conducting a case control study consisting of patient questionaires sent to physicians. Ellis said the company has received half of the questionaires and that data could be compiled by the first quarter of 1987. She commented that so far, the information suggests that drinking or vigorous exercise the day or evening before an episode of flank pain may be factors in occurrence of the reaction. Committee member Marlene Egger, PhD, University of Utah, suggested that a patient insert be developed to extend information to the patient and increase cooperation in follow-up. Temple said the agency "will certainly explore" the suggestion. Harter noted that FDA initially suggested a patient information sheet and that McNeil had chosen a sticker to go on each bottle of the drug as an alternative. The sticker advises patients to drink two glasses of fluid with the medication and to stop taking the drug if low back pain occurs.
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