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IBUPROFEN CAN CAUSE "ACUTE RENAL DETERIORATION"

Executive Summary

IBUPROFEN CAN CAUSE "ACUTE RENAL DETERIORATION" in people with asymptomatic, mild chronic kidney disease, according to a Johns Hopkins University study of just 12 women published in the April 15 issue of the Annals of Internal Medicine. The prospectively randomized, triple-crossover study evaluated the effects of three chemically distinct nonsteroidal anti-inflammatory drugs (NSAIDs) -- ibuprofen, sulindac and piroxicam -- on renal function in the female patients with serum creatinine levels between 130 and 270 mumol/L (1.5 and 3.0 mg/dL). Ten of the women (mean age, 58) had "underlying rheumatologic disease," or arthritis, "that was sufficiently stable to withstand a washout period without NSAID therapy," state authors Andre Whelton, MD, et al. There was at least a one-month interval between the treatment periods. After eight days of 800 mg ibuprofen three times a day, serum creatinine levels in two patients rose from 194 at baseline to 336 and 354 mumol/L, and the patients were withdrawn from therapy. A third patient developed hyperkalemia (from a baseline serum potassium level of 4.5 to 6.3 mumol/L). However, following cessation of ibuprofen, serum creatinine levles "decreased and approached baseline values by day 12," the study states. The remaining nine women showed changes in kidney function but did not experience kidney failure, defined as an increase in serum creatinine of 130/mumol/L or more, or a serum potassium value in excess of 6 mumol/L. In contrast, "all patients tolerated the 11-day course of both piroxicam and sulindac without interruption," the authors note. Whelton, et al., conclude that "inhibition of renal prostaglandin synthesis by ibuprofen is the probable explanation for the development of acute renal deterioration in our study." They also note that the patients "who ultimately developed renal dysfunction" had lower baseline levels of prostaglandin concentration than other patients, possibly putting them at "increased risk of acute renal failure because of a diminished capacity to compensate for any further reduction of prostaglandins caused by NSAID therapy." When the three patients who initially were withdrawn from ibuprofen therapy were rechallenged at a dose of 400 mg three times daily, "changes in renal function variables were less marked," the authors note. Drug therapy was "discontinued on day eight in two patients" when serum creatinine levels increased from 194 at baseline to 274 mumol/L in one patient, and 256 mumol/L in another. As before, after withdrawal of ibuprofen, serum creatinine levels returned to baseline levels. Noting that "patients with previously undiagnosed mild renal impairment may consume therapeutic doses of ibuprofen without supervision," the authors comment that "the non-prescription status of ibuprofen is of special concern." They warn that "in the setting of mild renal impairment, it is conceivable that clinically relevant renal impairment may result." Ibuprofen was approved for sale as a non-prescription drug in 1985. It reportedly accounts for about 20% of the annual $2.5 bil. in over-the-counter sales of pain relievers. Regarding piroxicam and sulindac, the Johns Hopkins researchers state that "additional studies are needed to assess [their] risk in patients with more pronounced renal impairment and in patients receiving longer courses of therapy, which, according to our data, may result in drug accumulation." In an editorial appearing in the same issue, Michael Murray, MD, Purdue University, and D. Craig Brater, MD, Indiana University, called for warning labels on ibuprofen to be more explicit, echoing the recommendation of the National Kidney Foundation. FDA should urge consumers "with any serious condition" to confer with their physicians before using ibuprofen, the physicians said. In June, FDA plans to ask ibuprofen manufacturers to "highlight" the statement: "If you experience any symptoms which are unrelated to the condition for which you took ibuprofen, consult a doctor before taking any more of it." Whitehall Labs (Advil) responded to the study by pointing out that "the 12 women in this study were patients identified with serious medical conditions, and all had chronic renal failure for at least two months prior to study admission." Consequently, the company said: "We do not believe the findings of this study apply to the safety of nonprescription ibuprofen in the general population." Whitehall stressed that "the renal concern being addressed is a very rare event [and that] very few reports of these reactions have been reported to the company or to the FDA despite a climate of careful review of this condition by medical specialists."
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