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BOEHRINGER MANNHEIM DIURETIC DEMADEX APPROVED AUG. 23 FOR HYPERTENSION AND EDEMA, FIRM’s FIRST NDA; TORSEMIDE WILL BE FOURTH LOOP DIURETIC ON U.S. MARKET

Executive Summary

Boehringer Mannheim's diuretic Demadex (torsemide) was approved by FDA Aug. 23 for treatment of hypertension and edema associated with congestive heart failure, hepatic disease and renal disease. Demadex is the first NDA approval for Rockville, Md.-based Boehringer Mannheim Pharmaceuticals Corp. The drug was designated "1S" by FDA, indicating a new molecular entity given a standard, non-priority review. Launch is awaiting FDA clearance of promotional materials and inventory build-up, the firm indicated. Torsemide will be the fourth loop diuretic on the market. Its three predecessors, ethacrynic acid (Merck's Edecrin), furosemide (Hoechst's Lasix) and bumetanide (Roche's Bumex), are all off- patent. Lasix is indicated for the same conditions as Demadex, while Bumex and Edecrin are not indicated for hypertension. Boehringer Mannheim, however, expects that the primary market for Demadex will be for edema, where it will compete mainly against furosemide and bumetanide. Separate NDAs for Demadex tablets (20-136) and injection ampuls (20-137) were filed Feb. 28, 1991. Torsemide, formerly tradenamed Presaril, had been "approvable" since June 7 ("The Pink Sheet" July 12, T&G-14). FDA's Cardiovascular & Renal Drugs Advisory Committee recommended torsemide for approval in April 1992 but did not recommend the drug's use in treating edema associated with renal disease ("The Pink Sheet" May 4, 1992, p. 7). The committee's recommendation against the renal disease indication resulted from its discomfort with a lack of long-term data for the use of diuretics in that condition, Boehringer Mannheim noted. Demadex labeling states that "chronic use of any diuretic in renal or hepatic disease has not been studied in adequate and well-controlled trials." Demadex labeling does not include a boldface warning carried by other loop diuretics against the possibility of electrolyte depletion. Boehringer Mannheim, however, has been told by FDA not to make a comparative claim based on that difference. "The effect of Demadex on serum lipids and electrolytes might appear, from the labeling, to be less than that of existing diuretics," FDA's approval letter states. "As you discussed with [Cardiovascular and Renal Drug Products Division Director] Raymond Lipicky, these differences are probably attributed to the fact that equi-effective doses have not been compared. We therefore expect that your promotional materials for Demadex will make no explicit or implicit suggestion of superiority of your drug with respect to these effects," FDA said. Lasix, Bumex and Edecrin labeling carries boldface warnings stating that they are "potent" diuretics "which, if given in excessive amounts, can lead to a profound diuresis with water and electrolyte depletion." Demadex labeling does not warn that "patientss receiving diuretics should be observed for clinical evidence of electrolyte imbalance, hypovolemia, or prerenal azotemia." The label adds that "in patients with congestive heart failure, hepatic cirrhosis, or renal disease treated with Demadex (torsemide) at doses higher than those studied in U.S. antihypertensive trials, hypokalemia was observed with great frequency, in a dose-related manner." Demadex labeling also warns against loop diuretic-associated tinnitus and hearing loss that has "been observed after oral Demadex," although "it is not certain that these events were attributable to Demadex." Torsemide is contraindicated in patients who are anuric. Demadex, like Edecrin, is pregnancy category B while other loop diuretics are category C. Boehringer Mannheim licensed worldwide rights to torsemide from the Belgian firm A. C. Christiaens. Burroughs Wellcome will manufacture the drug in the U.S. in scored tablets of 5, 10, 20 and 100 mg and 10 mg/ml vials of 2 ml and 5 ml. Boehringer Mannheim has a presence in the cardiovascular market through a copromotion of Wyeth-Ayerst's vasodilator Ismo. The firm's 230-person sales force also copromotes Hoechst's Diabeta and markets an acetaminophen/hydrocodone combination Anexsia.

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