Alosetron Withdrawn after Linkage to Ischemic Colitis
By William T. Elliott, MD, FACP
Glaxo Wellcome is withdrawing alosetron (lotronex) from the u.s. market after less than a year of availability. The drug, which was approved for the treatment of women with diarrhea predominant irritable bowel syndrome, was linked to the development of ischemic colitis. Five deaths have been attributed to alosetron use. The company plans to distribute a "Dear Doctor" letter to all physicians apprising them of the discontinuation of the product and encouraging them to switch patients to alternative therapies. Meanwhile, Novartis is proceeding with plans to launch their own drug for irritable bowel syndrome. Tegaserod (Zelmac) will be targeted at patients with constipation predominant irritable bowel syndrome, and company officials stress that it is a "completely different" drug than alosetron.
COX-2 inhibitors have been associated with a lower rate of endoscopically seen gastric and duodenal ulcers compared to traditional NSAIDs. A new study shows that this translates into clinically relevant outcomes. More than 300 centers and more than 8000 patients older than the age of 50 with rheumatoid arthritis (RA) were randomized to receive naproxen 500 mg twice a day (a traditional NSAID) or refocoxib (Vioxx) 50 mg daily (a COX-2 inhibitor). The primary end point was confirmed clinical upper gastrointestinal events (gastroduodenal perforation or obstruction, upper gastrointestinal bleeding, and symptomatic gastroduodenal ulcers). Both drugs were effective agents for treating RA. During the mean follow-up of nine months, patients taking naproxen were more than twice as likely to develop a gastrointestinal event (4.5/100 patient-years with naproxen vs 2.1/100 patient-years for refocoxib—relative risk, 0.5; 95% confidence interval, 0.3 to 0.6; P < 0.001). COX-2 inhibitors have minimal effect on platelet function, and it is interesting that the rate of myocardial infarction was significantly lower in the naproxen group (N Engl J Med 2000;343:1520-1528).
Mifepristone (also known as RU-487) will start shipping to doctors’ offices in early December. The drug was approved in September after years of evaluation and legal wrangling, but it has taken the manufacturer several months to work out issues regarding distribution. Mifepristone will not be available in pharmacies, rather the FDA has decided that it will only be available in physician’s offices, and only physicians who meet certain requirements will be able to dispense it. Those requirements include ability to accurately assess gestational age and availability of surgical abortion or other emergency intervention. Large HMOs as well as small physician’s offices are trying to work out the details of this unusual distribution and dispensing program.
Activated protein C is a new sepsis treatment under investigation by Eli Lilly. The drug, which is an endogenous anticoagulant, treats the coagulation response to sepsis rather than targeting the bacteria that cause the disease. A recent study using the new agent was halted when a clear reduction in 28-day all-cause mortality was seen. Mortality in sepsis is the result of inflammation and coagulation. Until now, most nonantibiotic therapies for sepsis have targeted inflammation. Activated protein C is the first agent to effectively combat the pathologic coagulation cascade in sepsis, and the results are promising. Lilly is planning to publish their data on the drug in February 2001, and will petition the FDA for approval soon after. A trade name has already been picked for the agent—Zovant.
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