The maker of the abortion drug mifepristone has again announced it is adding to the warnings section of the product's package insert—less than a year after a previous revision—to include information on four deaths that have occurred in women using the drug.
The previous revision warned that cases of sepsis associated with mifepristone use have been reported. Sepsis was the cause of death in all four cases that prompted the latest revision, according to a public health advisory issued by the Food and Drug Administration last month.
In two of the cases, the organism involved was Clostridium sordellii, known to colonize the intestinal tract and rectal area, but rarely to cause infection, although it can cause surgical and postpartum infections and has caused infections in patients receiving tissue transplants.
The same organism was involved in a fifth death that occurred in Canada during a clinical trial of mifepristone (Mifeprex) conducted in 2001.
The organism involved in the other two fatal cases that have occurred in the United States since the approval of the drug has not been identified.
All four fatal cases in the United States have occurred in California—two in 2003, one in 2004, and one in 2005.
The two important features common to all the deaths, which are noted in the new warnings, are that the women used the regimen of mifepristone followed by vaginal misoprostol, rather than the FDA-approved regimen of mifepristone followed by oral misoprostol. In addition, the women did not have the typical clinical appearance of sepsis when they presented for medical attention in that they did not have fevers.
The new warning advises physicians to tell patients to see a doctor if they develop diarrhea, nausea, and/or vomiting, with or without abdominal pain in the days after taking mifepristone.
Physicians are being asked to suspect sepsis in those patients. Signs include a rapid pulse, low blood pressure, a significant leucocytosis, and hemoconcentration.
Nothing else is really known about the cases, and the company is continuing to investigate with the help of government agencies, Cynthia Summers, Dr.P.H., director of marketing and public affairs for the manufacturer, Danco Laboratories, told this newspaper.
According to Danco Laboratories, mifepristone has now been prescribed more than 460,000 times in the United States since its approval in 2000. That makes the rate of fatal sepsis lower than 1 in 100,000.
“There are no alarm bells going off because of this rate. But we are watching very closely,” Steven Galston, acting director of the FDA's Center for Drug Evaluation and Research, said at a press conference announcing the new warnings.
The news about these cases is important, particularly for emergency department physicians, but it is not likely to change practice, Philip D. Darney, M.D., chief of obstetrics and gynecology at San Francisco General Hospital, said during an interview.
He noted that although FDA approved the regimen that involves oral misoprostol, the regimen with intravaginal misoprostol actually has much more clinical trial data behind it. None of that data has suggested any kind of safety problem.
“I think it is very unlikely that intravaginal use has anything to do with the infections,” he said.
David A. Grimes, M.D., who recently wrote an editorial about the safety of mifepristone and medical abortion (Contraception 2005;71:161), said in an interview that the labeling change has not altered his opinion that medical abortion is extremely safe.
Danco Laboratories' response to the cases has been “responsible and scientifically appropriate,” but there are no details to specifically implicate either mifepristone or intravaginal use of misoprostol at this point, noted Dr. Grimes, who is vice president for biomedical affairs at Family Health International Research, Triangle Park, N.C.
The FDA said it is not advising that physicians prescribe prophylactic antibiotics with mifepristone because the risk of sepsis does not appear to offset the risks of prophylaxis and because it is not known what antibiotic regimen might be effective.
However, patients in whom an infection is suspected should be treated immediately with antibiotics that include coverage of anaerobic bacteria such as Clostridium sordellii.
The FDA's public health advisory on sepsis and medical abortion can be found at www.fda.gov/cder/drug/advisory/mifeprex.htm.
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