Bristol-Myers Squibb (BMS) announced that this month it would stop manufacturing and shipping its Serzone brand of the combined serotonin-norepinephrine reuptake inhibitor and 5-HT2 antagonist nefazodone. The announcement brings to a close a rocky nine-and-a-half-year run for the antidepressant, which has been tied to serious adverse effects on the liver and played a part in documented medication errors, due to name confusion.
BMS cited financial and business concerns for the decision, noting declining sales since the introduction of generic formulations in September 2003. However, most industry analysts said the company pulled the drug in the face of numerous lawsuits and increasing pressure from regulators to remove the product voluntarily rather than being ordered to do so. With a voluntary removal, BMS is protected from the impact of an official FDA determination that the drug was removed from the market for safety reasons. Such a determination could have seriously damaged the company's position in legal proceedings.
Generic formulations of nefazodone are available from nine manufacturers, and at press time there was no immediate indication of any similar action by any of the nine companies.
Approved by the FDA in December 1994, nefazodone soon became associated with severe and possibly irreversible liver failure, leading to the necessity of a liver transplant and/or death. By early 2002 the FDA had told BMS to add a black-box warning to nefazodone's label and produce a new patient-information packet to be dispensed with each prescription. At that time, the FDA based its order on postmarketing experience of prescriptions to more than 7 million patients and cited a “rate of 3-4 times the estimated background rate of liver failure” (Psychiatric News, February 1, 2002). Generic nefazodone also carries the warning.
A year later, in January 2003, BMS voluntarily removed Serzone from the European market after regulators there expressed concern over the liver effects. In May 2003 the FDA requested a label change warning prescribers of 23 medication-error reports in which Serzone had been confused with AstraZeneca's second-generation antipsychotic Seroquel.
Then, on November 27, 2003, Health Canada ordered the product removed from the Canadian market, citing “51 cases of serious liver damage, including cirrhosis leading to transplant and death.” That left the drug on the market only in the United States, Australia, and New Zealand. (BMS announced the simultaneous withdrawal of the product from those markets as well.)
Last year the consumer advocacy group Public Citizen sued the FDA, seeking to force the agency to remove Serzone and generic equivalents for safety reasons. That suit will continue, Public Citizen said, to force the removal of all nefazodone products from the market.
To date the FDA's Adverse Events Reporting System has received at least 55 reports of fulminant liver failure tied to the drug, including 20 deaths. In addition, another 39 cases of less-severe liver injury have been reported.▪
