Do Not Use! Life-threatening Liver Toxicity with the Antidepressant Nefazadone (SERZONE)

The Food and Drug Administration (FDA) informed pharmaceutical giant Bristol-Myers Squibb Co. on December 10, 2001 that it must add a black box warning to the professional product label, or “package insert,” for the antidepressant nefazodone (SERZONE), informing doctors and pharmacists that life-threatening liver damage can occur with this drug. A black box warning is the strongest type of warning that the FDA can require on a drug’s label. This action follows a warning issued by Canadian government authorities earlier this summer.

The risk of liver failure with nefazodone use appears to be about three to four times the estimated background rate of liver disease, which is likely an underestimate because of the extent of under-reporting of adverse drug reactions. The FDA estimates that only 1 in 10 serious reactions are ever reported to the agency. Therefore, the true rate of liver failure with this drug is probably considerably greater.

Nefazodone was cleared for marketing in December 1994. In 2000, there were over 4.5 million nefazodone prescriptions dispensed in the U.S.

A July 2000 change in nefazodone’s professional product labeling was buried in this fine print reference to the drug’s association with liver toxicity: “Rare reports of liver necrosis [liver cell death] and liver failure, in some cases leading to liver transplantation and/or death.”

Liver failure resulting in death or liver transplant occurred from two weeks to six months after starting nefazodone. Some reports described patients experiencing early, non-specific symptoms of liver toxicity such as loss of appetite, malaise, and gastrointestinal symptoms. However, other reports did not indicate that patients had experienced the early symptoms of toxicity.

The full text of the new boxed warning follows:

WARNING
Cases of life-threatening hepatic failure have been reported in patients treated with SERZONE. The reported rate in the United States is about 1 case of liver failure resulting in death or transplant per 250,000—300,000 patient-years of SERZONE treatment. The total patient-years is a summation of each patient’s duration of exposure expressed in years. For example, one patient-year is equal to two patients each treated for six months, three patients each treated for four months, etc.

Ordinarily, treatment with SERZONE should not be initiated in individuals with active liver disease or with elevated baseline serum transaminases. There is no evidence that pre-existing liver disease increases the likelihood of developing liver failure, however, baseline abnormalities can complicate patient monitoring.

Patients should be advised to be alert for signs and symptoms of liver dysfunction (jaundice, anorexia, gastrointestinal complaints, malaise, etc.) and to report them to their doctor immediately if they occur.

SERZONE should be discontinued if clinical signs or symptoms suggest liver failure. Patients who develop evidence of hepatocellular injury such as increased serum AST or serum ALT levels three times the upper limit of NORMAL, while on SERZONE should be withdrawn from the drug. These patients should be presumed to be at increased risk for liver injury if SERZONE is reintroduced. Accordingly, such patients should not be considered for re-treatment.

Nefazodone’s new labeling also contains a chilling statement about using blood tests to monitor for liver toxicity by measuring the levels of liver enzymes: “Periodic serum transaminase [liver enzymes] testing has not been proven to prevent serious injury but it is generally believed that early detection of drug-induced hepatic injury along with immediate withdrawal of the suspect drug enhances the likelihood for recovery.”

There are currently two dozen antidepressants, in at least four pharmacologic classes, available on the market in the U.S. Not one of these drugs has been shown to be superior to another in the treatment of depression in controlled clinical trials. The best way to differentiate one from another, as is the case with most families of drugs which have similar efficacy, is on the basis of their known toxicities. Clearly, nefazodone possesses a known significant toxicity, the possibility of liver failure and death.

What You Can Do

If you have never before been treated with an antidepressant, there is no medical reason why you should be started on nefazodone.

If you are currently taking nefazodone, discuss with your doctor switching to one of the numerous other, safer antidepressant drugs on the market.