Serzone

Serzone Facts
Serzone is an anti-depressant. It is often used to treat a specific form of depression. Unfortunately Serzone has been linked to liver failure. According to the manufacturer the rate of liver failure associated with Serzone use is about 3-4 times than greater than non-users.

Bristol-Myers Squibb Co. the maker of Serzone issued a manufacturer's warning on January 9, 2002, telling health care providers that "cases of life-threatening hepatic failure have been reported in patients treated with SERZONE." The warning suggests that numerous patients have experienced or will suffer liver failure.

U.S. psychiatrists first became concerned about the Serzone causing liver failure after the Canadian government issued a warning about the drug in the summer of 2001.

The U.S. FDA told Bristol-Myers Squibb Co. that it must include a "Black Box" warning on all Serzone labels on December 7, 2001.

Such a warning is designed to inform patients about life-threatening liver damage that can occur when using Serzone. The FDA required the warning to advise that patients could suffer from liver failure, leading to death or the need for a liver transplant. A Black Box warning is the strongest type of warning and is designed to let physicians and patients know of serious side effects associated with a particular drug. In addition to warning labels, Serzone patients will also be provided with patient insert warnings. Bristol-Myers Squibb has also been ordered to issue a letter to doctors warning about potential liver failure.

FDA tells Bristol-Myers to add black box Serzone warning--December, 2001
The US Food and Drug Administration has told drug maker Bristol-Myers Squibb Co. that it must include a black-box warning on its label for the antidepressant Serzone (nefazodone) telling patients that life-threatening liver damage can occur when using the drug.

The FDA estimated the reported rate in this country is about one case of liver failure for every 250,000 to 300,000 patients using the drug for one year.

The language the FDA will require on Serzone package labels will include warnings that "cases of life-threatening hepatic failure have been reported in patients treated with Serzone".

The black-box designation refers to a black outline surrounding a section of the label and of the Physicians' Desk Reference, reserved for only the most serious side effects. When doctors see this warning they will not use the drug unless it is a last resort for life threatening cases.

Serzone does about $400 million in annual sales. A black-box warning will seriously decrease the sales of Serzone.

Below is the black box warning.

Letter to Doctors
The FDA ordered Bristal-Meyers Squibb to send a drug warning letter to all doctors about the danger of liver failure when using Serzone in addition to adding the black-box warning to the label and revising the patient information label.

Below is a reprint of the letter issued by Bristal-Meyers Squibb:

IMPORTANT DRUG WARNING INCLUDING BLACK BOX INFORMATION

Dear Healthcare Practitioner:

We have updated the prescribing information for Serzone to warn of rare cases of liver failure leading to transplant and/or death in patients receiving nefazodone HCL. This

information is based on post marketing experience in more than 7.2 million patients in the United States.

The following black box WARNING has been added to the Serzone prescribing information:

Cases of life-threatening hepatic failure have been reported in patients treated with SERZONE.

The reported rate in the United States is about I 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, 1 patient-year is equal to 2 patients each treated for 6 months, 3 patients each treated for 4 months, etc. (See WARNINGS).

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 (see PRECAUTIONS: Information for Patients). Patients who develop evidence of hepatocellular injury such as increased serum AST or serum ALT levels plus or minus 3 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.

Additional details of the risk of liver failure associated with Serzone are included in a bolded statement in the WARNINGS section:

The reported rate in the United States is about I case of liver failure resulting in death or transplant per 250,000 300,000 patient-years of SERZONE treatment This represents a rate of about 3-4 times the estimated background rate of liver failure. This rate is an underestimate because of under reporting, and the true risk could be considerably greater than this. A large cohort study of antidepressant users found no cases of liver failure leading to death or transplant among SERZONE users in about 30,000 patient-years of exposure. The spontaneous report data and the cohort study results provide estimates of the upper and lower limits of the risk of liver failure in nefazodone treated patients, but are not capable of providing a precise risk estimate.

The time to liver injury for the reported liver failure cases resulting in death or transplant generally ranged from 2 weeks to 6 months on SERZONE therapy. Although some reports described dark urine and nonspecific prodromal symptoms (e.g., anorexia, malaise, and gastrointestinal symptoms), other reports did not describe the onset of clear prodromal symptoms prior to the onset of jaundice.

The physician may consider the value of liver function testing. Periodic serum transaminase 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.

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. Ongoing clinical assessment of patients should govern physician interventions, including diagnostic evaluations and treatment.

SERZONE should be discontinued if clinical signs or symptoms suggest liver failure (see PRECAUTIONS-information for Patients). Patients who develop evidence of hepatocellular injury such as increased serum AST or serum ALT levels - 3 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.

Because it is difficult to monitor for changes in liver function in patients whose liver function is already abnormal, we have added a statement in CONTRAINDICATIONS:

SERZONE tablets are contraindicated in patients who were withdrawn from SERZONE because of evidence of liver injury (see Boxed Warning).

In view of the above changes to the SERZONE labeling, the "Information for Patients" section of the PRECAUTIONS has been expanded to warn patients of the potential risk of hepatotoxicity associated with SERZONE therapy:

Hepatotoxicity

Patients should be informed that SERZONE therapy has been associated with liver abnormalities ranging from asymptornatic reversible serum transaminase increases to cases of liver failure resulting in transplant and/or death. At present, there is no way to predict who is likely to develop liver failure. Ordinarily, patients with active liver disease should not be treated with SERZONE. Patients should be advised to be alert for signs of liver dysfunction Jaundice, anorexia, gastrointestinal complaints, malaise, etc.) and to report them to their doctor immediately if they occur.

Changes consistent with these WARNINGS have been included in a Patient Package Insert that will be provided with the product packaging. For detailed information on approved indications and additional safety information please refer to the SERZONE package insert. A full copy of the current SERZONE Package insert is enclosed.

Sincerely
Darlene M. Jody, M.D.
Vice President, Medical Marketing
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