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Important Safety Information on Nefazodone HCI: Severe and Serious Hepatic Events

Date: 2001-06-28

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IMPORTANT DRUG SAFETY INFORMATION

June 28, 2001

IMPORTANT SAFETY INFORMATION ON NEFAZODONE HCI: SEVERE AND SERIOUS HEPATIC EVENTS

Dear Health Care Professional,

Apotex Inc. would like to advise you of very rare reports of severe liver injury temporally associated with the use of the antidepressant, nefazodone HCl. Nefazodone, sold by Apotex Inc. under the tradename, Apo-Nefazodone, is indicated for the symptomatic relief of depressive illness.

Nefazodone has been evaluated in more than 8000 clinical trial subjects and has been used by approximately 8.3 million patients worldwide since its market introduction in 1994. Worldwide post-marketing safety experience has resulted in the identification of 109 serious (requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, is life-threatening or results in death) hepatic adverse events in temporal association with nefazodone. These include 23 cases of liver failure worldwide of which 16 led to transplantation and/or death. Among an estimated 650,000 patients treated with nefazodone in Canada, four cases of liver failure have been reported of which two required liver transplantation. Nefazodone has also been temporally associated with hepatic adverse events such as jaundice, hepatitis and hepatocellular necrosis in patients receiving therapeutic doses. Reporting rates determined on the basis of spontaneously reported post-marketing adverse events are generally presumed to underestimate the risks associated with drug treatments.

Although some of the reported cases of severe hepatic injury have confounding factors such as concomitant medications, alcohol, or the presence of underlying disease, a possible causal role for nefazodone cannot be excluded. Among the cases of liver failure, two-thirds had the onset of symptoms within the first 4 months of initiation of treatment. Cases of liver injury have occurred as early as a few weeks after initiation of therapy or after continuous use for up to 1-2 years.

Clinical manifestations of severe hepatic injury in patients have included the following: anorexia, fatigue, asthenia, malaise, abdominal pain, nausea, vomiting, discoloured stools, dark urine, prolonged coagulation, weight loss, jaundice, ascites, confusion, asterixis, encephalopathy, and hepatic coma. Laboratory evidence of hepatotoxicity has included increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, -glutamyl transpeptidase (GGT), and bilirubin, as well as increased prothrombin times.

Prior to prescribing nefazodone, physicians should counsel their patients to be alert to the premonitory signs and symptoms listed above and to seek emergency medical attention if these develop. The appearance of signs and symptoms of hepatotoxicity, or the development of abnormal aminotransferase and/or bilirubin levels while on treatment is an indication for immediate termination of nefazodone treatment and close monitoring of the patient. In most cases, discontinuation of nefazodone has been associated with recovery, while in rare cases hepatic dysfunction has progressed to liver failure and, even less frequently, death, in spite of discontinuation of the drug. The occurrence of liver injury can be fatal even if properly recognized and managed.

Health care professionals are also reminded that nefazodone is a potent inhibitor of the hepatic drug metabolizing enzyme, CYP3A4, and has the potential to decrease the metabolism of many concomitantly administered drugs and other xenobiotics, potentially increasing the toxicity of these agents.

Apotex Inc. continues to work actively with Health Canada to monitor adverse event reports and to ensure that up-to-date information regarding the use of nefazodone is available. Revisions to the existing product monograph with respect to serious liver injury have been requested by Health Canada. Copies of the current product monograph for Apo-Nefazodone are available on request from Apotex Inc. Health Care Professionals will be advised of the revisions as soon as possible.

The identification, characterization, and management of drug-related adverse events are dependent on the active participation of healthcare professionals in adverse drug reaction reporting programmes. Any occurrences of hepatic injury or other serious and/or unexpected adverse events should be reported to the Medical Information Division of Apotex Inc. at 1-800-667-4708 or by fax at 416-401-3807, and to the Bureau of Licensed Product Assessment, Health Canada (see below).

Your professional commitment in this regard has an important role in protecting the well-being of your patients by contributing to early signal detection and informed drug use.

Yours sincerely,

original signed by

John Hems
Director, Regulatory Affairs Apotex Inc.

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