Important Safety Information - Nefazodone - Bristol-Myers Squibb & Linson
Pharama Inc.
Therapeutic Products Directorate (TPD) and Biologic and
Genetic Therapies Directorate (BGTD) posts safety alerts, public health
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This is duplicated text of a letter from Bristol-Myers Squibb Canada
Inc and Linson Pharama Inc.
Contact the company for a copy of any references, attachments or enclosures.
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Bristol-Myers Squibb Canada Inc.
Linson Pharama Inc.
IMPORTANT
SAFETY INFORMATION
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Important Safety Information
on NEFAZODONE HCL: Severe and Serious Hepatic Events
June 20, 2001
Dear Health Care Professional,
Bristol-Myers Squibb Canada Inc. and Linson Pharma Inc. would like to
advise you of very rare reports of severe liver injury temporally associated
with the use of the antidepressant nefazodone HCl sold by Bristol-Myers
Squibb under the tradename Serzone-5HT2 and by Linson under
the tradename LinNefazodone. 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.
Bristol-Myers Squibb and Linson Pharma continue 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 monographs with respect to serious liver injury have
been requested by Health Canada. Copies of the current product monographs
are available on request from Bristol-Myers Squibb (Serzone-5HT2) or Linson
(LinNefazodone). 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 Bristol-Myers Squibb (Serzone-5HT2) at 1-800-267-1088 Ext.
2293 or by fax at 1-888-267-6211, or to Linson (LinNefazodone) at 1-866-554-6766
or by fax at 1-514-333-4206.
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
Vicky Esposito
Senior Director
Regulatory Affairs and Quality Assurance
Bristol-Myers Squibb Canada Inc.
original signed by
Laura King
Associate Director
Regulatory Affairs
Linson Pharma Inc.
Any suspected adverse drug reactions can also be reported to:
Canadian Adverse Drug Reaction Monitoring Program (CADRMP)
Bureau of Licensed Product Assessment
Therapeutic Products Directorate
HEALTH CANADA
Address Locator: 0201C2
OTTAWA, Ontario, K1A 1B9
Tel: (613) 957-0337 or Fax: (613) 957-0335
cadrmp@hc-sc.gc.ca
The ADR Reporting Form can be found in
The Canadian Compendium of Pharmaceuticals and Specialties,
or on the TPD website, along with the ADR
Guidelines
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