WHO Pharmaceuticals Newsletter 2003, No. 01
(2003; 12 pages) View the PDF document
Table of Contents
Open this folder and view contentsREGULATORY MATTERS
Open this folder and view contentsSAFETY OF MEDICINES
View the documentNEFAZODONE
Open this folder and view contentsFEATURE


Nefazodone (Serzone, Serzonil, Nefadar, Dutonin, Rulivan) is an antidepressant with a structure and mechanism of action distinct from that of selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants. The product has been marketed worldwide since 1994. An estimated 11 million people have been prescribed this drug so far.

As with many other newer antidepressants, hepatobiliary adverse reactions have been associated with nefazodone usage. In its September 2000 meeting the Medicines Adverse Reactions Committee (MARC) in New Zealand noted that a rate of hepatic reactions of 3.9/1000 had been recorded for nefazodone with the New Zealand Intensive Medicines Monitoring Programme (IMMP). At that time 235 reports of nefazodone-associated hepatic reactions had been filed with the WHO database for adverse drug reactions. Based on this MARC recommended asking the sponsor company to update the data sheet by dropping the comment that a causal association between nefazodone and increased liver enzymes and hepatitis had not been established(1).

From the time the drug was introduced in Canada (1994) to July 24, 2002 a total of 123 reports of nefazodone-related adverse biliary reactions were registered with Health Canada. Health Canada, in July 2001, issued a public advisory related to the risk of severe liver injury associated with the use of nefazodone. It also directed the manufacturers of various nefazodone preparations (Serzone-5HT2, Lin-Nefazodone and Apo-Nefazodone) to issue letters to health professionals recommending that patients be counselled about the risk of hepatotoxic effects before the initiation of nefazodone therapy and that close monitoring be undertaken should signs of hepatotoxiciy or abnormal liver aminotransferase or bilirubin levels develop during treatment(2,3).

Nefazodone was registered in Sweden in 1995(4), and was later taken off the market in 2002 when the company (Bristol-Myers Squibb, BMS) voluntarily withdrew the product from Sweden amidst concerns of hepatic adverse reactions. The Netherlands Medicine Assessments Board announced in November 2002 that it would investigate nefazodone (Dutonin) and hepatic effects reported with the drug. Shortly after, in a December 2002 letter to the Dutch Medicines Evaluation Board (CBG), BMS announced that it would voluntarily stop selling nefazodone in Netherlands after April 2003; the company also planned to notify Danish authorities of a similar withdrawal in Denmark in the near future. More recently, on 8 January 2003, the company announced its plan to stop selling nefazodone in all European countries while continuing to market it outside of Europe(5). According to a company spokesperson, commercial reasons were behind this move. Following the company’s decision and based on the outcome of a benefit-risk assessment, the Spanish Medicines Agency endorsed the voluntary suspension in Spain. The Agency held that the risk of hepatotoxicity outweighed the possible therapeutic advantages of nefazodone over other available antidepressants. Prescribers have been directed not to start new patients on nefazodone and to prescribe alternative treatments to those currently on nefazodone(6).

In the USA, through spontaneous reporting via MedWatch, 109 cases of serious liver injuries linked with nefazodone (Serzone) have been reported. In at least 23 cases nefazodone (Serzone) users experienced liver failure and 16 underwent a liver transplant and/or died. FDA estimates that the reported rate of liver failure in patients who used nefazodone (Serzone) for at least one year is about one case in every 250,000 to 300,000, with liver failure usually occurring in the first two weeks to 6 months of starting therapy. BMS, under advice from FDA, has introduced a black box warning to nefazodone prescribing information, warning about reports of hepatic failure with the drug, the need to be vigilant to these effects etc(7).

In addition to reports of hepatotoxicity, post-marketing reports of priapism, frequent hypotension (though not severe) and occasional episodes of frank syncope have been recorded with nefazodone. Drug interactions are important considerations as well. Nefazodone is metabolized by (and is an inhibitor of) the CYP4503A4 enzyme. Thus, other drugs that inhibit CYP4503A4 (ketoconazole, erythromycin, and itraconazole) may delay nefazodone clearance. In contrast, drugs such as carbamazepine and rifampin may increase nefazodone clearance by inducing CYP4503A4. Nefazodone is contraindicated in patients taking astemizole, terfenadine or cisapride(8).

To date there are 449 reports of nefazodone-related hepatic reactions in the WHO ADR-database. The bulk of the ADR data on nefazodone (as with most drugs) comes from spontaneous reporting, a system that is inherently limited by, among other factors, a tendency to underreport. To that extent, this figure might not be very representative of the actual nature of the problem. Nefazodone will remain a molecule of interest and vigilance, at least in those countries where it will continue to be available.


1. Minutes of the New Zealand Medicines Adverse Reactions Committee meeting, 6 Sept 2000. Available from URL: http://www.medsafe.govt.nz

2. ‘Dear Healthcare Professional’ letter from Apotex Inc, Canada, 28 June 2001. Available from URL: http://www.hc-sc.gc.ca

3. Canadian Adverse Reaction Newsletter Vol. 13, Issue 1, Jan 2003. Available from URL: http://www.hc-sc.gc.ca

4. WHO ADR Newsletter, 1, pg 4, 1998. Available from URL: http://www.who-umc.org

5. Reuters News, as reported on UK Medical Information (UKMI) website http://www.druginfozone.org

6. Communication to Health Professionals from Spanish Medicines Agency, 7 Jan 2003. Available from URL: http://www.msc.es/agemed/csmh/notas/nefazodona.asp

7. ‘Dear Healthcare Practitioner’ letter from Bristol-Myers Squibb. Available from URL: http://www.fda.gov/medwatch/SAFETY/2002/serzone_deardoc.PDF

8. Canadian Journal of Psychiatry 47:375-377, 2002. Available from URL: http://www.cpa-apc.org


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