Advertisement
ADVANCED SEARCH

This Article Full Text (PDF) [Early Release] Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Choi, S. Search for Related Content PubMed PubMed Citation Articles by Choi, S. Related Collections Drugs: psychiatry Adverse drug reactions

Nefazodone (Serzone) withdrawn because of hepatotoxicity

Editorial Fellow CMAJ

Reason for posting: Because of concerns of hepatotoxicity, the sale of the antidepressant nefazodone hydrochloride (Serzone) will be discontinued by the manufacturer effective Nov. 27, 2003. Since the drug's introduction in 1994, there have been 51 Canadian reports of adverse hepatic events, including jaundice, hepatitis and hepatocellular necrosis. In 2 of these cases the patients subsequently underwent liver transplantation. Also, an article published earlier this year found an unexpectedly high number of reports of hepatic injury associated with nefazodone in the World Health Organization's database of adverse drug reactions.¹

Figure.

The drug: Nefazodone is an antidepressant structurally distinct from selective serotonin reuptake inhibitors (SSRIs), tricyclics, tetracyclics and monoamine oxidase inhibitors. It achieves its clinical effects by inhibiting the reuptake of primarily serotonin but also norepinephrine and by antagonizing the postsynaptic 5-HT₂ receptor and ₁-adrenergic receptors. Nefazodone is metabolized by the cytochrome p450 isoenzyme, CYP 3A4, but it is also an inhibitor of this enzyme, which results in potential interactions with numerous drugs, including HMG–CoA (3-hydroxy-3-methylglutaryl–coenzyme A) reductase inhibitors, carbamazepine and macrolide antibiotics.

What to do: If you have patients who are currently taking nefazodone, then you should switch the treatment to an alternative therapy before Nov. 27, 2003, taking into account the patient's past response to antidepressants, risk of overdose, side effects, drug interactions and cost.² SSRIs remain the most popular class of antidepressants; however, if your patient has responded well to nefazodone, other drugs are available that have similar mechanisms of action, specifically those inhibiting both serotonin and norepinephrine reuptake.³ Should you choose a monoamine oxidase inhibitor, a washout period of 1 week is recommended after discontinuing nefazodone.

If patients who are taking nefazodone show signs or symptoms of hepatic dysfunction, then the drug should be stopped immediately and the patient investigated for other potential causes. In addition, these patients should be closely followed for progression of hepatic problems. The majority of reported cases of hepatotoxicity associated with nefazodone occurred within the first 4 months of starting the drug. In one report, only 17 (53%) of 32 patients who had nefazodone-induced liver dysfunction recovered without sequelae.⁴

Stephen Choi Editorial Fellow CMAJ

References

1. Spigset O, Hagg S, Bate A. Hepatic injury and pancreatitis during treatment with serotonin reuptake inhibitors: data from the World Health Organization (WHO) database of adverse drug reactions. Int Clin Psychopharmacol 2003;18:157-61.[Medline]
2. Remick RA. Diagnosis and management of depression in primary care: a clinical update and review. CMAJ 2002;167(11):1253-60.[Abstract/Free Full Text]
3. Kent JM. SNaRIs, NaSSAs, and NaRIs: new agents for the treatment of depression [published erratum in Lancet 2000;355:2000]. Lancet 2000;355:911-8.
4. Stewart DE. Hepatic adverse reactions associated with nefazodone. Can J Psychiatry 2002; 47: 375-7.[Medline]

This article has been cited by other articles:

				J. J. Xu, P. V. Henstock, M. C. Dunn, A. R. Smith, J. R. Chabot, and D. de Graaf Cellular Imaging Predictions of Clinical Drug-Induced Liver Injury Toxicol. Sci., September 1, 2008; 105(1): 97 - 105. [Abstract] [Full Text] [PDF]

				J. N. Bauman, K. S. Frederick, A. Sawant, R. L. Walsky, L. M. Cox, R. S. Obach, and A. S. Kalgutkar Comparison of the Bioactivation Potential of the Antidepressant and Hepatotoxin Nefazodone with Aripiprazole, a Structural Analog and Marketed Drug Drug Metab. Dispos., June 1, 2008; 36(6): 1016 - 1029. [Abstract] [Full Text] [PDF]

				J. A. Dykens, J. D. Jamieson, L. D. Marroquin, S. Nadanaciva, J. J. Xu, M. C. Dunn, A. R. Smith, and Y. Will In Vitro Assessment of Mitochondrial Dysfunction and Cytotoxicity of Nefazodone, Trazodone, and Buspirone Toxicol. Sci., June 1, 2008; 103(2): 335 - 345. [Abstract] [Full Text] [PDF]

				C. B. Raymond, S. G. Morgan, and P. A. Caetano Antidepressant Utilization in British Columbia From 1996 to 2004: Increasing Prevalence but Not Incidence Psychiatr Serv, January 1, 2007; 58(1): 79 - 84. [Abstract] [Full Text] [PDF]

				A. S. Kalgutkar, A. D. N. Vaz, M. E. Lame, K. R. Henne, J. Soglia, S. X. Zhao, Y. A. Abramov, F. Lombardo, C. Collin, Z. S. Hendsch, et al. BIOACTIVATION OF THE NONTRICYCLIC ANTIDEPRESSANT NEFAZODONE TO A REACTIVE QUINONE-IMINE SPECIES IN HUMAN LIVER MICROSOMES AND RECOMBINANT CYTOCHROME P450 3A4 Drug Metab. Dispos., February 1, 2005; 33(2): 243 - 253. [Abstract] [Full Text] [PDF]

				L. J. Fochtmann and A. J. Gelenberg Guideline Watch: Practice Guideline for the Treatment of Patients With Major Depressive Disorder, 2nd Edition Focus, January 1, 2005; 3(1): 34 - 42. [Full Text] [PDF]

				S. R. Sukkari and L. D. Sasich Incomplete patient drug information still a problem Can. Med. Assoc. J., November 9, 2004; 171(10): 1149 - 1150. [Full Text] [PDF]

This Article Full Text (PDF) [Early Release] Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Choi, S. Search for Related Content PubMed PubMed Citation Articles by Choi, S. Related Collections Drugs: psychiatry Adverse drug reactions

HOME	CURRENT ISSUE	PAST ISSUES	COLLECTIONS	HELP	SEARCH
Copyright 1995-2003, Canadian Medical Association. All rights reserved. ISSN 1488-2329 (e) 0820-3946 (p) All editorial matter in CMAJ represents the opinions of the authors and not necessarily those of the Canadian Medical Association.