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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Nefazodone

Last Update: March 6, 2020.

OVERVIEW

Introduction

Nefazodone is a serotoninergic modulating antidepressant that is used in therapy of depression, aggressive behavior and panic disorder. Nefazodone therapy has been associated with transient, usually asymptomatic elevations in serum aminotransferase levels and has been linked to several instances of clinically apparent acute liver injury some of which have been fatal.

Background

Nefazodone (ne faz' oh done) is a phenylpiperazine derivative whose mechanism of action is believed to be inhibition of serotonin and norepinephrine reuptake, which results in increased levels and activity of these neurotransmitters. However, the actual mechanism of action is unknown and nefazodone also is a weak serotonin and alpha-1 adrenergic antagonist. Nefazodone was approved for use in moderate and severe depression in the United States in 1988, but was subsequently linked to many cases of acute liver injury, some of which were fatal, and is no longer in common use. Current indications are for major depression that has not responded to conventional antidepressants where the risks of liver failure are discussed fully with the patient and considered warranted. Nefazodone is available in tablets of 50, 100, 150, 200 and 250 mg in several generic forms and formerly under the brand name of Serzone. The recommended dosage for depression in adults is 200 mg daily that can be increased in 100 mg amounts to a maximum of 600 mg daily. Common side effects of nefazodone are drowsiness, dizziness, headache, dry mouth, blurred vision, nausea, constipation or diarrhea, decreased libido, abnormal dreams, increased appetite and weight gain. Uncommon but potentially severe adverse events include suicidal thoughts and behaviors, activation of mania, serotonin syndrome, seizures, priapism, angle closure glaucoma, and severe hypersensitivity reactions including angioedema and Stevens Johnson syndrome.

Hepatotoxicity

Liver test abnormalities occur in a proportion of patients on nefazodone, but elevations are usually modest and usually do not require dose modification or discontinuation. Soon after its general availability, nefazodone was linked to several instances of acute, clinically apparent liver injury, some of which were fatal. The onset of injury varied from 6 weeks to 8 months and the pattern of serum enzyme elevations was typically hepatocellular. Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) were uncommon. Liver biopsy usually demonstrated an acute hepatitis with cholestasis and variable degrees of centrolobular (zone 3) necrosis. Systematic reviews suggested that the incidence of hepatic failure due to nefazodone is 1 per 250,000 to 300,000 patient-years of exposure. Because of this complication, nefazodone was withdrawn from use in many countries. Nefazodone, however, can be effective in patients with otherwise resistant forms of severe depression. For this reason, it remains available in the United States with the recommendation that it be used only if other antidepressants have been found to be ineffective and after full disclosure and discussion of the risks. It has a “black box” warning for hepatotoxicity.

Likelihood score: A (well known cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which nefazodone causes liver injury is not known. Nefazodone is extensively metabolized by the liver, mainly via the cytochrome P450 system (CYP3A4), and hepatotoxicity may be mediated by toxic intermediates of its metabolism. Nefazodone is also susceptible to multiple drug-drug interactions and doses of concurrent medications should be carefully chosen.

Outcome and Management

The serum aminotransferase elevations that occur on nefazodone therapy are usually self-limited, but require careful monitoring if they arise because of the risk of clinically apparent liver injury, which can be severe and even fatal. Several instances of acute liver failure have been attributed to nefazodone therapy and it is often mentioned in case series of acute liver failure due to medications. While routine monitoring of liver tests is not recommended with nefazodone therapy, monitoring for signs and symptoms of liver injury (and full explanation of the meaning of such symptoms to the patient) is strongly recommended. Persons with intolerance to nefazodone may have similar reactions to other antidepressants and careful monitoring is warranted if other such agents are used.

Drug Class: Antidepressant Agents, Miscellaneous

Other Drugs in the Subclass: Trazodone

CASE REPORT

Case 1. Acute liver failure due to nefazodone.(1)

A 52 year old man developed fatigue and nausea 6 weeks after starting nefazodone (300 mg daily) for a long standing depression that had not responded adequately to conventional antidepressants. He had no previous history of liver disease, did not drink alcohol and had no risk factors for viral hepatitis. His liver enzymes were known to be normal in the past. Other medications included an herbal sleeping aid (valerian and passionflower) and ergotamines for occasional headaches. Laboratory test results included marked elevations in serum aminotransferase levels (ALT 1947 U/L, AST 836 U/L), with minimal increases in GGT (88 U/L) and normal bilirubin levels. All medications were stopped and he was observed. Over the next week, he became jaundiced and his prothrombin index (Quick) fell (from 53% of normal to 27%). He was transferred to a liver transplant center. Tests for hepatitis A, B and C were negative as were serologic tests for acute cytomegalovirus, herpes simplex and Ebstein Barr Virus infection. Abdominal imaging initially showed a normal appearing liver, but a slight amount of ascites. Two weeks later, magnetic resonance imaging demonstrated a shrunken liver and worsening ascites. A liver biopsy showed a cellular and canalicular cholestasis with marked portal inflammation and periportal necrosis and fibrosis with lobular collapse. He remained markedly jaundiced and developed marked ascites and hepatic encephalopathy. Fourteen weeks after starting nefazodone and 8 weeks after stopping it, he underwent liver transplantation. Despite this, he developed postoperative complications and died of disseminated aspergillosis 4 weeks later.

Key Points

Medication:Nefazodone (300 mg daily)
Pattern:Hepatocellular (R=26)
Severity:5+ (liver transplantation, death)
Latency:6 weeks
Recovery:None
Other medications:Passionflower, valerian, ergotamines

Laboratory Values

Time After
Starting
Time After
Stopping
ALT
(U/L)
GGT
(U/L)
Bilirubin
(mg/dL)
Other
PrePre2126
5 weeksPreNormalNormalNormal
6 weeks0194788NormalAdmission
7 weeks7 days10318913.9Transfer to transplant center
8 days11088518.9Prothrombin time: 30%
9 weeks3 weeks872934.9
10 weeks4 weeks452841.4
12 weeks6 weeks221141.4Encephalopathy
14 weeks8 weeks141843.9Prothrombin time 25%
8 weeksLiver transplantation
Normal Values<25<29<1.2

Comment

Nefazodone has been linked to many instances of severe acute hepatocellular injury arising 2 to 24 weeks after starting therapy. The injury is typically hepatocellular and can be severe. Autoimmune and immunoallergic features are not common. In the current instance, nefazodone was discontinued promptly, but the liver injury was severe enough that hepatic failure arose that did not resolve over the next 4 to 8 weeks, leading to a liver transplant but subsequent death from complications. The sleeping aid that was started at the same time as nefazodone is a commonly used herbal mixture that has not been specifically linked to liver injury.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Nefazodone – Generic, Serzone®

DRUG CLASS

Antidepressant Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Nefazodone82752-99-6C25-H32-Cl-N5-O2.Cl-Himage 135014183 in the ncbi pubchem database

CITED REFERENCES

1.
Ehrentraut S, Rothenhäusler HB, Gerbes AL, Rau HG, Thiel M, Schirren CA, Kapfhammer HP. Nervenarzt. 2002;73:686–9. [Acute liver failure in nefazodone therapy? A case report] [PubMed: 12212533]

ANNOTATED BIBLIOGRAPHY

References updated: 26 February 2020

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  • Chen VC, Lin CF, Hsieh YH, Liang HY, Huang KY, Chiu WC, Lee Y, McIntyre RS, et al. Hepatocellular carcinoma and antidepressants: a nationwide population-based study. Oncotarget. 2017;8:30464–70. [PMC free article: PMC5444756] [PubMed: 27783998]
    (Among almost 50,000 cases of hepatocellular carcinoma registered in the Taiwan National Health Insurance Research Database, the rate of antidepressant use was lower than in approximately 250,000 matched controls from the database).
  • Bunchorntavakul C, Reddy KR. Drug hepatotoxicity: newer agents. Clin Liver Dis. 2017;21:115–34. [PubMed: 27842767]
    (Review of hepatotoxicity of recently approved medications mentions that liver injury in recently approved agents and only rare instances have been linked to antidepressant use, highest rates associated with duloxetine, although instances of severe hepatitis and acute liver failure have been reported with nefazodone and trazodone).
  • Ferrajolo C, Scavone C, Donati M, Bortolami O, Stoppa G, Motola D, Vannacci A, et al. DILI-IT Study Group. Antidepressant-induced acute liver injury: a case-control study in an Italian inpatient population. Drug Saf. 2018;41:95–102. [PubMed: 28770534]
    (Among 179 cases of hospitalizations for unexplained acute liver injury enrolled in an Italian prospective study between 2010 and 2014, 17 had been exposed to antidepressants including citalopram [n=4], sertraline [n=3], amitriptyline [n=3] and paroxetine [n=2], and mirtazapine [n=1], and another was exposed to both trazodone and mirtazapine; none had received nefazodone which had been withdrawn in Italy).
  • Billioti de Gage S, Collin C, Le-Tri T, Pariente A, Bégaud B, Verdoux H, Dray-Spira R, et al. Antidepressants and hepatotoxicity: a cohort study among 5 million individuals registered in the French National Health Insurance Database. CNS Drugs. 2018;32:673–84. [PMC free article: PMC6061298] [PubMed: 29959758]
    (Using the French National Health Insurance Database, 382 serious liver injuries were found in approximately 5 million persons initiating antidepressant therapy between 2010 and 2015, rates being 32.8 per 100,000 with mirtazapine, 22.2 with venlafaxine, 19.2 for SSRIs and 12.6 with duloxetine; nefazodone was not listed as it had been withdrawn from use before the period of analysis).
  • Pladevall-Vila M, Pottegård A, Schink T, Reutfors J, Morros R, Poblador-Plou B, Timmer A, et al. Risk of acute liver injury in agomelatine and other antidepressant users in four European countries: a cohort and nested case-control study using automated health data sources. CNS Drugs. 2019;33:383–95. [PMC free article: PMC6441103] [PubMed: 30830574]
    (Analysis of data sources from 4 European countries identified 3.2 million persons initiating antidepressant therapy among whom there was no increased risk for acute liver injury for agomelatine compared to citalopram, an SSRI with a low rate of hepatotoxicity; nefazodone not included in the analysis).
  • Schwasinger-Schmidt TE, Macaluso M. Other antidepressants. Handb Exp Pharmacol. 2019;250:325–55. [PubMed: 30194544]
    (Review of the pharmacology of antidepressants mentions that transient elevations in cholesterol and liver function tests can occur on mirtazapine therapy; nefazodone not discussed).
  • Drugs for depression. Med Lett Drugs Ther. 2020;62(1592):25–32. [PubMed: 32320387]
    (Concise review of the mechanism of action, clinical efficacy, safety and costs of drugs for depression; hepatotoxicity is mentioned only for nefazodone [now rarely used because of severe hepatotoxicity] and duloxetine [in heavy drinkers]).

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