OVERVIEW

CASE REPORT

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Bupropion	34911-55-2	C13-H18-Cl-N-O

ANNOTATED BIBLIOGRAPHY

References updated: 11 September 2017

• Zimmerman HJ. Antidepressants. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 493-8.

  (Expert review of hepatotoxicity published in 1999; bupropion listed in a table as a rare cause of hepatocellular injury).
• Larrey D, Ripault M-P. Bupropion. Hepatotoxicity of psychotropic drugs and drugs of abuse. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, p. 451.

  (Review of hepatotoxicity of antidepressants mentions that bupropion is considered very safe but that cases of liver injury have been reported during the post-marketing period including two cases of liver failure).
• O'Donnell JM, Shelton RC. Drug therapy of depression and anxiety disorders. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 397-416.

  (Textbook of pharmacology and therapeutics; bupropion appears to act via multiple mechanisms involving norepinephrine and dopamine).
• Tucker WE Jr. Preclinical toxicology of bupropion: an overview. J Clin Psychiatry 1983; 44: 60-62. PubMed Citation. [PubMed: 6406465]

  (In chronic dosing of animals there were slight to moderate increases in ALT and Alk P levels and 13% of animals developed focal nodular hyperplasia; no liver cancer).
• Fleet JVW, Manberg PJ, Miller LL, Harto-Truax N, Sato T, Fleck RJ, Stern WC, et al. Overview of clinically significant adverse reactions to bupropion. J Clin Psychiatry 1983; 44 (Sec 2): 191-6. [Not in PubMed] [PubMed: 6406456]

  (Pooled data on 1153 patients treated with bupropion; “Elevated liver enzymes occasionally found during chronic administration of high doses of bupropion in animals were not seen during short- or long term treatment with therapeutic doses in humans”).
• Oslin DW, Duffy K. The rise of serum aminotransferases in a patient treated with bupropion. J Clin Psychopharmacol. 1993; 13: 364-5. [PubMed: 8227497]

  (73 year old woman developed ALT elevations [5.4 times ULN] 54 days after starting bupropion, falling to normal within 10 days of stopping and recurring within 4 days with rechallenge [ALT 3.6 times ULN]).
• Grohmann R, Rüther E, Engel RR, Hippius H. Assessment of adverse drug reactions in psychiatric inpatients with the AMSP drug safety program: methods and first results for tricyclic antidepressants and SSRI. Pharmacopsychiatry 1999; 32: 21-8. [PubMed: 10071179]

  (Analysis of reporting of adverse events among pscyhiatric inpatients in 29 German hospitals between 1993 to 1997; 896 severe adverse events among 48,564 patients [1.8%], both total and hepatic events were more common with tricyclics than SSRIs).
• Hu KQ, Tiyyagura L, Kanel G, Redeker AG. Acute hepatitis induced by bupropion. Dig Dis Sci 2000; 45: 1872-3. [PubMed: 11052334]

  (41 year old man with chronic hepatitis C developed fever and malaise 41 days after starting bupropion [bilirubin 3.8 mg/dL, ALT 6660 U/L, Alk P 232 U/L, INR 1.7], resolving rapidly on stopping).
• Alvaro D, Onetti-Muda A, Moscatelli R, Atili AF. Acute cholestatic hepatitis induced by bupropion prescribed as pharmacological support to stop smoking. A case report. Dig Liver Dis 2001; 33: 703-6. [PubMed: 11785718]

  (49 year old woman developed jaundice one month after starting bupropion for smoking cessation [bilirubin 7.4 rising to 27.4 mg/dL, ALT 29 times ULN, Alk P 3 times ULN, ANA 1:80], improving with corticosteroid therapy and resolving within 50 days of stopping drug).
• Carvajal Garcia-Pando A, Garrcia del Pozo J, Sanchez A, Velasco M, Rueda de Castro A, Lucena MI. Hepatotoxicity associated with the new antidepressants. J Clin Psychiatry 2002; 63: 135-7. [PubMed: 11874214]

  (Analysis of cases of hepatotoxicity from antidepressants in Spanish Pharmacovigilance System from 1989-1999, identified 99 cases; among SSRIs, 26 due to fluoxetine, 14 paroxetine, 6 fluvoxamine, 5 sertraline, 3 venlafaxine and 2 citalopram; among tricyclics, 16 clomipramine, 7 amitriptyline, 6 imipramine; among miscellaneous, 3 nefazodone and 1 trazodone; but all similar in rate ~1-3 per 100,000 patient-years of exposure, except for nefazodone=29/100,000; bupropion not mentioned).
• Lucena M, Carvajal A, Andrade R, Velasco A. Antidepressant-induced hepatotoxicity. Expert Opin Drug Saf 2003; 2: 249-62. [PubMed: 12904104]

  (Review of hepatotoxicity of antidepressants; antidepressant use has increased markedly between 1992 and 2002, accounting for 5% of cases of hepatotoxicity; SSRIs are less likely to cause injury than tricyclics and MAO inhibitors; range of presentations, typically self-limited and rapid recovery; no hallmarks of hypersensitivity; bupropion not mentioned).
• Bagshaw SM, Cload B, Gilmour J, Leung ST, Bowen TJ. Drug-induced rash with eosinophilia and systemic symptoms syndrome with bupropion administration. Ann Allergy Asthma Immunol 2003; 90: 572-5. [PubMed: 12775141]

  (24 year old man developed fever, rash and eosinophilia [10%] 21 days after starting bupropion, with subsequent relapsing course, developing jaundice on day 40 [bilirubin 3.1 mg/dL, ALT 4040 U/L, Alk P 388 U/L, ANA 1:40], possible renal and pulmonary involvement, but ultimate improvement on corticosteroids).
• Khoo A-L, Tham L-S, Lee K-H, Lim G-K. Acute liver failure with concurrent bupropion and carbimazole therapy. Ann Pharmacother 2003; 37: 220-3. [PubMed: 12549952]

  (41 year old man developed jaundice and acute liver failure 10 weeks after stopping 10 day course of bupropion while also on long term carbimazole [bilirubin 29 rising to 84 mg/dL, ALT 674 U/L, Alk P 138 U/L, protime rising to 42.4 sec], dying of hepatic failure 11 days after admission).
• Boshier A, Wilton LV, Shakir SA. Evaluation of the safety of bupropion (Zyban) for smoking cessation from experience gained in general practice use in England in 2000. Eur J Clin Pharmacol 2003; 59: 767-73. PubMed Citation (Among 11,735 patients started on bupropion for smoking cessation on whom follow up was obtained by questionnaire from the prescribing physician, adverse events were reported in 350 [3%], but were mostly mild, nonspecific symptoms of insomnia, nausea, and dizziness; no mention of jaundice, hepatitis or death from liver injury).
• Degner D, Grohmann R, Kropp S, Rüther E, Bender S, Engel RR, Schmidt LG. Severe adverse drug reactions of antidepressants: results of the German multicenter drug surveillance program AMSP. Pharmacopsychiatry 2004; 37 Suppl 1: S39-45. PubMed Citation. [PubMed: 15052513]

  (Analysis of adverse drug reactions reported from 1993-2000 in 35 psychiatric hospitals; 0.7% of SSRI recipients had a severe adverse event; hepatic in 0.05%).
• Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug-induced liver injury in the United States. Liver Transpl 2004; 10: 1018-23. [PubMed: 15390328]

  (Among ~50,000 liver transplants done in the US between 1990 and 2002, 270 [0.5%] were done for drug induced acute liver failure, only four being due to antidepressants: nefazodone [2], bupropion [1], and paroxetine [1]).
• Andrade RJ, Lucena MI, Fernández MC, Pelaez G, Pachkoria K, García-Ruiz E, García-Muñoz B, et al.; Spanish Group for the Study of Drug-Induced Liver Disease. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 2005; 129: 512-21. [PubMed: 16083708]

  (Reports to a Spanish network found 461 cases of drug induced liver disease; antidepressants accounted for 23 cases [5%]).
• Björnsson E, Olsson R. Suspected drug-induced liver fatalities reported to the WHO database. Dig Liver Dis 2006; 38: 33-8. (Survey of drug induced liver fatalities reported to WHO database between 1968-2003 revealed 4690 reports; no antidepressant ranked among the top 21 agents that were linked to at least 50 cases each) [PubMed: 16054882]

  .
• Sabaté M, Ibáñez L, Pérez E, Vidal X, Buti M, Xiol X, Mas A, et al. Risk of acute liver injury associated with the use of drugs: a multicentre population survey. Aliment Pharmacol Ther 2007; 25: 1401-9. [PubMed: 17539979]

  (Among 126 cases of drug induced liver injury seen in Spain between 1993-2000, 3 were attributed to paroxetine and 3 to fluoxetine with a relative risk of injury to rate of use in the population of 3.0 and 1.8 respectively).
• DeSanty KP, Amabile CM. Antidepressant-induced liver injury. Ann Pharmacother 2007; 41: 1201-11. PubMed Citation. [PubMed: 17609231]

  (Review of antidepressant induced liver injury mentions that no cases of liver failure occurred during clinical trials of bupropion and elevated liver enzymes occurred in 0.1-1.0% of recipients, but that 5 cases of acute liver injury attributed to bupropion have been published, several of which were quite convincing).
• Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. [PMC free article: PMC3654244] [PubMed: 18955056]

  (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, 6 were attributed to duloxetine, 3 to atomoxetine, 2 to fluoxetine, 2 to bupropion, and 1 to sertraline as single agents).
• Carlos Titos-Arcos J, Hallal H, Collados V, Plaza-Aniorte J. [Acute hepatitis secondary to bupropion]. Gastronterol Hepatol 2008; 31: 549. [PubMed: 18928762]

  (48 year old man developed jaundice 1 month after starting bupropion [bilirubin 12.1 mg/dL, ALT 1405 U/L, Alk P 803 U/L, ANA 1:80], resolving within 3 months of stopping: Case 1).
• Humayun F, Shehab TM, Tworek JA, Fontana RJ. A fatal case of bupropion (Zyban) hepatotoxicity with autoimmune features: Case report. J Med Case Reports 2007; 1: 88. [PMC free article: PMC2008202] [PubMed: 17877816]

  (55 year old man developed jaundice 6 months after starting bupropion for smoking cessation [bilirubin 5.3 rising to 22.7 mg/dL, ALT 1459 U/L, Alk P 219 U/L, ANA 1:160], responding to prednisone therapy but relapsing when it was stopped, with progressive liver failure and death 105 days after onset).
• Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]

  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, 3 of which were linked to antidepressants: one each for nefazodone, fluoxetine and venlafaxine).
• Alonso Rodríguez L, Barcina Pajares R, Fuentes Vigil J, Gutiérrez González A, Rodríguez Pérez L. [Acute toxic hepatitis secondary to a single dose of bupropion]. Gastroenterol Hepatol 2010; 33: 547-9. Spanish. [PubMed: 20435378]

  (59 year old man developed abdominal pain 24 hours after a single 150 mg dose of bupropion [bilirubin 1.6 rising to 8.7 mg/dL, ALT 1116 U/L, Alk P 146 U/L], resolving rapidly within 3 weeks).
• Park SH, Ishino R. Liver injury associated with antidepressants. Curr Drug Saf 2013; 8: 207-23. [PubMed: 23914755]

  (Review of drug induced liver injury due to antidepressants; no discussion of bupropion).
• Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver iInjury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. [PubMed: 23419359]

  (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, none of which were attributed to bupropion).
• Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]

  (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases; one was attributed to amitryptilline, but none were attributed to buproprion or other antidepressants).
• Voican CS, Corruble E, Naveau S, Perlemuter G. Antidepressant-induced liver injury: a review for clinicians. Am J Psychiatry 2014; 171: 404-15. [PubMed: 24362450]

  (Review of hepatotoxicity of antidepressants, mentions that 7 cases of hepatocellular and cholestatic hepatitis have been reported with bupropion, despite infrequency of ALT elevations and absence of clinical cases during clinical trials).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 20 cases were attributed to antidepressant medications including 4 to bupropion).
• Tang DM, Koh C, Twaddell WS, von Rosenvinge EC, Han H. Acute hepatocellular drug-induced liver injury from bupropion and doxycycline. ACG Case Rep J 2015; 3: 66-8. [PMC free article: PMC4612764] [PubMed: 26504884]

  (29 year old man developed jaundice 14 days after starting doxycycline and bupropion [bilirubin 19.9 mg/dL, ALT 896 U/L, Alk P 234 U/L, INR 3.0], with resolution within 2 months of stopping both drugs and with prednisone therapy).