OVERVIEW

CASE REPORT

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Fluoxetine	54910-89-3	C17-H18-F3-N-O

ANNOTATED BIBLIOGRAPHY

References updated: 02 February 2018

• 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; mentions that there have been at least 6 reports of acute, symptomatic hepatic injury and one case of chronic hepatitis attributed to fluoxetine).
• Larrey D, Ripault MP. Hepatotoxicity of psychotropic drugs and drugs of abuse. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 443-62.

  (Review of hepatotoxicity of antidepressants; clinically apparent liver injury from the SSRIs is rare, and fluoxetine has been implicated in only a few isolated cases).
• O'Donnell JM, Shelton RC. Pharmacotherapy 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).
• Cooper GL. The safety of fluoxetine – an update. Br J Psychiatry 1988; 153: 77-86. [PubMed: 3074869]

  (Pooled data on 2938 patients on fluoxetine, 599 on tricyclics and 799 on placebo and postmarketing data on over 7500 fluoxetine treated patients; AST values above 100 U/L occurred in 0.5% of patients on fluoxetine, but there were no cases of clinically apparent liver injury).
• Lam KS, Blanchi A, Chavaillon JM. [Hepatitis probably secondary to the massive ingestion of fluvoxamine]. Gastroenterol Clin Biol 1988; 12: 398-9. [PubMed: 3133277]

  (63 year old woman took an overdose of fluvoxamine [~1500 mg] and within 24 hours had elevations in ALT [1059 U/L], Alk P [668 U/L] and bilirubin [1.4 mg/dL], which remained high for more than a month).
• Mars F, Dumas de la Roque G, Goissen P. [Acute hepatitis during treatment of fluoxetine]. Gastroenterol Clin Biol 1991; 15: 270-1. French. [PubMed: 2044897]

  (38 year old woman with severe mitral insufficiency developed fever and weakness 7 months after starting fluoxetine [bilirubin normal, ALT 444 U/L], resolving within one month of stopping therapy).
• Bobichon R, Bernard G, Mion F. [Acute hepatitis during treatment with fluoxetine]. Gastroenterol Clin Biol 1993; 17: 406-7. French. [PubMed: 8349086]

  (54 year old woman developed abdominal pain and jaundice 9 days after starting fluoxetine [bilirubin 5.1 mg/dL, ALT 323 U/L, GGT 185 U/L], resolving in 4 weeks of stopping).
• Castiella A, Arenas JI. Fluoxetine-hepatotoxicity. Am J Gastroenterol 1994; 89: 458-9. [PubMed: 8122673]

  (61 year old woman developed mild, asymptomatic elevations in ALT [61 U/L] and GGT [90 U/L] one month after starting fluoxetine, resolving rapidly with stopping; no mention of Alk P or bilirubin).
• Gram LF. Fluoxetine. N Engl J Med 1994; 331: 1354-62. [PubMed: 7935707]

  (Review of the pharmacology, clinical indications, efficacy and safety of fluoxetine; no discussion of hepatotoxicity or ALT elevations).
• Castiella A, Lopez P, Arenas JI. Fluoxetine. N Engl J Med 1994; 332: 960-1. [PubMed: 7877663]

  (Letter faulting review article on fluoxetine by Gram [1994] for not mentioning hepatotoxicity).
• Gram LF. Fluoxetine. N Engl J Med 1995; 332: 960-1.

  (Author’s reply to Castiella [1994] mentioning that there have been only 3 case reports of fluoxetine hepatotoxicity despite its use in 10-15 million patients).
• Friedenberg FK, Rothstein KD. Hepatitis secondary to fluoxetine treatment. Am J Psychiatry 1996; 153: 580. [PubMed: 8599417]

  (57 year old man developed fatigue 2 weeks after starting fluoxetine which worsened by 10 weeks [bilirubin normal, ALT 410 U/L, Alk P normal, GGT 860 U/L], resolving within 9 days of stopping).
• Cosme A, Barrio J, Lobo C, Gil Y, Castiella A, Arenas JI. Acute cholestasis by fluoxetine. Am J Gastroenterol 1996; 91: 2449-50. [PubMed: 8931446]

  (49 year old man developed jaundice 5 months after starting fluoxetine [bilirubin 13.6 mg/dL, ALT 88 U/L, Alk P 682 U/L], improving within 1-2 months of stopping).
• Johnston DE, Wheeler DE. Chronic hepatitis related to use of fluoxetine. Am J Gastroenterol 1997; 92: 1225-6. [PubMed: 9219808]

  (35 year old man with intermittent ALT elevations [62-106 U/L], low levels of HCV RNA, ANA 1:40 and liver biopsy showing chronic hepatitis, seemingly improving with stopping fluoxetine which had been taken for 10 months).
• Mourilhe P, Stokes PE. Risks and benefits of selective serotonin reuptake inhibitors in the treatment of depression. Drug Saf 1998; 18: 57-82. [PubMed: 9466088]

  (Review of pharmacology, efficacy and safety of SSRIs; no mention of ALT elevations or hepatotoxicity).
• 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 inpatients in 29 German hospitals between 1993 to 1997; 896 severe adverse events were reported among 48,564 patients [1.8%], both total and hepatic events were more common with tricyclics than SSRIs).
• Capella D, Bruguera M, Figueras A, Lapone R. Fluoxetine-induced hepatitis: why is postmarketing surveillance needed? Eur J Clin Pharmacol 1999; 55: 545-6. [PubMed: 10501826]

  (Analysis of Spanish System of Pharmacovigilance from 1982-1999 found 6 cases of acute hepatitis due to fluoxetine, latency of 5 days to 5 months, [bilirubin 3.2-15.2 mg/dL, ALT 116-2124 U/L, Alk P 1539-2463], all cases resolving within 1-3 months of stopping).
• Cai Q, Benson MA, Talbot TJ, Devadas G, Swanson HJ, Olson JL, Kirchner JP. Acute hepatitis due to fluoxetine therapy. Mayo Clin Proc 1999; 74: 692-4. [PubMed: 10405699]

  (Two cases of fluoxetine hepatotoxicity; 39 year old man developed jaundice 1-2 years after starting fluoxetine [bilirubin 5.9 mg/dL, ALT 272 U/L, Alk P 153 U/L], resolving within 4-6 months of stopping; 45 year old woman with jaundice arising after 3 months of fluoxetine [bilirubin 6.4 mg/dL, ALT 641 U/L, Alk P 210 U/L], resolving within 2 months of stopping).
• Shuster J. Fluoxetine and hepatitis. Nursing 2000; 30: 78. [PubMed: 11249443]

  (Summary of two cases published by Cai [1999] for a nursing journal).
• Carvajal García-Pando A, García del Pozo J, Sánchez AS, Velasco MA, Rueda de Castro AM, 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).
• 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).
• Spigset O, Hägg 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. [PubMed: 12702895]

  (Among 27,542 reports of hepatic injury in WHO database, 786 were related to SSRIs [3%], including citalopram 42, fluoxetine 222, fluvoxamine 54, paroxetine 191, sertraline 112, nefazodone 91 and venlafaxine 74; only nefazodone has an excess of hepatic reports in relationship to total reports).
• Milkiewicz P, Chilton AP, Hubscher SG, Elias E. Antidepressant induced cholestasis: hepatocellular redistribution of multidrug resistant protein (MRP2). Gut 2003; 52: 300-3. [PMC free article: PMC1774956] [PubMed: 12524417]

  (2 cases of cholestasis on antidepressants; 30 year old woman developed jaundice 8 weeks after starting citalopram [bilirubin 4.4 mg/dL, AST 33 U/L, Alk P 637 U/L], resolving within 2 months of stopping; 63 year old man developed jaundice 3 months after starting the tricylcic antidepressant dothiepin [bilirubin 9.4 mg/dL, AST 40 U/L, Alk P 600 U/L], resolving within 3 months of stopping while on corticosteroids, later tolerating fluoxetine for 12 months but redeveloping jaundice after 2 months of paroxetine [bilirubin 15.2 mg/dL, AST 36 U/L, Alk P 544 U/L], resolving within 6 months of stopping).
• 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: 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%).
• Pinzani V, Peyriere H, Hillaire-Buys D, Pageaux GP, Blayac BP, Larrey D. Specific serotonin recapture inhibitor (SSRI) antidepressants: hepatoxicity assessment in a large cohort in France. J Hepatol 2006; 44: S256. Not in PubMed.

  (Abstract: analysis of French Pharmacovigilance data on SSRIs found 63 cases of hepatotoxicity from paroxetine, 45 fluoxetine, 30 citalopram, 18 sertraline, and 2 fluvoxamine).
• 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: 17609231]

  (Review of drug induced liver injury and reports of injury from MAO inhibitors, SSRIs, tricyclics and atypical agents).
• 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 atomoxetine, 2 fluoxetine, 2 bupropion, and 1 sertraline as single agents).
• 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, including two linked to SSRIs, 1 to fluoxetine and 1 to venlafaxine).
• Park SH, Ishino R. Liver injury associated with antidepressants. Curr Drug Saf 2013; 8: 207-23. [PubMed: 23914755]

  (Review of antidepressant induced liver injury).
• 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, but none were attributed to an SSRI despite the fact that 5 SSRIs ranked among the top 30 most prescribed drugs in Iceland).
• 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, but none were attributed to fluoxetine or other SSRIs).
• 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 6 case reports of injury from fluoxetine with latency of 2 to 12 months, variable patterns of enzyme elevations, 1 resulting in chronic injury, none fatal).
• Chew AP, Lim WS, Tan KT. Donepezil-induced hepatotoxicity in an elderly adult taking fluoxetine. J Am Geriatr Soc 2014; 62: 2009-11. [PubMed: 25333550]

  (A 79 year old man with depression, Alzheimer disease and cirrhosis due to hepatitis was taking high doses of fluoxetine [80 mg daily] and lamivudine and developed fatigue and anorexia with abnormal liver tests 6 weeks after starting donepezil [bilirubin 1.5 mg/dL, ALT 177 U/L, Alk P 127 U/L], which resolved within 8 weeks of stopping both and did not recur on starting sertraline and memantine).
• Emslie GJ, Prakash A, Zhang Q, Pangallo BA, Bangs ME, March JS. A double-blind efficacy and safety study of duloxetine fixed doses in children and adolescents with major depressive disorder. J Child Adolesc Psychopharmacol 2014; 24: 170-9. [PMC free article: PMC4026396] [PubMed: 24815533]

  (Among 355 children or adolescents with depression treated for 10 weeks either duloxetine, fluoxetine or placebo, none had ALT elevations above 3 times ULN and there were no liver related serious adverse events).
• Emslie GJ, Wells TG, Prakash A, Zhang Q, Pangallo BA, Bangs ME, March JS. Acute and longer-term safety results from a pooled analysis of duloxetine studies for the treatment of children and adolescents with major depressive disorder. J Child Adolesc Psychopharmacol 2015; 25: 293-305. [PubMed: 25978741]

  (Among 800 children or adolescents with depression treated with duloxetine, fluoxetine or placebo for 10 weeks with a 26 week active extension, only 1 patient on duloxetine and 1 on fluoxetine had an ALT elevation above 3 times ULN, both of which resolved despite continuing therapy).
• 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. PubMed Citation. [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 [2%] were attributed to antidepressants including 5 due to SSRIs, 3 of which were due to escitalopram, 1 to sertraline and 1 to fluoxetine).
• Friedrich ME, Akimova E, Huf W, Konstantinidis A, Papageorgiou K, Winkler D, Toto S, et al. Drug-induced liver injury during antidepressant treatment: results of AMSP, a drug surveillance program. Int J Neuropsychopharmacol 2016; 19. pii: pyv126. PubMed Citation. [PMC free article: PMC4851269] [PubMed: 26721950]

  (Among 184,234 psychiatric inpatients from 80 hospitals, 149 cases [0.08%] of drug induced liver injury were reported, with very low rates reported for fluoxetine [0.02%: 1 of 4,682 patients exposed]).
• 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 Citation. [PubMed: 28770534]

  (Among 179 cases of hospitalizations for unexplained acute liver injury enrolled in an prospective study between 2010 and 2014, 17 had been exposed to antidepressants including 1 who received fluoxetine for 4 months [bilirubin 0.7 mg/dL, ALT 594 U/L, Alk P 202 U/L]).