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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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Last Update: January 8, 2018.



Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor widely used as an antidepressant and for neuropathic pain. Duloxetine therapy can be associated with transient asymptomatic elevations in serum aminotransferase levels and has been linked to rare instances of clinically apparent acute liver injury.


Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) that is used as an antidepressant and for neuropathic pain. By blocking the reuptake of serotonin and norepinephrine in CNS synaptic clefts, the brain levels of these neurotransmitters are increased, which is associated with an antidepressant effect. Duloxetine was approved for use in the United States in 2004 and is available in delayed release capsules of 20, 30 and 60 mg in multiple generic forms and under the brand name Cymbalta. Indications for duloxetine therapy include major depression, generalized anxiety disorders, fibromyalgia and neuropathic pain. The recommended dosage in adults is 40 to 60 mg daily, which can be raised to 120 mg daily based upon tolerance and clinical effects. Common side effects are drowsiness, dyspepsia, nausea, headache, increased sweating, increased appetite, weight gain, urinary retention and sexual dysfunction. Rare, but potentially severe adverse events include suicidal thoughts and behaviors, mania, postural hypotension, syncope and falls, serotonin syndrome, seizures, severe skin rash, hypersensitivity reactions, hyponatremia, and glaucoma.


Liver test abnormalities with ALT elevations above 3 times the upper limit of normal have been reported to occur in ~1% of patients on duloxetine, but elevations were usually self-limited and did not require dose modification or discontinuation. Rare instances of acute, clinically apparent episodes of liver injury with marked liver enzyme elevations with or without jaundice have been reported in patients on duloxetine. The onset of injury is usually within 1 to 6 months and the pattern of serum enzyme elevations is usually hepatocellular, but mixed and cholestatic forms have also been described. Fatal cases have been described but their relatedness to duloxetine has been quesitoned. Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) are uncommon.

Likelihood score: B (likely cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which duloxetine causes liver injury is not known, but is likely due to a metabolic byproduct. Duloxetine is metabolized by the liver, mainly via the cytochrome P450 system (CYP1A2 and 2D6) and is susceptible to drug-drug interactions with agents that alter activity of those microsomal enzymes (such as cimetidine and rifampin).

Outcome and Management

The serum aminotransferase elevations that occur on duloxetine therapy are usually self-limited and do not require dose modification or discontinuation of therapy. Rare instances of acute liver failure and chronic hepatitis have been attributed to duloxetine therapy. Persons with intolerance to duloxetine may have similar reactions to other SNRIs and SSRIs and careful monitoring is warranted if other such agents are used.

Drug Class: Antidepressant Agents

Other Drugs in the Subclass, SNRIs/SSRIs: Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Levomilnacipran, Paroxetine, Sertraline, Venlafaxine, Vilazodone, Vortioxetine



Duloxetine – Cymbalta®


Antidepressant Agents


Product labeling at DailyMed, National Library of Medicine, NIH


Duloxetine 116539-59-4 C18-H19-N-O-S
Image of Duloxetine Chemical Structure


References updated: 08 January 2018

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    (Expert review of hepatotoxicity published in 1999; duloxetine is not mentioned).
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    (Analysis of spontaneous reporting of hepatic adverse events between 2004 and 2005; 5 million persons received duloxetine for 1.5 million person-years of exposure; 406 hepatic events, 26 probable and 127 possible; 225 had enzyme elevations only, 37 severe hepatic injury, 9 hepatic failure and 12 deaths [but none from hepatic failure]; overall rate of hepatic events of .008%).
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    (Among 30 children with suspected drug induced liver injury, half [n=15] were due to antimicrobials [minocycline 4, INH 3, azithromycin 3] and the rest largely due to CNS agents and anticonvulsants; one case was attributed to amitriptyline, but no other antidepressant was listed).
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    (44 year old man on long term warfarin, simvastastin, amlodipine, gabapentin and insulin therapy had marked rise in INR within one week of starting duloxetine [INR 11.9, bilirubin normal, ALT 99], resolving within a few days of vitamin K and fresh frozen plasma therapy, likely due to drug interactions rather than hepatotoxicity).
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  • Yuan W, Williams B. Acute hepatic failure involving duloxetine hydrochloride. J Neuropsychiatry Clin Neurosci 2012; 24: E48-9. [PubMed: 22772703]
    (58 year old woman developed abdominal pain and confusion 4 months after an increase in chronic duloxetine dose from 60 to 90 mg daily [bilirubin 2.9, ALT 3270 U/L, Alk P 146 U/L, INR 1.8, creatinine 3.9 mg/dL], with rapid recovery on stopping; was also taking trazodone, acetaminophen and atorvastatin).
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    (Review of drug-drug interactions of antidepressants; duloxetine has extensive hepatic metabolism largely via CYP 1A2 so that levels can be increased by 1A2 inhibitors [cimetidine] and decreased by inducers [smoking, rifampin]; duloxetine is also a moderate CYP 2D6 inhibitor and may raise levels of risperidone and lower those of the active metabolite of tamoxifen).
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    (In a population based study from Iceland, 96 cases of drug induced liver injury were identified over a 2 year period, one of which was attributed to an antidepressant [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 lists and discusses 12 published cases attributed to duloxetine).
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    (Review of antidepressant induced liver injury mentions that duloxetine has been linked to cases of hepatocellular, mixed and cholestatic injury and its frequency is estimated to be 26.2 per 100,000 patient years [Wernicke 2008]).
  • 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, none of which were attributed to duloxetine).
  • 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 [2%] were attributed to antidepressants, including 7 to duloxetine [Vuppalanchi 2010]).
  • Lin ND, Norman H, Regev A, Perahia DG, Li H, Chang CL, Dore DD. Hepatic outcomes among adults taking duloxetine: a retrospective cohort study in a US health care claims database. BMC Gastroenterol 2015; 15: 134. [PMC free article: PMC4607169] [PubMed: 26467777]
    (Analysis of a US health care database of patients initiating duloxetine therapy between 2004 and 2010 identified no cases of acute liver failure, but 5 cases of clinically significant liver injury among 7632 person-years of duloxetine use [0.07%]).
  • Bunchorntavakul C, Reddy KR. Drug hepatotoxicity: newer agents. Clin Liver Dis 2017; 21: 115-34. [PubMed: 27842767]
    (Review of newly approved agents that have been linked to liver injury, including duloxetine).
  • 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. [PMC free article: PMC4851269] [PubMed: 26721950]
    (Monitoring of 184,234 inpatients in 80 psychiatric hospitals for liver injury during antidepressant treatment identified 149 cases including 3 among 8015 duloxetine treated subjects [0.04%], a rate similar to other SSRIs and SNRIs; no cases resulted in acute liver failure or death from liver disease).
  • 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 prospective study between 2010 and 2014, 17 had been exposed to antidepressants including one who received duloxetine for 2 years [bilirubin 1.1 mg/dL, ALT 696 U/L, Alk P 122 U/L]).


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