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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: August 25, 2021.



Atomoxetine is a selective norepinephrine reuptake inhibitor used primarily for therapy of attention deficit hyperactivity disorder. Atomoxetine has been linked to a low rate of serum aminotransferase elevations and to rare cases of acute, clinically apparent liver injury.


Atomoxetine (a" toe mox' e teen) is a selective norepinephrine reuptake inhibitor that blocks the presynaptic norepinephrine transporter leading to an increase in levels of this potent neurotransmitter, predominantly in the central nervous system. Therapy with atomoxetine has been shown to lead to improvements in levels of psychological functioning and performance in children and adults with suspected attention deficit/hyperactivity disorder (ADHD). Atomoxetine was approved for use in adults, adolescents and children above the age of 6 years with ADHD in the United States in 2002. Atomoxetine is available in capsules of 10, 18, 25, 40, 60, 80 and 100 mg in generic forms and under the brand name Strattera. The recommended initial dosage in adults is 40 mg once daily, with subsequent increases to a maintenance dose which averages 60 to 100 mg daily. The dosage in children is based upon body weight. Common side effects include headache, insomnia, irritability, dry mouth, erectile dysfunction, urinary hesitancy, gastrointestinal upset, nausea, constipation and rash. Uncommon but potential severe adverse events include suicidal ideation and behavior, cardiovascular symptoms and events, manic or aggressive behavior, priapism and hypersensitivity reactions.


Atomoxetine has been linked to serum aminotransferase elevations in a small proportion of patients (~0.5%). More importantly, there have been several reports of clinically apparent acute liver injury due to atomoxetine. The onset of injury was within 3 to 12 weeks of starting the medication. The typical pattern of serum enzyme elevations was hepatocellular with marked increases in serum aminotransferase levels (often >20 times upper limit of normal) and clinical features that resembled acute viral hepatitis. Most cases have been self-limited, but instances of acute liver failure sometimes requiring emergency liver transplantation have been reported. Immunoallergic features were not found, but several patients with acute injury had antinuclear antibody and at least one patient had other features that resembled autoimmune hepatitis (with typical liver histology and high levels of immunoglobulins in serum).

Likelihood score: C (probable cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which atomoxetine might cause liver injury is unknown. Atomoxetine is extensively metabolized in the liver by the cytochrome P450 system, predominantly CYP 2D6 and production of a toxic intermediate or immunogenic byproduct are reasonable explanations. Atomoxetine is susceptible to drug-drug interactions with other substrates that use CYP 2D6 as well as inducers and inhibitors of the enzyme. Patients who have low or absent levels of CYP 2D6 (poor metabolizers) may have high plasma levels of atomoxetine and have more severe adverse events when receiving conventional doses, and those with high CYP 2D6 levels (ultrafast metabolizers) may have low plasma levels and fail to respond to treatment.

Outcome and Management

The liver injury due to atomoxetine varies from minor, transient and asymptomatic elevations in serum aminotransferase levels to clinically apparent hepatitis that can be prolonged and even fatal. Chronic liver injury and vanishing bile duct syndrome due to atomoxetine have not been described. Atomoxetine should be discontinued if jaundice or symptoms of liver injury accompany serum enzyme elevations during treatment or if aminotransferase levels rise to above 5 times the upper limit of normal. There does not seem to be cross reactivity to hepatic injury between atomoxetine and other agents used for ADHD, but there may be cross reactivity with other norepinephrine reuptake inhibitors.

Drug Class: Central Nervous System Stimulants; ADHD Agents


Case 1. Acute hepatitis in a child treated with atomoxetine.(1)

A 12 year old girl with ADHD developed abdominal pain, nausea, diarrhea and jaundice three weeks after restarting atomoxetine (40 mg daily). She had no previous history of liver disease or risk factors for viral hepatitis. She had received atomoxetine for approximately one year, but stopped taking it when she ran out of the medication, leading to an interruption of therapy for 6 weeks before restarting. She was not taking any other medications, over-the-counter drugs or herbals. On examination, she was jaundiced and had mild right upper quadrant tenderness without hepatomegaly or other manifestations of chronic liver disease. She had no fever or rash. Laboratory tests showed a total bilirubin of 9.1 mg/dL (direct 5.5 mg/dL) and marked elevations in serum aminotransferase levels (ALT 3264 U/L, AST 2999 U/L), with minimal increase in alkaline phosphatase (231 U/L) and gamma glutamyl transpeptidase (108 U/L) (Table). Tests for hepatitis A, B and C were negative. Antinuclear antibody was positive in a titer of 1:160; smooth muscle antibody was negative. There was no hypergammaglobulinemia, and total IgG levels were normal (769 mg/dL). A liver biopsy showed focal hepatocyte necrosis and marked portal and parenchymal inflammatory infiltrates, with minimal fibrosis and normal bile ducts. Atomoxetine was discontinued and she was monitored on no specific therapy. She improved markedly over the next six weeks, and liver tests were normal when tested six months later.

Key Points

Medication:Atomoxetine (40 mg daily)
Pattern:Hepatocellular (R=39)
Severity:3+ (jaundice, hospitalization)
Latency:3 weeks (reexposure)
Recovery:~6 weeks
Other medications:None

Laboratory Values

Time After
Time After
Alk P
0Atomoxetine (40 mg daily) started
3 weeks019793638.0Atomoxetine stopped
5 weeks2 weeks9.8Liver biopsy
7 weeks4 weeks14381772.6
9 weeks6 weeks1071821.6
7 months6 months<151760.3
Normal Values <50 <397 <1.2


A young girl who had previously taken atomoxetine without difficulty developed an acute, self-limited hepatitis 3 weeks after restarting it. The hepatitis was accompanied by autoantibody formation, but without elevations in globulins or IgG levels. She improved upon stopping atomoxetine and corticosteroids were not used. Drug induced liver injury due to atomoxetine is rare, but several instances of an acute hepatitis-like syndrome arising within 3 to 12 weeks of starting or restarting the medication have been reported in patients without any other obvious reason for acute liver injury. The injury is usually hepatocellular with markedly elevated serum aminotransferase levels (as in this case). Recurrence with reexposure has been reported and should be avoided.



Atomoxetine – Generic, Strattera®


Central Nervous System Stimulants


Product labeling at DailyMed, National Library of Medicine, NIH


Atomoxetine 82248-59-7 C17-H21-N-O.Cl-H image 135013193 in the ncbi pubchem database


Lim JR, Faught PR, Chalasani NP, Molleston JP. Severe liver injury after initiating therapy with atomoxetine in two children. J Pediatr. 2006;148:831–4. [PubMed: 16769398]


References updated: 25 August 2021

Abbreviations: ADHD, attention deficit/hyperactivity disorder.

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    (Expert review of hepatotoxicity published in 1999; atomoxetine is not mentioned).
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    (Drugs approved for use in ADHD in the US include atomoxetine, amphetamines and methylphenidate; common side effects of atomoxetine include somnolence, nausea and decreased appetite; “Hepatic toxicity has been reported rarely”).
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    (Two cases; 12 year old girl developed jaundice 3 weeks after restarting atomoxetine [bilirubin 9.1 mg/dL, ALT 3264 U/L, Alk P 231 U/L, ANA 1:160, IgG 769 mg/dL], resolving in 8 weeks of stopping [Case 1]; 11 year old girl developed fatigue 3 months after starting atomoxetine [bilirubin 0.5 mg/dL, ALT 675 U/L, Alk P 96 U/L, ANA 1:320, IgG 7,390 mg/dL] and biopsy suggesting chronic hepatitis, hepatitis improving within a few weeks of starting prednisone).
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    (Among 30 children with suspected drug induced liver injury, 3 were attributed to atomoxetine and one to methylphenidate).
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    (10 year old boy developed fatigue 2 days and jaundice 5 days after starting atomoxetine [bilirubin 5.2 rising to 23.0 mg/dL, ALT 942 to 2832 U/L, Alk P 400 U/L, INR 4.1], with progressive liver failure, encephalopathy and emergency living donor liver transplantation).
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    (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 atomoxetine).
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    (Atomoxetine is metabolized by CYP 2D6 and is sensitive to the effects of various variants that can create ultrafast, normal, intermediate or poor metabolizers, which can create low or high plasma levels with conventional dosages).
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    (Among 391 Asian adults with ADHD treated with atomoxetine or placebo for 10 weeks, improvements in ADHD rating scores were greater with atomoxetine and adverse events included nausea, decreased appetite, drug mouth, thirst, vomiting, weight loss, dizziness and dysuria, discontinuations occurring in 5% vs 1.5% of placebo recipients; no mention of ALT elevations or hepatotoxicity).
  • Tumuluru RV, Corbett-Dick P, Aman MG, Smith T, Arnold LE, Pan X, Buchan-Page KA, et al. Adverse events of atomoxetine in a double-blind placebo-controlled study in children with autism. J Child Adolesc Psychopharmacol. 2017;27:708–14. [PMC free article: PMC5651962] [PubMed: 28509573]
    (Among 128 children [ages 5 to 14 years] with ADHD treated with atomoxetine alone or placebo with or without parent training, adverse events linked to atomoxetine included decrease in appetite and fatigue, and "no significant difference of changes in laboratory tests was noted" between the groups).
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    (Among 130 adults with cognitive impairment due to Parkinson disease treated with atomoxetine or placebo for 10 weeks, global scores of attention, working memory and processing speed did not improve with atomoxetine, but adverse events were more frequent, while laboratory monitoring of “liver function did not reveal any clinically significant changes”).
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    (Systematic review of efficacy and safety of drugs for ADHD based upon 48 trials [4169 participants]; makes no mention of ALT elevations or hepatotoxicity of any of the agents studied, including guanfacine).
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    (Review of the pharmacological therapy of ADHD with discussion of amphetamines, methylphenidate, atomoxetine, guanfacine and clonidine; no mention of ALT elevations during therapy or hepatotoxicity).
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    (Review of drug-drug interactions of agents used to treat ADHD mentions that there is little information on the metabolism of clonidine and possible drug-drug interactions).
  • Drugs for ADHD. Med Lett Drugs Ther. 2020;62(1590):9–15. [PubMed: 31999670]
    (Concise review of drugs for attention deficit/hyperactivity disorder mentions that atomoxetine is a nonstimulatory agent that is less effective but sometimes better tolerated than methylphenidate, rare but severe adverse events include hepatitis [rarely] growth delay, increase in blood pressure and pulse and priapism).
  • Abrams M, Hasan S, Mehta A. liver enzyme elevation from atomoxetine use–a case report. J Child Adolesc Psychopharmacol. 2021;31:322–323. [PubMed: 33970028]
    (17 year old transgender male with ADHD on long term atomoxetine was found to have mild serum aminotransferase elevations without symptoms [ALT 71 U/L initially and then 52 U/L 3 months and 19 U/L 6 months after stopping]; no information on body weight, ultrasound findings, or hepatitis serology).


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