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. Atomoxetine was approved for use in adults, adolescents and children above the age of 6 years with attention deficit hyperactivity disorder 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 potentiall severe adverse events include suicidal ideation and behavior, cardiovascular symptoms and events, manic or aggressive behavior 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.
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 there are any symptoms of liver injury that accompany serum enzyme elevations. There does not seem to be cross reactivity to hepatic injury with the other agents used for attention deficit hyperactivity disorder, but there may be cross reactivity with other norepinephrine reuptake inhibitors.
Case 1. Acute hepatitis in a child treated with atomoxetine.
[Modified from Case 1 of: 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 Citation]
A 12 year old girl with attention deficit-hyperactivity disorder 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.
|Medication:||Atomoxetine (40 mg daily)|
|Pattern:|| Hepatocellular (R=39)|
||3+ (jaundice, hospitalization)|
||3 weeks (re-exposure)|
|| ~6 weeks|
|Time After Starting
||Time After Stopping
||Alk P (U/L)
||Atomoxetine (40 mg daily) started
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.
REPRESENTATIVE TRADE NAMES
Atomoxetine – Generic, Strattera®
Central Nervous System Stimulants
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NUMBER
References updated: 27 July 2017
Abbreviations: ADHD, attention deficit hyperactivity disorder
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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 Citation (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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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. PubMed Citation (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 one attributed to cocaine and one to ecstasy but none to atomoxetine).
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ADHD Registry. CNS Drugs 2015; 29: 865-77. PubMed Citation (The Italian ADHD Registry of children treated with methylphenidate [n=1350] and atomoxetine [n=753] included adverse events reports in 27% of cases and serious events in 4%, more frequently with atomoxetine among which were 3 cases of hyperbilirubinemia which were considered possibly life-threatening).
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