Drug-Induced Liver Injury in Children: Atomoxetine and Nonstimulants for ADHD

Drug-induced liver injury (DILI) is most commonly reported with acetaminophen products and isotretinoin¹ ; other medications such as antibiotics and anticonvulsants are also commonly implicated.^1,2 Excluding undetermined causes, DILI has been found to be a more prevalent cause of acute liver failure in children than autoimmune hepatitis and viruses^.3

Atomoxetine, a nonstimulant medication approved for attention-deficit/hyperactivity disorder (ADHD), has also been associated with DILI in children. Approximately 2% of children newly diagnosed with ADHD are started on atomoxetine; the remainder start treatment with stimulants, methylphenidate in particular.⁴ This trend is likely due to guidelines that recommend stimulants based on their superior efficacy compared with atomoxetine,⁵ or lack of reimbursement for atomoxetine without a previous stimulant failure.⁶ In 2004, the FDA issued a serious liver injury warning to atomoxetine’s packaging due to post marketing data detailing 6 case reports of liver injury.⁷ As of 2002, 59 cases of suspected atomoxetine DILI have been reported⁸ —only 8 of the 59 are confirmed as being due to atomoxetine use, the other 51 are only suspected. However, atomoxetine is an attractive alternative to traditional stimulant therapy in ADHD due to its milder sideeffect profile and its status as a noncontrolled substance.

This review will summarize information about atomoxetine, DILI in children, and published cases of DILI with atomoxetine; additionally, it will identify children and adolescents who may be at an increased risk for DILI with atomoxetine, provide clinicians with recommendations regarding monitoring, and discuss approved and nonapproved alternative nonstimulant options for the treatment of ADHD.

Atomoxetine

Atomoxetine is a nonstimulant medication indicated for ADHD. It is approved for children 6 years and older and works by blocking the presynaptic reuptake of norepinephrine.⁹ Atomoxetine is metabolized by cytochrome P450 (CYP) 2D6 liver enzymes. Inhibitors of CYP2D6—such as the psychiatric medications paroxetine, fluoxetine, and bupropion—can increase plasma concentrations of atomoxetine. Although atomoxetine has a milder side-effect profile compared with stimulant medications, it, like stimulants, can also be associated with decreased appetite, nausea, vomiting, and abdominal pain. Unlike stimulants, atomoxetine has a black box warning for suicidal ideation in children and adolescents; however, it lacks the black box warning for abuse potential. In addition to the risk of hepatotoxicity, additional warnings include those for cardiac events, emergence of psychotic or manic symptoms, risk of priapism, and worsening of aggressive behavior.⁹

Efficacy studies comparing atomoxetine with stimulants such as methylphenidate have revealed inconsistent results. Atomoxetine was not inferior to immediate-release methylphenidate,¹⁰ yet it was less effective than osmotically released methylphenidate¹¹ and extended-release (ER) mixed amphetamine salts.¹² Additionally, atomoxetine has a delayed onset which can be as long as 4 weeks, unlike stimulants, which can show therapeutic benefits within hours.13

The 2011 American Academy of Pediatrics (AAP) guidelines5 recommend atomoxetine as a second-line treatment for ADHD after stimulants have failed or have proved intolerable.

Drug-Induced Liver Injury in Children

DILI in children appears to be a rare occurrence. A 2010 case analysis on adverse drug reactions (ADRs) in children found that 1% of ADRs were attributed to hepatic events.¹

The presenting symptoms of DILI in children are similar to those in adults. The most common include jaundice, abdominal pain, and nausea. In the same study that evaluated 30 children who developed DILI, laboratory results included elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT); median levels were 503/727 units/liter (U/L) (AST/ ALT) with 75% of subjects reaching levels above 1500 for both measures. While jaundice is common in children with DILI, it is generally less likely in children than in adults.^2,7

Hepatocellular damage is a more commonly reported cause of DILI in children compared with cholestatic injury.⁷ Case studies with atomoxetine suggest primarily idiosyncratic causes; 2 published cases confirmed autoimmune mechanisms.^14,15

Lack of CYP2D6 maturity and the potential for genetic differences in metabolism do not appear to be the cause of acute liver injury with atomoxetine in children and adolescents. By 5 years of age, a child’s level of the CYP2D6 enzyme is 75% of that of an average adult,16 and pharmacokinetic data from atomoxetine studies suggest that in terms of activity and phenotypic differences in metabolism rates, CYP2D6 is equivalent in children and adults.¹⁷

Documented Cases of DILI With Atomoxetine

Currently, there are 8 published case studies of atomoxetine-induced hepatitis—1 was later attributed to type 1 autoimmune hepatitis.¹ Five of the 8 cases involved females (

Table

), and in 3 of the 5 female patient cases, ALTs were greater than 2900 U/L. Although there does not seem to be a clear correlation between the timing of drug initiation and DILI, age may be a predictive factor for females as the most significant increase in ALT was reported in an 8-year-old female. In most cases, the affected children began to show symptoms within weeks of initiating therapy, and the earliest case emerged after 2 days—in that case, a liver transplant in a 10-year-old male resulted. His experience highlights the potential acuity in younger patients; additionally, this case was quite different from the other 7, in which recovery occurred in both males and females over a time span ranging from 2 weeks to 6 months after discontinuation of atomoxetine.

Females ranged in age from 8 to 12.8 years,^7,14 with the 8-year-old taking the relatively low daily dose of 25 mg.¹⁸ Males ranged in age from 7.8 to 14 years.^7,15,18 In 4 of the cases, symptoms were apparent within less than 1 month; in the other 4, symptom onset occurred between 4 months¹⁸ and 23 months after treatment initiation^.7 This variability in timing of symptom onset highlights the possible need for routine monitoring of liver function with patients on atomoxetine starting within the first month of treatment.

The youngest reported case, case A, was an 8-year-old female who was on atomoxetine therapy for 1 month at 25 mg daily prior to symptom onset. She had received a single dose of mebendazole and intermittent acetaminophen prior to presentation. She had a 2-day history of emesis and abdominal pain. Liver enzymes revealed 4505/4266 U/L (AST/ALT). Total bilirubin was 8.0 mg/dL. Physically the patient was jaundiced with scleral icterus and hepatomegaly. Viral serology was negative and a toxicology screen confirmed undetectable acetaminophen concentrations. The patient also received N-acetylcysteine prior to ruling out acetaminophen toxicity. Biopsy results indicated portal inflammation composed of lymphocytes, neutrophils, and few eosinophils. Atomoxetine was discontinued and liver function tests (LFTs) improved over the next 13 days.¹⁸

In 4 additional cases, the females were older. In 2 of them (B and C, below), symptoms first appeared in case B within 3 weeks of initiating atomoxetine, while symptoms first appeared within 4 months for case C.¹⁴ In the other 2 (D and E, below), symptoms presented at 4 and 17 months.⁷ In case B, a 12-year-old female presented to the hospital—3 weeks after restarting 40 mg atomoxetine daily—with symptoms of abdominal pain, severe lethargy, nausea, diarrhea, right upper quadrant tenderness, and jaundice. She was negative for hepatomegaly and LFTs were 2999/3264 U/L (AST/ALT) with total bilirubin of 9.1 mg/dL; the patient had not received other medications. Viral serology was negative and liver biopsy showed focal hepatocyte necrosis. Atomoxetine was discontinued and LFTs returned to normal 6 months later.¹⁴ In case C, an 11-year-old female who was titrated from 10 mg daily to 30 mg daily over 3 months presented with symptoms of severe fatigue and a temperature >37°C that developed over 10 days. LFTs were 1483/675 U/L (AST/ ALT) and total bilirubin was 0.5 mg/dL. Viral serology was negative and liver biopsy revealed hepatitis with focal portal inflammatory bridging and fibrosis. Atomoxetine was discontinued and the patient was treated with prednisone and azathioprine. Liver enzymes improved to 34/61 U/L (AST/ALT) and total bilirubin remained at 0.5 mg/dL after 5 months.¹⁴

Female cases of DILI with atomoxetine where symptoms appeared later than 3 months after initiation include case D, an 11.5-year-old female who presented with a peak ALT of 732 U/L, alkaline phosphatase (ALP) of 222 U/L, and total bilirubin of 1.6 mg/dL. The patient was on 117 days of atomoxetine therapy until the onset of symptoms. The dose was not reported and a possible association between atomoxetine and hepatitis with bridging fibrosis was determined.⁷

In case E, a 12.8-year-old female had been on atomoxetine for 510 days before presenting with nausea, abdominal pain, and jaundice, with peak ALT and ALP of 2999 and 296 U/L, respectively. Peak total bilirubin was 11.5 mg/dL. The dose was not reported and she was diagnosed with cholestatic hepatitis with extensive interface hepatitis.⁷

Male cases of atomoxetine DILI included boys aged 7.8 (case F), 10 (case H), and 14 (case G) years. The youngest, case F, was on atomoxetine for 699 days until experiencing nausea, abdominal pain, and severe lethargy. Liver enzymes revealed 781/321 U/L (ALT/ALP) and peak total bilirubin of 1.1 mg/dL. He was diagnosed with mild chronic hepatitis and no cholestasis. Atomoxetine was discontinued and symptoms resolved^.7

In case G, the 14-year-old male taking atomoxetine, sertraline, and omeprazole began to experience symptoms 3 to 4 months after initiating atomoxetine 40 mg twice daily. He presented to the emergency department with 24 times (×) and 31× the upper limit of normal (ULN) (AST/ALT) and total bilirubin of 1.2 times UNL; autoimmune conditions were ruled out. Atomoxetine and sertraline were discontinued and the patient’s liver function returned to normal within 2 months.

The same 14-year-old male was rechallenged with atomoxetine 40 mg daily and within 5 weeks of initiating therapy ALT was 233 UNL and total bilirubin was 143 UNL. A liver biopsy showed neutrophilic inflammatory reaction and cholestatic congestion, but no fatty change, no zonal predominance, and overall no distinguishing features. The patient’s LFTs normalized over the following 4 months when atomoxetine was discontinued and supportive care was instituted.¹⁸

The most severe case, Case H, was a 10-year-old boy who had a history of taking imipramine and methylphenidate with normal liver tests prior to starting atomoxetine 40 mg daily. After 2 days of atomoxetine treatment, the patient began to experience fever, weakness, drowsiness, and vomiting. Viral serology was negative. LFTs were 913/942 U/L (AST/ALT) and total bilirubin was 5.2 mg/dL. On day 5, he developed scleral icterus and LFTs continued to increase to 4040/2832 U/L (AST/ALT), with total bilirubin of 6.5 mg/dL. He was subsequently diagnosed with acute liver failure and plasmapheresis was performed for 4 days. Despite these measures, hepatic encephalopathy developed and the patient was referred for liver transplant and is receiving tacrolimus and mycophenolate for immunosuppressive treatment.¹⁵

Other Approved Options for the Treatment of ADHD

Clonidine ER and guanfacine ER, both alpha2 -adrenergic agonists, are approved by the FDA as options for monotherapy in the treatment of ADHD or as adjunctive therapy with stimulants. The American Academy of Pediatrics (AAP) guidelines recommend either clonidine ER or guanfacine ER as nonstimulant options with slightly less evidence for efficacy when compared with atomoxetine.⁵ Both medications are associated with drowsiness, dizziness, headache, fatigue, and xerostomia.^19,20 It is not recommended to take guanfacine ER with a high-fat meal as this can increase the area under the curve by up to 40%.20 Liver test abnormalities and/ or hepatitis are listed as potential but rare side effects and neither medication has a warning^19,20 or case reports amantadine²⁷ and venlafaxine²⁸ were tested head-to-head against methylphenidate and there were no differences in rating scales between the medications, indicating similar efficacies in ADHD symptom reduction. Amantadine has rarely been associated with a reversible increase in liver enzymes,²⁹ and venlafaxine has several case reports of DILI that resolved when venlafaxine was discontinued.^30-33 There are no reported cases of DILI in children with either amantadine or venlafaxine. Buspirone^34,35 and gingko biloba³⁶ both were associated with reduction of ADHD symptoms, though they were neither equivalent nor superior to methylphenidate.of DILI.

CONCLUSIONS

Stimulants are considered first-line therapy for ADHD and have superior efficacy over nonstimulant choices that are FDA-approved for ADHD. Due to the potential for intolerability and abuse of stimulants, atomoxetine is a nonstimulant second-line choice that has a milder side-effect profile and lacks abuse potential. Unlike the stimulants, however, atomoxetine has a warning for DILI, particularly in the pediatric population. Considering the variability of DILI symptom onset (2 days to 23 months), routine monitoring of LFTs is recommended during therapy and initially within the first 30 days of treatment. If a patient presents with symptoms of hepatotoxicity, or if an increase in LFTs is observed subsequent to atomoxetine use, prompt discontinuation of atomoxetine is recommended and a rechallenge should not be considered. An alternative second-line therapy that has shown benefits in symptom reduction for ADHD is recommended. The alpha2 -adrenergic agonists clonidine ER and guanfacine ER are both approved and recommended as alternatives to atomoxetine by the AAP and do not have hepatotoxic warnings. Non-approved considerations may include bupropion, amantadine, or venlafaxine, which have been shown in randomized, blinded clinical trials to be as effective in symptom reduction as methylphenidate. Both bupropion and venlafaxine have recorded cases of DILI in adult patients yet do not have hepatotoxic warnings. In order to offer patients and clinicians more options, additional medications with a lack of abuse potential and improved tolerability are needed for the treatment of ADHD.