QuarterWatch (Special Report): Adverse drug events in children less than 18 years old
January 16, 2014

QuarterWatch™ is an ISMP surveillance program that monitors serious, disabling, and fatal adverse drug events (ADEs) reported to the US Food and Drug Administration (FDA) by manufacturers, healthcare professionals, and the public. The goal of QuarterWatch™ is to improve patient safety through the identification of signals that may represent important drug safety issues. The term signal means evidence judged to be substantial enough to warrant publication but which requires further investigation to determine its frequency of occurrence and establish a causal relationship to the suspect drug. The latest QuarterWatch™ examines ADEs in children less than age 18 that have been reported to FDA during a 5-year span between 2008 and 2012.

Reporting Totals

During these 5 years, 45,610 ADEs were reported in children less than 18 years old. Of these, approximately 64% (29,298) involved reports of a serious injury. The number of reports in children grew substantially over time—from 6,320 in 2008 to 11,401 in 2012. The rate of increase in pediatric reports (80%) was the same as the rate of increase for adult reports during that time. The 5-year totals included 2,935 (6%) deaths, 10,032 (22%) cases that required hospitalization, 774 (2%) cases that required intervention, 1,430 (3%) cases considered life-threatening, and 816 (2%) cases of disability. A U-shaped curve of the data revealed that the greatest number of cases occurred in the first year of a child’s life, then declined and leveled off until adolescence, when cases again rose rapidly.

Comparison of Reported and Actual Events

The 45,610 ADEs in children reported to FDA likely represent just a portion of the actual events, according to a 2009 FDA study.1 Data from various years and sources reveal that a mean of about 586,000 children visit the doctor’s office or other outpatient facility for treatment of ADEs, mostly involving mild rashes or gastrointestinal (GI) distress.2 More severe ADEs account for an additional 160,000 emergency room visits per year, mostly to treat unintentional overdoses and allergic reactions.3 More serious ADEs in children that cause hospital admissions are difficult to estimate. Published data suggest that approximately 1 to 2 per 100 children experience an ADE requiring medical treatment per year.1-3 Overall, improvements are needed to expand active surveillance and spontaneous reporting of ADEs in children.1

15 Most Frequently Reported Drugs

To identify signals of potential safety problems in children, a subset of serious adverse event reports that resulted from normal or expected use of the drugs was identified. These more restrictive criteria captured 16,992 reports involving 741 different drugs between 2008 and 2012. Just 15 (2%) of the 741 drugs accounted for 41% of all reports in this category during the 5-year period (Table 1, see page 2 in PDF version). Although only 6 of the 15 drugs have intended psychotropic effects, psychiatric adverse events were prominent for 10 of the 15 drugs. They included suicidal ideation (n=714), aggression (n=686), and abnormal behavior (n=580). Suicidal behaviors were not limited to thoughts of suicide but also included 274 completed suicides, 159 attempted suicides, and 100 cases labeled “self-injurious behavior.” Also reported were various forms of psychosis, including hallucination (n=276), psychotic disorder (n=124), and paranoia (n=74).

Highlights of the List

Three drugs used to treat ADHD. Psychiatric side effects, particularly suicidal behaviors, aggression, hallucinations, and other manifestations of psychosis, were predominant for methylphenidate (CONCERTA, RITALIN), lisdexamfetamine (VYVANSE), and atomoxetine (STRATTERA), three medications often used to treat attention deficit hyperactivity disorder (ADHD). Atomoxetine shares a suicidal behavior warning in official prescribing information similar to antidepressants. The two central nervous system stimulants, lisdexamfetamine and methylphenidate, are not required to warn about suicidal behaviors, even though such events were reported in 26% and 14% of all cases, respectively, in the data we analyzed. Previously, FDA studied the incidence of hallucinations and other forms of psychosis when taking the stimulants and required a warning about these potential adverse effects.4 FDA should also assess the need for a warning for the more frequently reported suicidal thoughts and behaviors.

Non-psychiatric adverse effects were also reported with these three drugs. The most frequently reported adverse event for methylphenidate was 37 cases of sudden death; the prescribing information currently contains a warning about this, but the literature is mixed.5-6 Cardiac effects were also reported for atomoxetine, including chest pain (n=16), syncope (n=11), and prolonged QT interval (n=10). Movement disorders were reported for lisdexamfetamine, including dyskinesia (n=17), tics (n=16), and tremor (n=9). Weight loss or arrested growth was also reported for all three drugs.

Three antipsychotic drugs. The full spectrum of antipsychotic adverse drug effects that occur in adults was also reported in children for ARIPiprazole (ABILIFY), QUEtiapine (SEROQUEL), and risperiDONE (RISPERDAL). Suicidal behaviors were reported for all three drugs, accounting for 25% of QUEtiapine cases, 19% of risperiDONE cases, and 10% of ARIPiprazole cases. Reports of dyskinesia, tics, weight gain, and sexual organ adverse effects were seen for ARIPiprazole, QUEtiapine, and risperiDONE. The reports occurred in children being treated for a wide range of disorders but most frequently depression or bipolar disorder.

Asthma and acne drugs. Montelukast (SINGULAIR) for asthma and allergies, and ISOtretinoin (CLARAVIS) for acne, are notable examples of drugs with numerous reported psychiatric effects but no intended psychotropic action. Montelukast produced a high number of serious adverse event reports, predominantly psychiatric effects including suicidal behaviors, aggression, and depression. Reports surged in 2008, and then tapered off substantially. For ISOtretinoin, suicidal behaviors number among other prominent adverse effects, including birth defects, warranting consideration prior to use of this medication for severe and resistant acne. Other major reported adverse effects included depressed mood (n=101) and colitis (n=20). 

Analgesic and anticonvulsant drugs. Among the over-the-counter (OTC) and prescription analgesics used in children, ibuprofen produced an unexpectedly large number of cases (n=32) of severe hypersensitivity and skin reactions, notably Stevens-Johnson syndrome and toxic epidermal necrolysis. These skin reactions were seldom reported for acetaminophen and naproxen. Severe skin reactions were even more numerous for another top-15 drug, the anticonvulsant lamoTRIgine (LAMICTAL) (n=66), which currently carries a warning about this adverse effect in its official labeling. Its first-line use as adjunctive therapy for seizures should be reevaluated, and its approved use for maintenance in bipolar disorder should be reconsidered.

Two anti-TNF agents. Reports for two anti-tumor necrosis factor (anti-TNF) agents showed that adverse events occurred in two different populations. InFLIXimab (REMICADE) events (n=1,772) primarily affected the GI tract and occurred in patients treated for GI tract disorders including Crohn’s disease and ulcerative colitis. The largest group of adverse events suggested treatment failures, which the manufacturer attributed to disease flares despite an overall benefit of treatment. Etanercept (ENBREL) adverse events (n= 231) were primarily reported in patients treated for juvenile idiopathic arthritis and psoriasis and were frequently related to infection and infusion site reactions. Because of differences in juvenile patient populations and likely differences in exposure (inFLIXimab has more indications for treatment in children), the 7-fold difference in the number of reported serious ADEs does not necessarily imply higher relative risks for inFLIXimab compared to etanercept. However, the results in both children and adults continue to show that anti-TNF agents are high-risk treatments requiring vigilance.

Where Cases Were Few

Three of the most widely used drugs in children accounted for few reported serious adverse events in our analysis. For example, 28 million pediatric patients out of a population of 74 million were prescribed amoxicillin and/or azithromycin in 2010.7 However, azithromycin accounted for only 51 reports over 5 years, and amoxicillin only 41 reports. Albuterol, another drug often used with children, was prescribed to about 7% of all children7 but accounted for only 56 serious adverse events in our primary analysis group. The low volume of reports for these medications may not only attest to the safety of these widely used drugs, but also reflect short-term or intermittent use as well as very low reporting rates.

Read the full QuarterWatch™ report at:  


1) Johann-Liang R, Wyeth J, Chen M, Cope JU. Pediatric drug surveillance and the Food and Drug Administration’s adverse event reporting system: an overview of reports, 2003-2007. Pharmacoepidemiol Drug Saf. 2009;18(1):24–7.

2) Bourgeois FT, Mandl KD, Valim C, Shannon MW. Pediatric adverse drug events in the outpatient setting: an 11-year national analysis. Pediatrics. 2009;124(4):e744–50.

3) Cohen AL, Budnitz DS, Weidenbach KN, et al. National surveillance of emergency department visits for outpatient adverse drug events in children and adolescents. J Pediatr. 2008;152(3):416–21.

4) Mosholder AD, Gelperin K, Hammad TA, Phelan K, Johann-Liang R. Hallucinations and other psychotic symptoms associated with the use of attention-deficit/hyperactivity disorder drugs in children. Pediatrics. 2009;123(2):611–6.

5) Olfson M, Huang C, Gerhard T, et al. Stimulants and cardiovascular events in youth with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2012;51:147–56.

6) Winterstein AG, Gerhard T, Kubilis P, et al. Cardiovascular safety of central nervous system stimulants in children and adolescents: population based cohort study. BMJ. 2012;345:e4627.

7) Chai G, Governale L, McMahon AW, et al. Trends of outpatient prescription drug utilization in US children, 2002-2010. Pediatrics. 2010;130(1):23–31.

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