Video Abstract
Off-label drug use in children is common and potentially harmful. In most previous off-label use research, authors studied hospitalized children, specific drug classes, or non-US settings. We characterized frequencies, trends, and reasons for off-label systemic drug orders for children in ambulatory US settings.
Using nationally representative surveys of office-based physicians (National Ambulatory Medical Care Surveys, 2006–2015), we studied off-label orders of systemic drugs for children age <18 based on US Food and Drug Administration–approved labeling for age, weight, and indication. We characterized the top classes and diagnoses with off-label orders and analyzed factors and trends of off-label orders using logistic regression.
Physicians ordered ≥1 off-label systemic drug at 18.5% (95% confidence interval: 17.7%–19.3%) of visits, usually (74.6%) because of unapproved conditions. Off-label ordering was most common proportionally in neonates (83%) and in absolute terms among adolescents (322 orders out of 1000 visits). Off-label ordering was associated with female sex, subspecialists, polypharmacy, and chronic conditions. Rates and reasons for off-label orders varied considerably by age. Relative and absolute rates of off-label orders rose over time. Among common classes, off-label orders for antihistamines and several psychotropics increased over time, whereas off-label orders for several classes of antibiotics were stable or declined.
US office-based physicians have ordered systemic drugs off label for children at increasing rates, most often for unapproved conditions, despite recent efforts to increase evidence and drug approvals for children. These findings can help inform education, research, and policies around effective, safe use of medications in children.
In past studies, pediatric off-label use was shown to be common and potentially harmful, but researchers have focused predominantly on acute care settings, specific classes of drugs, outpatient prescribing outside the United States, or older data sources.
In 2006–2015, US office-based physicians ordered systemic drugs off label for children at rising rates, particularly for unapproved conditions. Updated data on common off-label drugs, classes, and unapproved conditions treated in children will help inform education, research, and policies.
Children often take drugs off label, outside of an approved age, indication, weight, dose, formulation, or route of administration.1–3 Off-label prescribing has been associated with higher rates of adverse effects in children.4 However, off-label prescribing is legal and can represent best practice on the basis of extensive clinical experience and supporting evidence of efficacy and safety, particularly when no labeled alternatives exist.1,5 Laws and policies including the Best Pharmaceuticals for Children Act (2002), Pediatric Research Equity Act (2003), and the European Pediatric Regulation (2007) have incentivized or mandated pediatric clinical trials, intending to increase the quality of evidence and number of drugs approved for children.6–8 Nonetheless, many drugs remain off-label for children, and legislative efforts to stimulate clinical trials for both new and off-patent drugs may not yet have realized their potential.9,10
Reported rates of off-label drug use in children vary widely across studies, owing to differences in definitions of off-label usage, methodology and sampling, composition of the study population (eg, age range), number of drugs considered, geography, and settings of care (eg, inpatient versus ambulatory).3 Particularly high rates of off-label pediatric drug use have been reported in inpatient settings (36%–92%), especially neonatal and PICUs (80%–97%).3,4,11 Nonetheless, the vast majority of children receive care and medicines exclusively in the outpatient setting.12 Studies of off-label prescribing in outpatient settings have often been focused on select drugs or drug classes (eg, antidepressants).13,14 A more comprehensive study of pediatric drug prescribing in ambulatory US settings was limited to 4 years of data through 2004.15 More recent studies on outpatient off-label pediatric drug use have come predominantly from European countries, which have different systems of care, prescribing practices, regulations, and populations than the United States.16–21 We sought to describe recent patterns of drugs ordered off label in a US-representative ambulatory pediatric population, including time trends and common diagnoses with off-label orders, focusing on systemic drugs because of their greater potential for drug toxicity.
Methods
Study Design and Setting
We conducted a retrospective study of serial, cross-sectional data from the National Ambulatory Medical Care Survey (NAMCS) (2006–2015).22 This annual survey is used to collect anonymous, visit-level data from US office-based physicians, including demographics, reasons for visit, diagnoses, and drugs provided or ordered at the visit, including recommended over-the-counter (OTC) drugs. NAMCS data are collected through a probability-based, complex sampling design that allows researchers to produce nationally representative estimates. This study was determined by the Rutgers Institutional Review Board to be nonhuman subjects research (Pro20170000577).
Study Population
We included all visits for children <18 years old. We focused on the 141 drugs predominantly or exclusively used in systemic formulations and ordered at least 30 times in the data set (Supplemental Information, Supplemental Table 6). We used the Anatomical Therapeutic Chemical (ATC) classification to present drug data based on broad categories (level 1) and drug classes (level 3) corresponding to the predominant systemic use (Supplemental Information). We excluded from consideration vaccines, vitamins, and drugs no longer US Food and Drug Administration (FDA)–approved because of withdrawal of market authorization (mostly cough medicines).
Off-Label Definitions
Our main outcomes of interest were absolute and relative prevalence rates of off-label orders of systemic drugs. Absolute prevalence was defined as the number of drugs ordered per 1000 visits; relative prevalence was defined as the percentage of off-label orders among all ordered drugs. We defined off-label usage on the basis of US drug labeling as recorded in the Prescribers’ Digital Reference and the FDA Web site in 2018.23,24 Off-label status was determined by using the following criteria (see also Supplemental Information, Off-Label Definitions):
Age: Drugs were considered off label by age when ordered for children younger than the approved age for any indication.
Weight: Drugs were considered off label by weight when weight was specified in the product labeling and drugs were ordered for a child weighing less than the approved weight for any age or indication. Drugs were considered possibly off label when weight was missing.
Indication: Drugs were considered off label by indication when ordered in visits without a documented condition corresponding to an FDA-approved indication. For each ordered drug at each visit, FDA-approved indications were compared with recorded diagnoses (up to 5 International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes), chronic disease indicators (checkboxes for asthma, depression, etc), and reasons for visit (up to 5 additional symptoms, diagnoses, or other reasons recorded in the NAMCS). Each unmatched drug-visit observation was manually reviewed by 2 individuals, including a practicing pediatrician (D.B.H.). Drugs were considered possibly off label when ordered for nonspecific diagnoses or symptoms broader than the listed FDA-approved indication.
Overall: A drug was considered off label overall when it was off label by age, weight, or indication or ordered for an approved indication at an unapproved age or (when applicable) weight. A drug was considered possibly off label overall when deemed to be possibly off label by indication or weight but not off label by age.
Dose information was unavailable and not considered for off-label status determination.
Independent Variables
Independent variables of interest included age subgroups, sex, race and ethnicity, US geographic region, insurance status, physician specialty, number of systemic drugs ordered, presence of a chronic condition, and calendar year (Supplemental Information).
Data Analysis
We estimated absolute prevalence of systemic and off-label systemic drug orders with 95% confidence intervals (CIs) by taking the mean of orders per visit across visits and multiplying by 1000 to produce rates per 1000 visits. We estimated relative prevalence of off-label drug orders with 95% CI by tabulating the percentage of off-label orders across all visits and visits with systemic drug orders. All estimates were repeated for drug categories, drug classes, drugs, calendar year, and age subgroups. We presented results for the drug classes most commonly ordered off label, including the most common drugs within each class and the most common diagnoses for off-label orders at the level of 3-digit ICD-9-CM codes, excluding nonspecific codes (V20 health supervision child and V67 follow-up examination). We estimated the association of calendar time and other covariates with off-label orders among visits with ≥1 systemic drug order using multivariable logistic regression. We used model-based predictive margins to estimate covariate-specific probabilities of off-label orders with 95% CI. We also used logistic regression to evaluate the relative change in off-label orders over time for more-common drug classes. We performed sensitivity analyses classifying possibly off-label orders as off label.
Analyses were conducted on Stata/MP 14 and 15.1 (Stata Corp, College Station, TX), accounting for the complex sampling design to produce nationally representative estimates. All P values were 2 sided and used an α of .05.
Results
Prevalence of Off-Label Orders
Of the 1.74 billion ambulatory pediatric visits estimated over the 10 years of NAMCS data used in this study, 41.5% (95% CI: 40.5%–42.6%) of these visits resulted in ≥1 order of the 141 systemic drugs studied, totaling 108.0 (95% CI: 105.2–110.9) million orders per year. A total of 18.5% of visits (44.5% of visits with systemic drugs) included ≥1 off-label systemic drug order or 41.2 million off-label orders per year (Table 1). An additional 1.6% of visits had possibly off-label orders because of nonspecific documentation. Of drugs considered off label or possibly off label, 74.6% were off label by indication, 17.6% were off label by age, 0.6% were off label by weight, and 4.7% were off label on the basis of the combination of age, indication, and (when applicable) weight (Table 1).
In absolute terms, off-label orders were most common among adolescents (321.5 orders per 1000 visits) and least common among neonates (52.0 orders per 1000 visits), reflecting to some degree the overall prevalence of systemic drug orders (Table 2). In relative terms, the youngest age groups were most likely to receive medications off label: ∼83% of all neonatal visits and 49% of infant visits with ≥1 systemic drug included ≥1 off-label drug order, compared with 39% to 44% of visits for other age groups (Table 3). Additionally, visits for girls, offices in the South, subspecialists, and presence of polypharmacy or a chronic condition, but not race, ethnicity, or insurance type, were associated with increased relative rates of off-label orders (Table 3).
Among drug categories (ATC level 1), the absolute prevalence of off-label orders was highest for anti-infectives (75 orders per 1000 visits), followed by respiratory drugs and nervous system drugs (each ∼54 orders per 1000 visits) (Table 4). The absolute prevalence of off-label orders for all other drug categories was <30 orders per 1000 visits. Considerable age-related variation in rates of off-label orders existed for certain drug categories, including anti-infective, respiratory, nervous system, and genitourinary drugs, reflecting underlying differences in overall orders by age (Table 4). Of all drug categories and all age groups, absolute rates of off-label orders were highest in nervous system drugs for adolescents (123 orders per 1000 visits). The relative prevalence of off-label orders was variable across drug categories (highest overall for alimentary and genitourinary drugs) and age groups (generally highest for neonates) (Table 5).
According to drug class (ATC level 3), antihistamines were the drug class most commonly ordered off label, followed by penicillins, macrolides plus clindamycin, antidepressants, and cephalosporins (Supplemental Table 7). Within each drug class, the drugs most commonly ordered off label tended to reflect the prevalence of orders overall; however, the relative prevalence of off-label orders occasionally diverged for drugs within the same class (eg, antidepressants: sertraline, 93% and fluoxetine, 37%; nonsteroidal antiinflammatory drugs [NSAIDs]: ibuprofen, 5% and diclofenac, 100%) (Supplemental Table 8). The most common diagnoses in visits with off-label orders generally corresponded to off-label indications (eg, antihistamines for upper respiratory tract infections, antidepressants for attention-deficit/hyperactivity disorder [ADHD]) (Supplemental Table 7). However, certain more-common diagnoses corresponded to indications approved for some but not all drugs within the class (eg, amoxicillin-clavulanate, not approved for pharyngitis) or drugs ordered off label by age (eg, stimulants for young children with ADHD, laxatives for children with constipation). Some diagnoses for visits with off-label drugs were related to approved indications (eg, antihistamines for asthma) yet without documentation of the related conditions (eg, allergic rhinitis). Age groups differed in the drug classes most commonly ordered off label (Supplemental Tables 9 through 13) and the most common diagnoses for off-label ordering (Supplemental Table 14).
Trends of Off-Label Orders
Absolute rates of off-label drug orders increased throughout the study period, predominantly reflecting a rise in off-label orders by indication (Fig 1). After adjusting for other factors, relative rates of off-label ordering were also higher in later years (47.2% in 2012–2015 vs 41.9% in 2006–2008) (Table 3). In analyses by drug class, absolute rates of off-label orders rose over time for numerous classes, including antihistamines, several classes of psychotropic drugs (antidepressants, stimulants, antiepileptics, antiadrenergics), anti-inflammatory drugs (corticosteroids, NSAIDs), and certain gastrointestinal (GI) drugs (reflux drugs, antiemetics) (Supplemental Figs 2–4). Relative changes over time in class-specific off-label orders generally paralleled the observed changes in absolute rates; relative declines were seen for penicillins and antipsychotics along with a marked increase for antiemetics (Supplemental Figs 5–7).
Sensitivity Analyses
In sensitivity analyses, a broader definition of off-label drugs (including possibly off-label orders) produced slightly higher estimates of absolute off-label prevalence and modestly changed the order of the most commonly off-label drug classes; overall, the findings were highly consistent (Supplemental Fig 8, Supplemental Tables 15 through 19).
Discussion
Across 10 years of national US data, office-based physicians ordered ≥1 systemic off-label drug in nearly 1 in 5 of all pediatric visits, most commonly for an unapproved condition. In absolute terms, visits for adolescents most commonly resulted in off-label orders, but in relative terms, off-label ordering was highest among neonates, for whom roughly 5 of 6 systemic drugs ordered were off label. Relative rates of off-label orders were also higher in visits for girls, for children with a chronic condition or multiple drug orders, for subspecialists, and in the US South. The drug classes most commonly ordered off-label were antihistamines (especially for respiratory infections and conditions), several classes of antibiotics (especially for viral infections), and antidepressants (especially for ADHD). GI drugs were more commonly ordered off label for infants, whereas off-label psychotropic drug ordering was highest for adolescents. In both absolute and relative terms, off-label ordering has risen over time, most notably for unapproved conditions. Rates of off-label ordering have increased for antihistamines and several classes of psychotropic, anti-inflammatory, and GI drugs, whereas off-label orders for certain antibiotic classes and antipsychotics have declined.
In an older study in which researchers examined pediatric off-label drug orders using the same data source (NAMCS, 2001–2004), it was found that over 60% of visits with prescribed drugs included off-label orders, significantly higher than our estimated 45%.15 Despite the common data source, that study differed from ours in its inclusion of nonsystemic drugs and exclusion of OTC drugs. In our study, we also used additional information (ie, chronic disease checkboxes and reasons for visit) to establish concordance with labeled indications, which may have also contributed to the lower estimates of off-label orders. In other pediatric studies from US ambulatory settings that have been focused on antidepressants and antipsychotics, researchers have reported similar (and high) relative rates and reasons for off-label prescribing.25,26
Our findings were also consistent with declining trends in antibiotic prescribing over the last 20 years, particularly for certain drug classes, including penicillins and cephalosporins.27,28 Our study also corroborates a recent US antibiotic use study in which it was shown that ∼1/3 of antibiotics dispensed for commercially insured children were either clinically inappropriate or without documented diagnoses, whereas nearly half of all fills were of questionable appropriateness.29 On the other hand, certain class-specific changes in off-label orders (eg, for antihistamines, psychotropic agents) contrast with overall pediatric prescribing trends reported elsewhere.28 These discrepancies may relate to our focus on off-label orders as well as differences in data source and exposure definitions; in our study using the NAMCS, we captured physician-reported data on prescribed and recommended OTC drugs, whereas in a study using the National Health and Nutrition Examination Survey, researchers were focused on self-reported data on prescribed (not OTC) drugs taken (not ordered) in the previous month.
Our findings show lower rates of off-label orders than in other studies from acute and critical care settings.30 Although hospitalized children are a high-risk group for drug-related adverse effects, the vast majority of children are treated exclusively in outpatient settings, where tolerance of risk is also much lower.
It is more difficult to compare our findings with pediatric studies of outpatient off-label drugs from other countries, given the differences in pediatric populations (including age ranges considered), prescribing practices, definitions of off-label usage (age alone, consideration of dose, etc), and number and types of drugs considered.3,11,17,21,31,32 A recent study from southwestern France also showed that indication was a more-common reason for off-label prescribing than age or dose, with relatively high rates of off-label prescribing of antihistamines and antibiotics as well as among children prescribed multiple drugs.16 Overall rates of off-label prescribing were lower overall (as with multiple other European studies), but this may relate in part to their consideration of nonsystemic drugs and assumption that antibiotics prescribed for viral infections were not off label, along with geographic differences in prescribing.3,11,16
Although the prescribing and use of medicines off label is common in pediatrics, off-label drug use is not always off evidence.1,5 Certain more-common indications we identified as off label were, in fact, supported by high-quality evidence, for example, glucocorticoids for croup and ondansetron for vomiting.33,34 Indeed, frequency of off-label use is only 1 of several aspects that should be considered when prioritizing pediatric drug research and policies, including the potential for benefit (eg, common diseases as well as rare diseases with high morbidity or mortality), risk of adverse effects (including from drug-drug interactions), level of uncertainty about relative risks and benefits, and availability of therapeutic alternatives.35–37 Although legislation in the United States and Europe has stimulated research and approvals of drugs for children, in recent studies, it has been shown that completion of required pediatric trials has been delayed beyond the FDA-mandated times.38–40 Additionally, the reporting of results from some required studies in trial registries (eg, ClinicalTrials.gov) and peer-reviewed journals has been incomplete (eg, 15%–24% of completed studies without reported results) and suboptimal (eg, missing elements about study design and reasons for study discontinuation).38,39 Furthermore, efforts to advance research about off-patent drugs, including the Best Pharmaceuticals for Children Act priority list and the European Pediatric Use Marketing Authorization, may be insufficient in producing all of the necessary evidence for safe and effective use of off-patent medicines in children.10,36,41,42 Our study’s focus on systemic drugs (given their greater potential for toxicity) and enumeration of the most common indications with off-label orders complements other efforts to prioritize research and policies for off-label, off-evidence medicines in children.
Our study had several strengths, including its long study period, large and nationally representative study population, and comprehensive evaluation of >140 of the most common systemic drugs ordered for children in clinics across the United States. These data enabled us to identify recent increases in off-label ordering, highlight the drugs and conditions with the most off-label orders, and identify factors associated with off-label drugs that have not been reported in smaller studies.
This study also had limitations. The cross-sectional data within NAMCSs may have limited ascertainment of all relevant indications for drug orders, including historical diagnoses. We excluded less commonly ordered drugs, whose concordance with labeling may have been different from included medications. We were also unable to ascertain drug formulation or dosage, which is a common reason for off-label usage in some settings, thus resulting in a systematic underestimation in overall off-label use.30,43,44 The NAMCS provides data on medicines ordered by physicians, which include medicines not dispensed to or consumed by patients and do not include OTC medicines not ordered by physicians or received in other settings (eg, inpatient). Finally, we did not formally evaluate the evidence behind off-label drugs and indications reported in this study.
Conclusions
Office-based physicians commonly order systemic drugs for children off label, particularly for unapproved conditions. Despite legislation to generate more data on the effects of drugs in children, off-label orders have risen in recent years, most notably of antihistamines and psychotropic drugs, such as antidepressants. The rates and reasons for off-label orders vary by age, with more off-label orders for GI conditions in the youngest age groups, psychiatric conditions in older age groups, and infections and respiratory conditions across age groups. These results can help inform ongoing education, research, and policies around efficacious, effective, and safe use of medications in children.
Acknowledgments
Brian Cao and Matthew Del Signore assisted with manual reviews of visit data, and Edward Nonnenmacher assisted with data collection and presentation.
Ms Hoon conceptualized and designed the study, conducted the analyses, interpreted study data, drafted the initial manuscript, and reviewed and revised the manuscript; Ms Kapadia and Mr Taylor conducted the analyses, interpreted study data, and critically reviewed the manuscript for important intellectual content; Drs Gerhard and Strom conceptualized and designed the study, interpreted study data, and critically reviewed the manuscript for important intellectual content; Dr Horton conceptualized and designed the study, conducted the analyses, interpreted study data, and critically reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2019-1571.
FUNDING: Funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH) (under awards K23-AR070286 and L40-AR070497) and the Rutgers Robert Wood Johnson Medical School Summer Research Fellowship. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funded by the National Institutes of Health (NIH).
- ADHD
attention-deficit/hyperactivity disorder
- ATC
Anatomical Therapeutic Chemical
- CI
confidence interval
- FDA
US Food and Drug Administration
- GI
gastrointestinal
- ICD-9-CM
International Classification of Diseases
- Ninth Revision
Clinical Modification
- NAMCS
National Ambulatory Medical Care Survey
- NSAID
nonsteroidal antiinflammatory drug
- OTC
over-the-counter
References
Competing Interests
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
FINANCIAL DISCLOSURE: Dr Gerhard has received grant funding on unrelated matters from Bristol-Myers Squibb and consulted on unrelated matters for Bristol-Myers Squibb and Eli Lilly. Dr Strom has consulted on unrelated matters for AstraZeneca; Bayer; Celgene; Janssen; Lundbeck; Innovative Science Solutions, LLC; and McKesson Specialty Arizona Inc. Dr Horton has received grant funding on unrelated matters from Bristol-Myers Squibb; and Ms Hoon, Ms Kapadia, and Mr Taylor have indicated they have no financial relationships relevant to this article to disclose.
![FIGURE 1. Yearly absolute prevalence of systemic drug orders for children in US ambulatory settings (2006–2015): yearly national rates of orders per 1000 ambulatory visits between 2006 and 2015 for any systemic drug (purple) and systemic drugs ordered off label (based on age [light green], indication [medium green], or age, indication, and/or weight [dark green]). Error bars represent 95% CIs.](https://aap2.silverchair-cdn.com/aap2/content_public/journal/pediatrics/144/4/10.1542_peds.2019-0896/7/m_peds_20190896_f1.jpeg?Expires=1728799818&Signature=bB~NiHMdOXoIPtZvxmjgQ8uE7CRUKMnoxNRbwZ31phhsmYSI0ZCG9aM7kAbqhzn6fsyDDs3xDsiJ46f0cdXAzqhe-UGdra64HGxlzKoaIUDnOT1wAsXApAGEuQclYSwAXEwulZuxZaRmP0b2m57dYGHyPbHW3BXwXUAzY0QrFNQBNSZLbixkRz2TylLi274I0tBHe5xU3OUzMajmj6wXnpX1ec2Gth~MFzHugaEGpF6DAG3KxmJEOCFK9gXxhGVo7aoqrPzQZ61k8jrXZtkgJlUOi50h1~O95wJiHDRP4U5OZB7Wq1Lt9wC-9fH7j7dzqHru6I-K8PzngOHa8yzSmg__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
