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Pediatric Drug Labeling: Still an Unfinished Need

Tobin, Joseph R. MD

doi: 10.1213/ANE.0b013e31826af996

From the Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC.

Accepted for publication July 13, 2012.

Funding: Funded solely by the Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC.

Conflicts of Interest: See Disclosures at the end of the article.

Reprints will not be available from the authors.

Address correspondence to Joseph R. Tobin, MD, Department of Anesthesiology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1009. Address e-mail to

Appearing in this issue of Anesthesia & Analgesia are 2 clinical manuscripts reporting hospital audits of the use of sedative, analgesic, and anesthetic medications in children. The authors of these reports used robust databases to examine pediatric pharmacology prescribing in the inpatient environment. Although drug labeling for use in the pediatric population may be improving, the results from these investigations suggest a substantial use of agents “off-label” in children. This practice is quite common and considered superior to denying children the benefits of these agents in the practice of anesthesiology.

In their report, Lasky et al. reveal “the prevalence of use of specific medications among hospitalized children in 2008.”1 Their dataset includes greater than 875,000 hospitalized children admitted to 423 hospitals that participated. The analysis included >12 million drug administrations to children from birth to age 18 years. They analyze and report the frequency of use of specific agents and combinations of anesthetic-related agents by age. They do not attempt to analyze the proportion of these encounters that involved off-label use of a drug, but they effectively argue the observation that it is common. Furthermore, they cite work that offers 4 different dose range recommendations of a common drug: oxycodone.a This is one observation that demonstrates the need for better pediatric labeling.

Focusing only on opioid medications, hospitalized children received opioids in a frequency of 1% to nearly 30%. Opioid use is only a surrogate of all pharmacology prescribing in children, but it is notable because of the known serious (if not infrequent) side effects associated with opioid use. In their analysis, they identify 33 entities and 11 combinations of agents prescribed for children. Some drugs of particular interest to anesthesiologists were found to have been prescribed to children with some common frequency. Lidocaine (11%), midazolam (4.5%), acetaminophen (14%), and fentanyl and morphine (both >6%) were noted. These frequencies do not seem high when we focus on children for whom surgical anesthesia is required, but these data entries include children admitted for any reason. These agents are among many drugs prescribed to children of any age with restricted or no pediatric data to support labeling.

In another study, Smith et al. report their audit of commonly used agents in pediatric anesthesia associated with age-appropriate use consistent with labeling, off-label use of drugs with age-restricted labeling, and drugs prescribed with no labeling for children.2 They report the rate of off-label use in children over a 14-month interval. They cite use of over 100 agents, 34% without any pediatric labeling, and 38% with age-restricted labeling. “Drugs were administered off-label in 73.4% of cases.”

These findings are consistent with previous reports of off-label drug use in children. From 1971 to 1991, the number of agents in the Physician’s Desk Reference without pediatric labeling remained essentially unchanged at 78%–81%. To improve this situation, the United States Congress has empowered the United States Food and Drug Administration (US FDA) with multiple tools to stimulate the appropriate studies for labeling of drugs in children. From these initiatives, more than 100 labels now include pediatric information. Although this seems like progress, this is unacceptable on behalf of the children we care for daily.

This is not a new conversation. It is a longstanding challenge we face as health care providers. Although my comments are primarily directed at children as the “therapeutic orphans” in drug development and testing, our obstetrical colleagues share the similar opinion that advances in drug labeling for obstetrical indications are significantly hampered.3 Other investigators have commented on the lack of appreciation of gender differences in clinical trials designs.4 Each of these limitations is slowing our progress. The US FDA often gets blame in these discussions, but they are following the rules and regulations placed upon them by Congress. The FDA won awards for their speedy handling of development and approval of antiretroviral therapies for treatment of human immunodeficiency virus infections. The FDA has also been a vanguard agency with regard to postmarketing surveillance (which resulted in voluntary withdrawal of rapacuronium from the market), and its diligent requirement offurther data from the sponsor of Sugammedex, which is still not approved in the US.

The American Academy of Pediatrics’ last recommendation statement regarding off-label use is from 2002.5 They have recently published guidelines for ethical conduct of studies to evaluate drugs in pediatric populations.6 Although this is welcome and should provide some perspective on appropriate trial designs, the cry to attention should be that children continue to be unwelcome research subjects because of perceived high risk of liability, and insufficient motivation for sponsors to perform trials in this vulnerable population. Despite the passage of the FDA Modernization Act, the Best Pharmaceuticals in Children Act, the enactment of the Pediatric Research Equity Act, and the Newborn Drug Development Initiative7 (a collaboration by the FDA and the National Institute on Child Health and Development), there is still hesitation by pharmaceutical sponsors to perform pediatric clinical trials. Anesthesiologists should raise their voices with others to advocate on behalf of the children we care for daily, demanding improved labeling of agents in this population.

Anesthesiologists are becoming increasingly aware of the debate regarding possible neurotoxicity in the developing brain with exposure to anesthetic agents. Multiple animal models suggest both anatomic injury (apoptosis) and learning impairment when young animals are exposed to commonly used anesthetics. These observations must now be reconsidered in light of results in a new report using different models to approach these experiments.8 Our goals are to provide safe, vigilant anesthetic care to our patients, and we need further data to do so.

Six years ago, Dr. Davis, Dr. Shafer, and I opined on the difficulties of performing pediatric research and the scholarship that is later published in this field. We expressed our views that this complex situation might amount to another “Gordian Knot.”9 How much further down the road to a solution are we? On a day-by-day basis, we have to develop strategies to cope with national drug shortages with the more widespread implications on all patients’ safety.10 Despite these daily institutional logistic issues, we cannot lose sight regarding further drug labeling in children. We still have a long way to go when a contemporary publication2 suggests that the off-label use rate is still 70+% in children.

The 2 studies in this issue provide us with contemporary insight and evidence that the problem of off-label use in children is not solved. I am an advocate for the off-label use of agents in children as opposed to not having them available at all. Nonetheless, we need to continue to advocate for performing trials that will provide us with better developmental pharmacology data and responses across large populations of children. These 2 large studies are great additions to our literature. With increasing use of electronic medical records, investigators have tools to perform large observational studies, determine adverse reaction incidences, and develop age-related side effect profiles for us to improve our prescribing in children.

In 2012, Purdue Pharma announced its plan to move forward with clinical trials of its formulation “Oxycontin” in children. Leaders in pediatric anesthesia spoke favorably of this plan even while many in the press felt that the issues of potential abuse should outweigh the planned prospective trials to attempt to label and use this moiety safely in this population. Chronic pain in children is seriously underrecognized in comparison with the prevalence of chronic pain in adults. This is one more circumstance in which labeling in children would be very beneficial to anesthesiologists and their patients.

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Name: Joseph R. Tobin, MD.

Contribution: This author wrote the manuscript.

Conflicts of Interest: Dr. Tobin is a consultant to the US Food and Drug Administration for multiple committees’ evaluation of sponsors’ proposals brought to the committees for review. He has previously performed multiple clinical trials, but has not received any financial support for clinical trials work currently or in the past year.

This manuscript was handled by: Peter J. Davis, MD.

a McPhillips H, Stille C, Smith D, Pearson J, Stull J, Hecht J, Andrade S, Miller M, Davis R Methodological challenges in describing medication dosing errors in children and methodology. In: Henriksen K, Battles J, Markes E, eds. Advances in Patient Safety: From Research to Implementation. Vol 1–4. AHRQ Publication Nos. 050021 (1–4). February 2005. Agency for Healthcare Research and Quality, Rockville, MD. Available at: Accessed July 9, 2012. Cited Here...

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© 2012 International Anesthesia Research Society