Comment: Adverse Drug Reactions in Pediatric Emergency Medicine.

We read with interest the article by Darnis et al titled “Adverse Drug Reactions in Pediatric Emergency Medicine” published in Annals of Pharmacotherapy. They studied the incidence of adverse drug reactions (ADRs) among a pediatric emergency department population, found an ADR incidence of 1.09%, and conclude that there is considerable misuse of medications among young teenagers and a high incidence of overmedication in younger age groups. Darnis et al stated, “Our results highlighted that 1.88% of the medications were used off-label, causing neurological ADRs; all were administered in outpatient care. The use of medications off-label represents between 11% and 37% of outpatient prescriptions. Prescribing medications offlabel is a real problem because it appears to increase the risk of iatrogenic consequences in children. ” We are puzzled by the aforementioned statement. If offlabel accounted for 11% to 37% of the outpatient prescriptions, yet only caused 1.88% of ADRs, that would translate into a positive statement such as “off-label prescription significantly lessened the chance of ADRs. ” Rather, in other words, only 1.88% of the medications were prescribed offlabel, which means that 98.12% of ADRs of the medications were prescribed on-label, which directly contradicts the statement by Darnis et al, “Prescribing medications offlabel is a real problem because it appears to increase the risk of iatrogenic consequences in children. ” In an article titled, “Off-label prescribing to children in the United States outpatient setting,” Bazzano et al studied the frequency of off-label prescribing to children at United States outpatient visits and determined how drug class, patient age, and physician specialty relate to off-label prescribing. They found that 62% of outpatient pediatric visits included off-label prescribing. Approximately 96% of cardiovascular-renal, 86% of pain, 80% of gastrointestinal, and 67% of pulmonary and dermatological medication prescriptions were off-label. They concluded that despite recent studies and labeling changes of pediatric medications, the majority of pediatric outpatient visits involve off-label prescribing across all medication categories. Furthermore, offlabel prescribing is more frequent for younger children and those receiving care from specialist pediatricians. The Policy Statement of the American Academy of Pediatrics states that off-label drug use remains an important public health issue for infants, children, and adolescents because an overwhelming number of drugs still have no information in the labeling for use in pediatrics. The purpose of off-label use is to benefit the individual patient. Practitioners use their professional judgment to determine these uses. As such, the term off-label does not imply improper but the best available evidence and the importance of the benefit for the individual patient. Indeed, knowledge of the benefits and risks of prescription drugs is based mainly on published reports of clinical trials, yet the medical literature may present an incomplete and potentially biased sample of clinical trials. In 2012, researchers at the biotechnology firm Amgen in Thousand Oaks, California, reported that they could replicate only 6 out of 53 landmark studies in oncology and hematology. Earlier this year, a large project that attempted to replicate 100 psychology studies managed to reproduce only slightly more than a third. Therefore, on-label drug use does not automatically guarantee safe, effective, or even applicable treatment for an individual patient encountered in clinical practice. The arrival and subsequent withdrawal of rofecoxib (Vioxx) is a good example to illustrate this point. Despite preapproval studies that showed that rofecoxib had 4 times the risk of heart attacks when compared with naproxen, the Food and Drug Administration approval board accepted the manufacturer’s argument that this was the result of a previously unknown cardioprotective effect of naproxen rather than a risk of rofecoxib, and the drug was approved. In 2005, Brawlier et al revealed the results of a randomized, placebo-controlled study that rofecoxib users suffered a higher rate of heart attacks and other cardiovascular disorders than patients taking no medication. The drug was pulled from the market after 5 years. It is estimated that rofecoxib caused between 88 000 and 140 000 cases of serious heart disease, and roughly half of these patients died. In this regard, it is critical that clinical decision making should always be guided by the best available evidence and the well-being of an individual patient. However, each physician should be critical about pharmacological data, in general, even if it is for on-label use and always be meticulous and thorough when prescribing any medications. In summary, evidencebased health care should always combine the best information with physician expertise and individual patient need.