Safety of Drugs Commonly Used Off-Label in Children Despite Insufficient Evidence of Efficacy and Safety

成人的药物安全性和有效性并不能保证同样的药物在儿童中的安全性和有效性。 在美国，为儿童订购的全身性药物中，有40%是标签外的(在FDA之外使用)。 批准的年龄、适应症等)。此外，儿童的非标签使用率正在上升，特别是在 治疗适应症在任何年龄都未经批准。非标签药物的使用、过度使用和联合使用(综合药房) 无根据的适应症药物每年可能使数百万儿童面临与严重药物相关的风险 危害超过了治疗的不确定益处。这个团队的长期目标是提高明智的， 循证用药将为临床决策提供信息，并使儿童更健康和 更安全。该项目的具体目标是描述与毒品有关的严重危害的风险。 尽管疗效和安全性证据不足，但一些最常见药物的儿童仍在使用： 精神药物。中心假设是，在儿童中使用某些精神药物与 增加了严重伤害的风险。使用精神药物作为应用实例的原因有很多：1) 儿童中无支持的非标签使用的高流行率和不断上升的流行率；2)没有足够的证据表明 儿童；3)潜在的严重或致命伤害；4)对儿童的潜在伤害大于成人；5)危急 治疗需求；6)现有的治疗替代方案(例如，更安全的药物、非药物干预)； 以及7)可衡量的结果。根据这些标准、文献中的差距和初步数据，这 提案集中于可能的严重危害(即自杀、心律失常和严重的皮肤反应)。 与抗抑郁剂(例如，文拉法辛)和抗癫痫药物/情绪稳定剂(AED)(例如， 拉莫三嗪)。具体地说，这项建议旨在评估：1)某些抗抑郁药物和 抗抑郁药增加或降低儿童自杀死亡的风险(目标1)；2)某些抗抑郁药和 AEDs可增加或降低儿童室性心律失常、心脏骤停或猝死的风险(目的 2)；以及3)某些抗癫痫药物/情绪稳定剂或药物组合增加或降低 儿童严重皮肤反应(目标3)。该项目团队将在两年内研究不同的儿科人群 国家索赔和电子健康记录数据库，以实现这些目标。这项研究将产生 可概括的、可操作的、临床相关的证据现在缺乏严重的相对和绝对风险 药物和药物组合的危害越来越多地在标签外和证据不足的情况下用于儿童。 这些罕见的结果不能通过临床试验进行可行的研究，因为需要非常大的规模。 样本大小。跨年龄组、诊断、药物剂量和伴随药物的比较不仅将 量化关键亚组中的风险，但也将阐明潜在的生物学和机制。这个项目还 开始了一项重要的新工作，将为改善药物证据的整体质量提供信息 尽管有效性和安全性证据不足，但儿童仍普遍使用。

Drug safety and effectiveness in adults does not assure safety and effectiveness of the same drugs in children. In the United States, >40% of systemic drugs ordered for children are off-label (used outside of an FDA- approved age, indication, etc.). Furthermore, rates of off-label use in children are rising, particularly for treatment indications unapproved at any age. Use, overuse, and combined use (polypharmacy) of off-label medicines for unsupported indications may put millions of children at risk each year for serious drug-related harms that outweigh uncertain benefits of treatment. This team’s long-term goal is to improve the judicious, evidence-based use of medicines that will inform clinical decision-making and make children healthier and safer. The specific objective of this project is to characterize the risks for serious drug-related harms in children from some of the drugs used most commonly despite insufficient evidence of efficacy and safety: psychotropic drugs. The central hypothesis is that use of certain psychotropic drugs in children is associated with increased risks of serious harms. Psychotropic drugs are used as applied examples for many reasons: 1) high and rising prevalence of unsupported off-label use in children; 2) insufficient evidence of efficacy in children; 3) potential for serious or fatal harms; 4) potentially greater harms in children than in adults; 5) critical therapeutic needs; 6) available therapeutic alternatives (e.g., safer drugs, non-pharmacologic interventions); and 7) measurable outcomes. Based on these criteria, gaps in the literature, and preliminary data, this proposal focuses on selected serious harms (namely, suicide, arrhythmias, and severe skin reactions) possibly associated with antidepressants (e.g., venlafaxine) and antiepileptic drugs/mood stabilizers (AEDs) (e.g., lamotrigine). Specifically, this proposal aims to evaluate the extent to which: 1) certain antidepressants and AEDs increase or decrease the risk of death by suicide in children (Aim 1); 2) certain antidepressants and AEDs increase or decrease the risk of ventricular arrhythmias, cardiac arrest, or sudden death in children (Aim 2); and 3) certain antiepileptic drugs/mood stabilizers or drug combinations increase or decrease the risk of severe skin reactions in children (Aim 3). The project team will study distinct pediatric populations within two national claims and electronic health records databases to accomplish these aims. This research will produce generalizable, actionable, clinically relevant evidence now lacking on relative and absolute risks of serious harms from drugs and drug combinations increasingly used off-label and with insufficient evidence in children. These rare outcomes cannot be feasibly studied with clinical trials due to the need for prohibitively large sample sizes. Comparisons across age groups, diagnoses, drug doses, and concomitant drugs will not only quantify risks in key subgroups but will also shed light on underlying biology and mechanisms. This project also begins an important new line of work that will inform improvements the overall quality of evidence for drugs that children commonly use despite insufficient evidence of efficacy and safety.