The Role of Unit-Dose Child-Resistant Packaging in Unintentional Childhood Exposures to Buprenorphine–Naloxone Tablets
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Buprenorphine–naloxone was among the most commonly implicated exposures in pediatric emergency department (ED) visits for unsupervised oral prescription medication ingestions in 2007–2011, resulting in high hospitalization rates [1, 2] and several deaths . Buprenorphine–naloxone products are available as sublingual tablets and, since August 2010, as sublingual film dispensed in child-resistant unit-dose packaging (UDP). Buprenorphine–naloxone tablets are dispensed in multidose bottles and, since July 2013, also in UDP. Several studies have detected decreasing rates of childhood exposures for buprenorphine–naloxone products since the introduction of the film [2, 4], and lower rates associated with the film compared to the tablet . However, only one study distinguished between the effects of the dosage form and UDP. Wang et al.  detected a statistically significant decline in poison control calls for childhood exposures to buprenorphine–naloxone tablets with increasing UDP use; however, the extent of decline far exceeded the UDP dispensing rate. To further investigate the effects of UDP, we compared ED visit rates for pediatric ingestion of buprenorphine–naloxone tablets prior to the introduction of UDP (2008–2011) with rates after the introduction of UDP (2015–2017), excluding a transition period.
We calculated utilization-adjusted rates of ED visits for buprenorphine–naloxone tablet ingestions by children aged < 6 years for 2008–2017 using two national samples: the 60-hospital National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance (NEISS-CADES) project and the IQVIA National Prescription Audit. NEISS-CADES cases are weighted based on the inverse probability of selection and adjusted for nonresponse and number of ED visits . IQVIA uses a proprietary algorithm to project national estimates of dispensed prescriptions. Using a two-tailed test, we compared prescription-adjusted ED visit rates between 2008–2011 and 2015–2017. We performed six sensitivity analyses with varying rules for categorizing ED visits involving tablet formulations only.
Based on 156 cases, there were an estimated 6892 (95% confidence interval [CI] 4134–9651) ED visits for buprenorphine–naloxone tablet ingestions by children aged < 6 years from 2008 to 2017. Most (58.4%; 95% CI 48.3–68.5) ED visits involved children under 2 years of age, 51.4% (95% CI 39.9–62.9) involved boys, and 71.0% (95% CI 55.8–86.2) resulted in hospitalization.
Most buprenorphine–naloxone tablets continue to be dispensed in multidose bottles, which limited power to detect significant change in ED visit rates. Although the finding of a 27.7% decrease in ED visit rates with 37.6% UDP penetration is consistent with a protective effect, statistical uncertainty precludes conclusive determination. Beside random error, longitudinal trends in ED visits overall and campaigns advocating for safe use and storage may also have contributed.
We encourage the use of UDP for buprenorphine–naloxone products, particularly for households with young children. Child-resistant UDP obviates the need for adults to re-secure bottle caps. This passive protection should limit unintentional ingestions by children [5, 6] and, if breached, limit the amount available for ingestion. With continued use of UDP and monitoring of ingestions, conclusive determination of impact should become possible.
We thank Dr. Tamra Meyer, PhD, MPH, and Dr. Judy Staffa, PhD, RPh, of the FDA, for supporting the interpretation of results and critical review of the manuscript.
Compliance with Ethical Standards
No funding was used for the preparation of this letter.
Conflict of interest
Christian Hampp, Maribeth C. Lovegrove, Daniel S. Budnitz, Justin Mathew, Amy Ho, and Jana McAninch have no conflicts of interest that are directly relevant to the content of this study.
This project meets the definition of a public health surveillance activity described in the US Code of Federal Regulations (CFR), 45 CFR 46.102(l)(2), and does not require human subjects review or institutional review board (IRB) approval.
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