Unit-Dose Packaging and Unintentional Buprenorphine-Naloxone Exposures

This is an observational surveillance study in which we use data from the RADARS System Poison Center Program.¹¹ In 2016, the RADARS System Poison Center Program obtained data from 50 regional US poison centers in 48 states, covering over 290 million people in urban, suburban, and rural regions, representing 94.3% of the national population on the basis of the 2010 US Census. The outcome was cases of unintentional (exploratory), unsupervised ingestion involving children <6 years old in which buprenorphine-naloxone products (tablet, film, or unknown formulations) or a single-entity buprenorphine tablet were mentioned. Buprenorphine patch, injection, and depot formulations were excluded. Following the approach used by Budnitz et al,¹⁰ the study time period was split into 3 periods: pre-UDP (first quarter 2008 through fourth quarter 2010), transition to UDP (first quarter 2011 through fourth quarter 2012), and post-UDP (first quarter 2013 through fourth quarter 2016). Estimates of the number of buprenorphine prescriptions dispensed by product type (single, combination, tablet film) as well as by UDP status were obtained from IQVIA.

In the primary analysis, we compared pediatric unintentional ingestions involving buprenorphine combination products across the study period in relation to the proportion of combination buprenorphine prescriptions with UDP. In a secondary analysis, we compared unintentional, unsupervised ingestions separately for buprenorphine-naloxone combination tablets and sublingual film and compared these to single-entity buprenorphine tablets. To account for increases in RADARS System Poison Center Program coverage and increases in the number of buprenorphine product prescriptions dispensed during the study period, exposure rates per prescriptions dispensed were estimated. By using drug use data within the coverage area of participating poison centers, exposure rates per prescriptions dispensed were calculated by dividing the number of exposures involving a buprenorphine product of interest by the number of prescriptions dispensed for that product within 3-digit zip code tabulation areas covered by poison centers participating in the RADARS System Poison Center Program. Rates were scaled per 100 000 prescriptions dispensed.

Poisson regression analysis was conducted to calculate the exposure rates per prescriptions dispensed with 95% confidence intervals (CIs) in each of the 3 study periods. In this model, the relative change in rates in the post-UDP period relative to the pre-UDP period was described and expressed as a percentage change. Because pediatric poison center cases showed an overall decline since 2008, a sensitivity analysis was conducted by repeating the Poisson regression above with the inclusion of the natural log of the number of poison center cases involving children <6 years old reported to all poison centers as a covariate (data available through 2015).

From January 2008 through December 2016, there were 6217 exposures to combination buprenorphine-naloxone products in children <6 years of age. There were 127 exposures to unknown formulations that were excluded from the analysis. Annual exposure counts from 2008 through 2016 were 618, 923, 1070, 718, 664, 526, 579, 560, and 559, respectively. The overall median age was 2.0 years (interquartile range: 1.5–2.0), and 3215 (51.7%) were boys (Table 1). In total, 1440 subjects (23.2%) reported no effect, 2381 (38.3%) reported minor effects, 1223 (19.7%) reported moderate effects, 114 (1.8%) reported major effects, and 3 reported deaths. As far as disposition, 1601 (25.8%) were evaluated and released in a health care facility, and 2949 (47.4%) were hospitalized.

From 2008 through 2010 (pre-UDP), there were 20.57 pediatric unintentional exposures involving a combination buprenorphine-naloxone product per 100 000 prescriptions dispensed. During the transition to UDP period, there were 8.77 pediatric unintentional exposures involving a combination buprenorphine-naloxone product per 100 000 prescriptions dispensed. In the post-UDP period (when more than 80% of combination buprenorphine-naloxone prescriptions dispensed were for products in UDP), there were 4.36 pediatric unintentional exposures involving a combination buprenorphine-naloxone product per 100 000 prescriptions dispensed. This represents a 78.8% (95% CI: 76.1%–81.3%; P < .001) relative decrease from the pre-UDP period. The decrease in the prescription-adjusted rate of pediatric unintentional exposures involving a combination buprenorphine-naloxone product dispensed coincided with the increase in the proportion of combination buprenorphine-naloxone prescriptions dispensed with UDP (Fig 1).

The total number of cases received by poison centers involving children <6 years old declined over the study period. We accounted for this trend by adjusting for the number of pediatric exposure cases reported to poison centers. After adjusting for the number of pediatric cases, the estimated decline in buprenorphine-naloxone combination products in the post-UDP period relative to the pre-UDP period was 69.9% (95% CI: 58.5%–78.1%; P < .001), suggesting the decrease was specific to buprenorphine-related exposures and not simply a secular trend.

In the secondary analysis, we examined rates over time by buprenorphine product type (Fig 2). Unintentional pediatric exposure rate per prescriptions for combination sublingual film, which had UDP since its introduction, remained consistent at ∼2.5 cases per 100 000 prescriptions and was the lowest of any formulation studied. Combination tablets had the highest exposure rate per prescriptions in the beginning of the study time period but then had a decline most notable in the post-UDP time period. Specifically, combination tablet exposure rates declined from a rate of 23.31 pediatric cases per 100 000 prescriptions in second quarter 2013 to 5.99 exposures per 100 000 prescriptions in fourth quarter 2016. Before second quarter 2013, the average quarterly rate was ∼20 exposures per 100 000 prescriptions dispensed. Single-entity tablets remained steady throughout the study period. Approximately 8 pediatric exposure cases per 100 000 prescriptions dispensed were observed for single-entity tablets. In contrast to decreasing rates of exposure cases, prescriptions for buprenorphine-naloxone sublingual film and combination products with UDP increased over the study period (Fig 3).

The shift from non-UDP to UDP in over 80% of buprenorphine-naloxone products was associated with a significant decrease in unintentional pediatric exposures reported to poison centers. Our findings of the impact of UDP were similar to those reported on the basis of NEISS-CADES data on ED visits for buprenorphine-naloxone ingestions.¹⁰ The film product has had UDP since its introduction to the market in 2010 (and was the only product available in the transition to UDP time period) and has had the lowest rate of unintentional pediatric exposures of the 3 product groups. A simultaneous decrease in the dispensed prescriptions of combination products without UDP may have also contributed to the decline in unintentional pediatric exposures (Fig 3).

In this study, we analyzed over 6000 actual cases from the RADARS System Poison Center Program rather than using estimates of ED visits from NEISS-CADES. By using poison center cases, which originated from both the home and health care settings, we have expanded both the range and content of information (medical outcome and disposition) in our evaluation of the impact UDP had on unintentional buprenorphine combination product exposures. In our results, in conjunction with previous research in which decreases in ED visits were demonstrated, the significant impact UDP has had on pediatric unintentional exposures to buprenorphine combination products is reflected. However, with an average 4.36 cases reported per 100 000 prescriptions dispensed and almost half of all cases requiring hospitalization, there is still opportunity to further decrease the risk to young children, specifically with the single-entity buprenorphine products because UDP has not been widely adopted for those products. This lack of adoption may also be the reason there was not a change from the pre- to post-UDP period for the single-entity products.

Prevention methods have long been a standard recommendation in limiting the impact of exposures and ingestion in the pediatric population. Packaging and engineering controls have been used effectively to reduce unintentional exposures since the 1960s.^12,–14 The Poison Prevention Packaging Act passed in 1970 requires many household substances and oral pharmaceuticals to be placed in child-resistant packaging.¹⁵ Flow restrictors are now being used for liquid medications, which has been shown to limit accessibility of their contents.¹⁶ The common push-turn pill bottle is a good deterrent to preventing access to pills and tablets. However, like most child-resistant containers, it is not childproof and only tested to be effective for 80% of children with the container for 10 minutes.¹⁵ Furthermore, the disadvantage of the pill bottle is that once opened, a child can access several pills, increasing the chance of ingesting a larger dose, which may lead to more serious toxicity. The advantage of UDP is that it acts as a barrier as well as limits the dose to potentially 1 tablet or film strip at a time. UDP is not a novel packaging technology. It was previously shown to reduce iron poisoning in young children when used for iron supplements.¹⁷ The application of UDP should be used for any medications that pose a significant risk to young children.

Poison prevention is a multifaceted approach and should not rely solely on packaging and engineering controls. In research, it has been demonstrated that opioid analgesics are also stored unsafely.¹⁸ As long as a product is within reach and/or available to a child, there is a risk for an unintentional exposure. As previously mentioned, child-resistant packaging is a barrier and should not be considered childproof. In 2012, the US Food and Drug Administration determined that a Risk Evaluation and Mitigation Strategy (REMS) for opioid analgesics was necessary for opioid analgesics, including buprenoprhine.¹⁹ The goal of this REMS is to reduce serious adverse outcomes resulting from inappropriate prescribing, misuse (including unintentional exposure), and abuse, while maintaining patient access to medications. Per the REMS, provider, patient, and pharmacy education must take place at the point of contact to emphasize the potential dangers and proper storage. This targeted counseling should take place at drug rehabilitation centers, addiction programs, and pain clinics because these are likely to have a higher concentration of patients taking buprenorphine and other prescription opioids.

There are limitations to our study. Poison centers underestimate the true rate of buprenorphine exposures because they are not used for all exposures, hence the reason trends over time rather than the specific quantified rates were looked at in our study. Not all poison centers participate in the RADARS system; the number of centers did increase during the study time period from 43 to 50. Zip codes covered by participating centers were used to calculate rates, and the number of zip codes increased from 697 to 877. This is an increase from 235 540 003 to 290 988 057 in estimated US censuses, accounting for over 94% of the US population. Poison center data rely on self-reports from caregivers and medical personnel. A potential confounder of the association between time period and the rate of childhood exposures per 100 000 prescriptions dispensed is a decline in the number of total exposure calls to poison centers involving children; however, this was controlled for in the sensitivity analysis and by looking at whether the decline is unique to combination tablets compared with other groups. There is also the potential for misclassification of the products. However, it is unlikely that misclassification of a few cases would make a significant difference in overall exposure rates between the different products. As alluded to previously, a decline in dispensed combination products without UDP may have also contributed to our observed decrease in unintentional pediatric exposures. However, there was an increase of UDP products that now represent over 80% of dispensed combination products. Furthermore, the pediatric exposure rate has continued to decline despite a recent slight increase in products without UDP (Fig 3). Finally, there may have been other contributing factors associated with the decrease in exposure rates, including the US Food and Drug Administration REMS program, more public awareness to the dangers of opioids in children, and responsible prescribing and use of buprenorphine.

There was a decrease in pediatric unintentional exposures to buprenorphine-naloxone products associated with increased use of UDP. As patient access expands and prescribing increases, there will likely be an increase in buprenorphine availability in the home, increasing the risk for pediatric exposures. Packaging and engineering controls, such as UDP, in addition to safe storage and education should be a mainstay in the approach to the prevention of unintentional buprenorphine pediatric exposures as well as exposures to other prescription opioids. It will be essential to follow the impact of increased use and prescribing of buprenorphine, along with preventive modalities, on the pediatric population.

CI

confidence interval

ED

emergency department

NEISS-CADES

National Electronic Injury Surveillance System–Cooperative Adverse Drug Event Surveillance

RADARS

Researched Abuse, Diversion, and Addiction-Related Surveillance

REMS

Risk Evaluation and Mitigation Strategy

UDP

unit-dose packaging