This is the full text version, you may consider using parts relevant to your opinions or experience:
January XX, 2021
Stephen Hahn, MD
Food and Drug Administration
C/O Dockets Management Staff (HFA-305)
5630 Fishers Lane, Rm. 1061
Rockville, MD 20852
RE: Docket No. FDA-2019-N-1845, “Fixed-Quantity Unit-of-Use Blister Packaging for Certain Immediate-Release Opioid Analgesics for Treatment of Acute Pain; Establishment of a Public Docket; Request for Comments"
Dear Commissioner Hahn:
On behalf of ____________, I write to provide input on the U.S. Food and Drug Administration’s (FDA) request for comments on a potential modification to the Opioid Analgesic Risk Evaluation and Mitigation Strategy (OA REMS) to require that certain solid, oral dosage forms of immediate-release (IR) opioid analgesics commonly prescribed for treatment of acute pain be made available in fixed-quantity unit-of-use blister packaging for outpatient dispensing.
_______ is supportive of expanding the use of unit-dose packaging and believes more must be done to reduce the risk of unintentional ingestion, diversion, and overdose.
________ shares the FDA’s serious concern about unintentional child opioid ingestion, and in reducing inappropriate access to opioids. Opioids were involved in over 47,600 overdose deaths in 2015, a number that has increased nearly sixfold since 1999.1 Drug overdoses of all kinds led to over 70,000 deaths in 2017, 2 causing more deaths than car crashes.3 These fatalities are the inflection point of a much larger trend of higher incidence of substance use disorders (SUDs) affecting millions of U.S. families and negatively impacting child health and well-being.
The opioid epidemic’s toll is due, in part, to access by children to prescription opioid drug products. In the last two decades, nearly nine thousand children and adolescents died from opioid poisonings, with the mortality rate increasing nearly threefold.4 This is an alarming increase, and we are concerned that this number will only grow as the epidemic continues its scourge. One study found that children of mothers prescribed opioids are at a substantially increased risk of opioid toxicity.5
________ is encouraged that FDA is exploring ways to prevent unintentional ingestion of opioids by young children. We respectfully offer the following feedback on this proposal, including suggestions to strengthen it in ways that can reduce child and adolescent morbidity and mortality resulting from unintentional child ingestion and adolescent use of diverted opioids.
Unintentional Ingestion of Opioids by Young Children is a Public Health Threat
Young children face a serious risk of poisoning morbidity and mortality from unintended opioid ingestion. A recent study in Pediatrics examined 2004 to 2015 data on opioid-related hospitalizations among children in children’s hospitals, finding that child opioid-related hospitalizations rose from 797 in 2004 to 1,504 in 2015. Over one-third of those hospitalizations were among children younger than 6, highlighting the significant need for protections against unintentional ingestion by young children.6 Public education and other measures are insufficient to address this issue. Policies to design out the hazard of unintentional ingestion through child-resistant unit-dose packaging are essential to reduce unintended child access to opioids.
Unit-of-use packaging for solid medications is an evidence-based, effective child-resistant packaging intervention that can reduce the risk of unintentional ingestion. A sole mechanism, such as a child resistant cap for the entire container, is not the solution for high-risk ingestion hazards. Significant poisoning from high-risk drugs occurs after the ingestion of a small number of therapeutic doses. Typically, fewer than five doses of such substances can result in serious adverse outcomes, including fatality.
Passive prevention interventions such as unit-dose blister packages have been shown to be more effective than conventional child-resistant caps. A study7 by Dr. Milton Tenenbein of the impacts of unit-dose packaging for iron supplements showed a decrease in the incidence of non intentional ingestion of a specific drug by young children and a decrease in mortality from poisoning by this drug after the introduction of unit-dose packaging. There was a decrease in the incidence of iron ingestion and a dramatic decrease in the number of deaths due to iron poisoning.8 Unit-dose packaging is a highly effective intervention, and should be considered for all medications with a high hazard for morbidity and mortality when taken as an overdose. Opioid analgesic products meet the criteria of particularly high-risk substances, and are a prime candidate for unit-dose packaging.
Applying these Requirements to More Potent Opioid Products Will Prevent Pediatric Poisoning
This proposal is directed toward lower-potency opioids, but omits drugs that are responsible for most of the opioid morbidity and nearly all of its mortality. The AAP encourages FDA to expand the requirement to drugs with high rates of morbidity and mortality, such as buprenorphine. Focusing first on the oral solid opioids that have the greatest poisoning morbidity and mortality would increase the public health benefits of the intervention. AAP supports greatly expanding the use of blister packaging to address those opioid products most associated with morbidity and mortality from poisoning. While we appreciate the progress outlined in this initial proposal, limiting its application to just seven commonly prescribed products is not a sufficient response to the unique child health threat posed by unintentional opioid ingestion.
Blister Packaging Requirements Provide Public Health Benefits
To turn the tide on the alarming increases in unintentional ingestion of opioids by children 5 and under, it is imperative that FDA require more effective child-resistant packaging for all opioid medications. AAP is encouraged that FDA is considering an OA REMS requirement that certain IR opioid analgesics commonly prescribed for the treatment of acute pain be available in blister packaging. This intervention will help prevent unintentional ingestion, diversion, and abuse. However, concerns of unintentional child ingestion exist far beyond this intervention’s target population of opioid-naïve patients with acute pain. Research from the U.S. Centers for Disease Control and Prevention (CDC) shows the efficacy of unit-dose packaging for buprenorphine and naloxone, prescriptions not currently included in the proposal:
Accounting for prescribing frequency, [emergency department (ED)] visits for unsupervised buprenorphine/naloxone ingestions declined 65.3%, from an estimated 28.2 ED visits per 100,000 dispensed prescriptions during 2008–2010 to an estimated 9.8 per 100,000 dispensed prescriptions during 2013–2015 (p = 0.011).The approximate two thirds reduction in the rate of ED visits by children for buprenorphine/naloxone ingestions as the proportion of prescriptions dispensed in unit-dose packaging increased to over 80%, suggests that packaging/formulation changes might reduce pediatric ingestions. A study of poison center calls for pediatric buprenorphine/naloxone exposures also found a significantly lower rate of calls involving film strips in unit-dose packaging, compared with tablets in multi-dose bottles (6). Other factors potentially contributing to the rate reduction include increased counseling of patients on safe use and storage (7) and a decline in pediatric medication ingestions overall (22% from 2010 to 2013) (8). 9
AAP appreciates the proposed use of OA REMS modification to require packaging changes rather than relying on guidance for this important public health intervention. We urge FDA to require unit dose blister packaging for all such opioid products. Blister packaging is a well-known and well established solution already in use,so requiring this intervention for solid, oral dosage forms of opioids would be a straightforward undertaking. We encourage FDA to work with the Consumer Product Safety Commission (CPSC) to ensure that all such blister packaging must meet the CPSC standards for child resistance outlined under the Poison Prevention Packaging Act.
Ongoing Monitoring of Packaging Modifications is Necessary
In addition to requiring that additional high-risk solid opioids be available in blister packaging, FDA should consider steps to encourage uptake and increase access to this packaging. AAP supports requiring application holders to periodically report on the production of their blister package configurations to track the use of these products. FDA should also consider requiring that a certain fraction of marketed products be in blister package configurations to encourage the broader use of these products. FDA should adopt additional measures as needed to ensure that the required blister packaging is sufficiently available and protective of children’s health.
Finally, it is critical to underscore that child-resistant does not mean child-proof. Child-resistant packaging is simply a first-line defense in preventing a child from accessing poisonous substances. Continued vigilance and regulatory oversight by FDA is critical to both public awareness of, and manufacturer efforts to prevent, unintentional ingestion of opioids.
Thank you for the opportunity to comment on the FDA's consideration of opioid packaging safety improvements. The agency is in a position to prevent thousands of ED visits and many deaths in the youngest children by promulgating a regulation for child-resistant packaging of opioid products. We urge the FDA to put this regulation into place expeditiously, and to closely monitor its success in preventing harm to children. We look forward to working with you to ensure that children and adolescents are protected from unintentional ingestion and inappropriate access to opioids. If we can be of further assistance, please contact ____________
1 - National Center for Health Statistics. National Vital Statistics System, Mortality. Retrieved from https://www.cdc.gov/nchs/data/databriefs/db329_tables-508.pdf#page=4.
2 - Drug Overdose Deaths. U.S. Centers for Disease Control and Prevention.
https://www.cdc.gov/drugoverdose/data/statedeaths.html. Published December 19, 2018. Accessed July 16, 2019.
3 - Early estimate of motor vehicle traffic fatalities in 2017. National Highway Traffic Safety Administration. https://crashstats.nhtsa.dot.gov/Api/Public/ViewPublication/812542. Published May 2018. Accessed July 16, 2019.
4 - Gaither JR, Shabanova V, Leventhal JM. US national trends in pediatric deaths from prescription and illicit opioids, 1999-2016. JAMA Netw Open. Published online December 28, 20181(8):e186558. doi:10.1001/jamanetworkopen.2018.6558
5 - Finkelstein Y, Macdonald EM, Gonzalez A, Sivilotti MLA, Mamdani MM, Juurlink DN, Canadian Drug Safety And Effectiveness Research Network (CDSERN). Overdose risk in children of young women prescribed opioids. Pediatrics. Mar 2017, 139 (3) e20162887; DOI: 10.1542/peds.2016-2887.
6 - Kane, J. et al (2018). Opioid-related critical care resource uses in U.S. children’s hospitals. Pediatrics. 141;4. Retrieved from http://pediatrics.aappublications.org/content/141/4/e20173335.
7 - Tenebein M, et al. Unit-dose packaging of iron supplements and reduction of iron poisoning in young children. Arch Pediatr Adolesc Med. 2005;159:557-560.
8 - Ibid.
9 - Pediatric Emergency Department Visits for Buprenorphine/Naloxone Ingestion – United States, 2008 – 2015. MMWR / October 21, 2016 / Vol. 65 / No. 41 US Department of Health and Human Services/Centers for Disease Control and Prevention.