[Federal Register Volume 87, Number 77 (Thursday, April 21, 2022)]
[Notices]
[Pages 23869-23876]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-08372]



[[Page 23869]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2022-N-0165]


Providing Mail-Back Envelopes and Education on Safe Disposal With 
Opioid Analgesics Dispensed in an Outpatient Setting; Establishment of 
a Public Docket; Request for Comments

AGENCY: Food and Drug Administration, Health and Human Services (HHS).

ACTION: Notice; establishment of a public docket; request for comments.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is 
announcing the establishment of a docket to solicit public comment on a 
potential modification to the Opioid Analgesic Risk Evaluation and 
Mitigation Strategy (OA REMS) to require that mail-back envelopes be 
dispensed and education on safe disposal provided with opioid 
analgesics dispensed in an outpatient setting. Such a requirement could 
reduce the amount of unused opioid analgesics in patients' homes, 
thereby reducing opportunities for nonmedical use, accidental exposure, 
and overdose, and possibly reducing the development of new opioid 
addiction.

DATES: Submit either electronic or written comments by June 21, 2022.

ADDRESSES: FDA is establishing a docket for public comment on this 
notice. The docket number is FDA-2022-N-0165. The docket will close on 
June 21, 2022. Submit either electronic or written comments by June 21, 
2022. Please note that late, untimely filed comments will not be 
considered. Electronic comments must be submitted on or before June 21, 
2022. The https://www.regulations.gov electronic filing system will 
accept comments until 11:59 p.m. Eastern Time at the end of June 21, 
2022. Comments received by mail/hand delivery/courier (for written/
paper submissions) will be considered timely if they are postmarked or 
the delivery service acceptance receipt is on or before that date.
    You may submit comments as follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2022-N-0165 for ``Providing Mail-Back Envelopes and Education on 
Safe Disposal With Opioid Analgesics Dispensed in an Outpatient 
Setting; Establishment of a Public Docket; Request for Comments.'' 
Received comments, those filed in a timely manner (see ADDRESSES), will 
be placed in the docket and, except for those submitted as 
``Confidential Submissions,'' publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m. 
and 4 p.m., Monday through Friday, 240-402-7500.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Patrick Raulerson, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 6260, Silver Spring, MD 20993, 301-796-
3522, [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    Nonmedical use,\1\ accidental exposure, and overdose associated 
with prescription opioid analgesics remain a serious problem in the 
United States. In 2019, prescription pain relievers, such as opioid 
analgesics, remained the most common class of prescription drugs used 
nonmedically in the United States, with approximately 9.7 million 
people aged 12 and older reporting past-year nonmedical use (Ref. 1). 
Many people who use opioids nonmedically start with prescription opioid 
analgesics and transition to illicit substances (Refs. 2 to 5). Also, 
from 2010 to 2018 there were over 48,000 accidental prescription opioid 
exposures in young children (Ref. 6).
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    \1\ We use the term ``nonmedical'' in this document to refer to 
misuse of a drug, abuse of a drug, or both. ``Misuse'' is the 
intentional use, for therapeutic purposes, of a drug in a manner 
other than prescribed. ``Abuse'' is the intentional, non-therapeutic 
use of a drug, even once, for its desirable psychological or 
physiological effects.
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    While the volume of prescription opioid analgesics dispensed has 
been

[[Page 23870]]

trending downward following a peak in 2012, there were still an 
estimated 140.6 million prescriptions, resulting in an estimated 8.7 
billion units (e.g., tablets or capsules) dispensed in 2021 from U.S. 
outpatient retail and mail order pharmacies (Ref. 7). As of 2020, 
despite the decrease in opioid dispensing, prescription opioids were 
involved in more than 16,000 fatal overdoses per year (Ref. 8), higher 
than the number seen at the peak of opioid analgesic dispensing in 2012 
(Ref. 9). The lethality of co-involved substances, such as heroin, 
illicitly manufactured fentanyl, and illicitly manufactured fentanyl 
analogues has also changed since 2012 and may partly explain why 
overdose deaths involving opioid analgesics persist, despite the 
reductions in prescribing.
    Patients commonly report having unused opioid analgesics after 
treatment of acute pain, such as pain following surgical procedures 
(Refs. 10 and 11). Opioid analgesics prescribed to treat chronic pain 
conditions can also result in unused drugs. When not properly disposed, 
these opioid analgesics provide opportunities for nonmedical use, 
accidental exposure, and overdose. Most people who reported past-year 
nonmedical use of prescription pain relievers obtained them through 
friends, relatives, or their own prescription (Ref. 1). Accordingly, 
FDA's efforts to address the opioid crisis include a focus on 
encouraging appropriate disposal of unused opioid analgesics.
    The Substance Use-Disorder Prevention that Promotes Opioid Recovery 
and Treatment for Patients and Communities Act (SUPPORT Act) (Pub. L. 
115-271), signed into law on October 24, 2018, provides FDA several new 
authorities to address the opioid crisis. The SUPPORT Act authorized 
FDA to require through a Risk Evaluation and Mitigation Strategy (REMS) 
that a safe disposal packaging or safe disposal system for the purposes 
of rendering the drug nonretrievable be dispensed to certain patients 
with opioids or other drugs that pose a serious risk of abuse or 
overdose if, among other things, FDA determines that such safe disposal 
packaging or system may mitigate such risks and is sufficiently 
available (21 U.S.C. 355-1(e)(4)).
    The purpose of this notice is to seek public comment on the 
potential application of this authority to require, under the Opioid 
Analgesic (OA) REMS, that mail-back envelopes and education on safe 
disposal be provided with opioid analgesics dispensed in outpatient 
settings. We recognize that this is just one possible application of 
FDA's new authorities in the Federal Food, Drug, and Cosmetic Act (FD&C 
Act) section 505-1(e)(4) (21 U.S.C. 355-1(e)(4)) related to packaging 
and disposal. We are considering, and invite comment on, other possible 
applications of these authorities, including novel packaging or other 
safe disposal options that would meet the SUPPORT Act standards. 
Furthermore, we actively encourage drug manufacturers and others to 
innovate in this space. We believe that the potential disposal 
requirement outlined below would provide patients and caregivers with a 
convenient additional option that would complement existing disposal 
options (e.g., take-back days, kiosks, flushing, and in-home disposal 
products). This potential requirement could be a significant and 
readily achievable step toward improving the safe use of opioid 
analgesics.
    FDA is establishing this docket to solicit input from stakeholders 
on all aspects of this potential requirement under the OA REMS, 
including comments on specific questions posed in section III of this 
notice.

II. Mail-Back Envelopes Dispensed With Opioid Analgesics in an 
Outpatient Setting

    In this section, we identify available data showing that many 
patients do not use all of their prescribed opioid analgesics. This 
well-documented outcome results in unused opioid analgesics that, if 
not securely stored, may be easily accessible and subject to nonmedical 
use, accidental exposure, and overdose. We summarize published 
literature regarding the potential impacts of in-home disposal options 
and whether they could increase disposal of unused opioid analgesics, 
especially when coupled with patient education on the importance of 
disposal. We then describe existing disposal options and programs, 
including take-back days, collection kiosks in pharmacies and other 
locations, flushing, in-home disposal, and mail-back envelopes. We also 
describe a potential requirement, as part of the OA REMS, that mail-
back envelopes and education on safe disposal be provided with opioid 
analgesics dispensed in an outpatient setting.

A. Unused, Improperly Stored Opioids Provide an Easily Accessible 
Supply of Opioids for Nonmedical Use, Accidental Exposure, and Overdose

    Many patients report having excess opioid analgesic tablets from 
prescriptions they received after surgical procedures. A systematic 
review from 2017 reported that after seven common surgical procedures, 
67 to 92 percent of patients had excess opioid analgesics (Ref. 11). A 
more recent systematic review that included articles published up to 
2019 determined that, in studies of patient-reported use of opioid 
analgesics after surgical procedures that reported on unused tablets, 
most studies reported that 50 to 70 percent of tablets went unused 
(Ref. 10). Articles published since the last systematic review continue 
to report excess tablets after treatment of acute pain from surgical 
procedures or from treatment in emergency departments (Refs. 12 to 21).
    Patients who are prescribed opioid analgesics to treat chronic pain 
may also have unused opioids requiring disposal, for example, when 
changing opioid therapy (new opioid ingredient or tablet strength), 
upon discontinuation of opioid therapy, or upon death. Removing unused 
opioids from a home is an important public health intervention as many 
studies report that patients frequently store opioid analgesic tablets 
in unsecure locations (Ref. 10), making them easily accessible for 
nonmedical use, accidental exposure, and overdose.

B. Provision of Education and In-Home Disposal Options May Increase 
Disposal of Unused Opioid Analgesics

    Educating patients about opioid analgesic disposal options may 
increase the disposal rate \2\ for unused opioids (Ref. 20). In a 
recent review of the literature examining opioid disposal options and 
practices, most studies found that fewer than 50 percent of patients 
disposed of their opioids (Ref. 20). The majority of studies that 
examined the effect of providing patient education on the rate of 
disposing of unused postoperative opioids found that patient education 
increased the disposal rate by 15 to 30 percent compared to patients 
who did not receive any additional education. Two investigations found 
that text message reminders also increased the disposal rate by 
approximately 30 percent in the text message reminder group compared to 
patients who did not receive reminders (Refs. 21 and 22).
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    \2\ The percent of patients who dispose of unused medications. 
This document specifically discusses disposal of opioid analgesic 
medications.
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    There is also limited evidence that providing a disposal option 
along with education increased the probability of disposal over that of 
providing education alone. For example, one study assessed the 
difference in postoperative disposal rates when patients were

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provided a take-home disposal method, patient education, or both (Ref. 
23). Compared to usual care, either patient education or providing a 
take-home disposal method increased the disposal rate approximately 12 
percent; for the group of patients who received both education and a 
take-home disposal method, the disposal rate increased by 19.5 percent. 
The four studies where a disposal kit was provided uniformly reported 
an increase in actual or planned disposal rates, and in three of four 
studies, the rates increased to over 50 percent of the study population 
(Refs. 23 to 26).
    While disposal products provided to patients in these studies were 
often not specified, and the study populations usually received them 
after hospital encounters for surgical procedures, it is reasonable to 
assume that similar increases in disposal rates may also occur with 
mail-back envelopes and for other situations outside of post-surgical 
pain. What is less clear is whether education provided in a retail 
pharmacy setting will be as successful as the patient education 
provided in a post-surgical setting. We are interested in descriptions 
of programs that provide mail-back envelopes specifically, as well as 
those in which patient counseling on disposal is provided at retail 
pharmacies. In addition to program descriptions, we are interested in 
data on the effectiveness of mail-back envelope provision and 
counseling on disposal provided at retail pharmacies in increasing 
opioid analgesic disposal rates.

C. New REMS Authority Over Drug Disposal and Packaging

    Section 3032 of the SUPPORT Act amended FDA's REMS authority. 
Specifically, as a part of a REMS, FDA may require that a drug for 
which there is a serious risk of an adverse event occurring from abuse 
or overdose be dispensed to certain patients with safe disposal 
packaging or a safe disposal system for purposes of rendering the drug 
``nonretrievable'' (as that term is defined in a regulation adopted by 
the Drug Enforcement Administration (DEA)), if FDA determines that such 
safe disposal packaging or system may mitigate such serious risk and is 
sufficiently available (see section 505-1(e)(4) of the FD&C Act). Under 
DEA regulations (21 CFR 1317.90(a)), the requirement to render 
controlled substances ``non-retrievable'' applies only to DEA 
registrants and does not apply to ultimate users or patients.\3\ 
However, in the SUPPORT Act, Congress made the ``nonretrievable'' 
standard applicable to any safe disposal packaging or system FDA may 
require under a REMS (see 21 U.S.C. 355-1(e)(4)). FDA may also require 
that a drug for which there is such serious risk be made available for 
dispensing to certain patients in unit-dose packaging, packaging that 
provides a set duration, or another packaging system that FDA 
determines may mitigate that risk (21 U.S.C. 355-1(e)(4)).
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    \3\ 79 FR 53520 at 53541, September 9, 2014.
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    A packaging or disposal requirement under this provision can be 
imposed for prescription drugs that are the subject of applications 
approved under section 505(c) of the FD&C Act (21 U.S.C. 355(c)) or 
section 351 of the Public Health Service Act, as well as drugs that are 
the subject of abbreviated new drug applications (ANDAs) approved under 
section 505(j) of the FD&C Act if a packaging or disposal requirement 
is required for the applicable reference listed drug (see section 505-
1(i)(1)(B) of the FD&C Act). FDA can permit packaging systems and safe 
disposal packaging or safe disposal systems for drugs that are the 
subject of ANDAs that are different from those required for the 
applicable reference listed drugs (see section 505-1(i)(2)(B) of the 
FD&C Act). FDA must take into consideration the burden on patients' 
access to the drug and the burden on the healthcare delivery system 
that would be associated with any such packaging or disposal 
requirement, and must consult with other relevant Federal Agencies with 
authorities over drug disposal packaging in certain circumstances (see 
section 505-1(e)(4) of the FD&C Act).
    The DEA has defined ``non-retrievable'' through regulation (21 CFR 
1300.05(b)). It means, in part, ``the condition or state to which a 
controlled substance shall be rendered following a process that 
permanently alters that controlled substance's physical or chemical 
condition or state through irreversible means and thereby renders the 
controlled substance unavailable and unusable for all practical 
purposes.'' The regulation further provides that ``a controlled 
substance is considered non-retrievable when it cannot be transformed 
to a physical or chemical condition or state as a controlled substance 
or controlled substance analogue,'' and that ``the purpose of 
destruction is to render the controlled substance(s) to a non-
retrievable state and thus prevent diversion of any such substance to 
illicit purposes'' (21 CFR 1300.05(b)).
    Under DEA regulations, an entity registered with the DEA \4\ may 
collect controlled substances from ultimate users, to include 
collection by mail-back packages or envelopes, for the purpose of 
destruction.\5\ To be considered ``destroyed,'' a mail-back package 
must be destroyed in compliance with applicable Federal, State, tribal, 
and local laws and regulations and must be rendered non-retrievable.\6\ 
Mail-back envelopes dispensed with opioid analgesics pursuant to a 
mail-back program that operates in compliance with DEA regulations and 
all other applicable laws would be ``for the purposes of rendering the 
drug nonretrievable,'' as required by section 505-1(e)(4) of the FD&C 
Act. There are multiple companies that operate DEA-registered mail-back 
programs and have mail-back envelopes commercially available, which 
could be utilized by drug manufacturers who would be subject to the 
potential REMS requirement described in this notice.
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    \4\ Manufacturers, distributors, reverse distributors, narcotic 
treatment programs, hospitals/clinics with an onsite pharmacy, and 
retail pharmacies that desire to be collectors shall modify their 
registration to obtain authorization to be a collector (21 CFR 
1317.40(a); 1301.51). A collector would need to submit a letter of 
request for modification of their registration to the Registration 
Unit at the DEA and include the registrant's name, address, 
registration number, and the type of collection (e.g., a mail-back 
program and/or a collection receptacle) that the collector intends 
to conduct.
    \5\ DEA regulations address take-back events, mail-back 
programs, and collection receptacles (21 CFR 1317.65, 1317.70, and 
1317.75, respectively).
    \6\ 21 CFR 1317.90(a).
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D. Mail-Back Envelopes in the Current Landscape of Opioid Disposal 
Options

    There are various options for safely disposing of opioid analgesics 
available to patients, all of which can achieve the goal of removing 
the risks associated with having unused and unsecured opioids stored in 
the home. There are both in-home disposal options (e.g., flushing, 
commercially available in-home disposal products) and disposal options 
outside of the home (i.e., collection kiosks, take-back events). FDA 
currently recommends disposing of opioids in permanent collection sites 
(e.g., kiosks in pharmacies) or at take-back events (Ref. 27). If these 
disposal options are not readily available, FDA recommends either 
flushing (for opioids on FDA's ``Flush List'' (Ref. 28) or mixing with 
an unpalatable substance and disposing in household trash (Ref. 27).
    However, each option has its own challenges, which can result in 
individuals being unable, unwilling, or reluctant to use them. For 
example, collection sites (e.g., kiosks) require

[[Page 23872]]

individuals to bring opioid analgesics out of the home to a public 
place, either a pharmacy or law enforcement facility. This requires 
planning, access to transportation, and follow-through. Some 
individuals are unable to readily or easily travel to a collection 
site. In addition, some individuals may be reluctant to bring opioid 
analgesics to a public location due to social stigma, or may fear 
entering law enforcement locations, especially while carrying opioid 
analgesics.
    In-home disposal options also have challenges. Many patients are 
reluctant to flush opioids (or other medications) due to environmental 
concerns (Ref. 28). FDA's recommendation to mix some opioids (i.e., 
those not on the ``flush list'') with an unpalatable substance and 
dispose in household trash is a multistep process some patients may be 
unwilling or reluctant to undertake. In addition, disposal of opioids 
in household trash may not prevent all accidental exposures.
    Commercially available in-home disposal products (e.g., DisposeRx 
packets or Deterra kits) commonly dispensed by some pharmacies are 
another option, but they also require multiple steps (e.g., emptying 
pills from one container into another container, adding water, shaking 
to mix contents, disposing in household trash) (Refs. 29 to 31), and 
some individuals may be reluctant to use them due to environmental 
concerns. Further, FDA's understanding is that these products may not 
render drugs ``nonretrievable'' within the meaning of the DEA 
regulation referenced in section 505-1(e)(4)(B). Mail-back envelopes 
require individuals to put the mail-back envelopes in a mailbox, which, 
for some individuals, may be physically distanced from their home 
(e.g., apartments, P.O. boxes, Native American reservations). 
Additionally, patients may be reluctant to put opioids in the mail for 
fear of diversion (Ref. 32). Some individuals may be more inclined to 
use one option; others a different option. Accordingly, FDA believes it 
is important to provide patients with a range of reasonable options, 
and to provide appropriate education on each of these options.
    FDA is aware that many organizations, both public and private, have 
ongoing efforts to increase safe disposal of unused opioids. For 
example, large retail pharmacy chains and many independent pharmacies 
operate drug disposal programs that include making drug disposal kiosks 
available in pharmacies, sponsoring drug ``take-back'' days and 
providing in-home disposal products (Refs. 33 to 37). It is our 
understanding that pharmacists often are instructed to counsel patients 
and include educational materials about safe disposal in conjunction 
with providing in-home disposal products. Some States and 
municipalities have passed legislation requiring manufacturers who sell 
drugs in their jurisdictions to fund drug disposal programs that can 
include subsidizing kiosks in pharmacies and/or the provision of in-
home disposal products, including, occasionally, mail-back envelopes 
(Refs. 38 to 40).
    The Agency believes it is important for patients to have multiple 
options for disposing of unused opioids, including kiosks, take-back 
events, and in-home disposal options. Mail-back envelopes are one 
option that has multiple favorable characteristics. They do not require 
patients to mix medications with water, chemicals, or other substances. 
Mail-back envelopes are also required to be postage paid,\7\ thereby 
providing patients with a free disposal option. Further, most patients 
can mail these envelopes from their home. Additionally, the DEA and the 
U.S. Postal Service (USPS) have regulations and policies to ensure that 
mail-back envelopes are fit for purpose.\8\ The USPS has longstanding 
policies in place to safely and securely transport mail-back envelopes 
to the location where they will be destroyed.\9\ Finally, unlike other 
alternatives described here, the DEA requires mail-back envelopes to be 
disposed of in a manner that renders them non-retrievable,\10\ which is 
typically accomplished through incineration. As a result, mail-back 
envelopes (along with collection kiosks) result in less opioids in the 
water supply and landfills than is associated with other disposal 
options.
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    \7\ 21 CFR 1317.70(c)(4). DEA added this requirement because it 
believed that ``pre-paid postage will ensure that the package is not 
returned to sender, which will help reduce its handling and 
therefore, the diversion risks'' (79 FR 53520 at 53536, September 9, 
2014).
    \8\ See 21 CFR 1317.70; USPS Publication 52, Mail-back programs.
    \9\ Mail-back collectors are required to provide mail recipients 
with readymade packaging and labels that comply with USPS 
regulations for mailing controlled substances, including unique 
Intelligent Mail package barcodes. See USPS Publication 52, Mail-
back programs.
    \10\ See 21 CFR 1317.70(a); 1317.90(a).
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    FDA recognizes that, notwithstanding these benefits, mail-back 
envelopes are, at present, relatively underutilized. Large retail 
pharmacy chains have focused on take-back days, kiosks, and a provision 
of commercially available in-home disposal products (Refs. 33 to 37), 
while it appears manufacturers subject to State-mandated disposal 
requirements have primarily focused on collection kiosks. FDA 
anticipates that a REMS-mandated disposal program for opioid analgesics 
focused on provision of mail-back envelopes, together with education on 
multiple safe disposal options, could complement these existing opioid 
disposal programs.

E. Approach Under Consideration: Mail-Back Envelopes and Education on 
Proper Disposal Must Be Provided to Patients With Opioid Analgesics 
Dispensed in Outpatient Pharmacies

    FDA is considering adding a mail-back envelope requirement to the 
OA REMS to require that all opioid analgesics, including immediate-
release (IR), extended-release (ER), and long-acting (LA) formulations, 
used in the outpatient setting that are subject to the OA REMS be 
dispensed with mail-back envelopes.
    Although most studies reported excess opioid analgesics after a 
surgical procedure (Refs. 10 and 11), suggesting the need to target 
disposal options for patients with acute pain, the pharmacist at the 
time of dispensing may find it difficult to differentiate whether a 
patient is being treated for acute or chronic pain. For example, using 
specific formulations of opioid analgesics as a proxy for 
distinguishing between acute or chronic pain would not be appropriate 
because patients with chronic pain may take both IR and ER or LA 
formulations. In fact, most patients receiving an opioid analgesic, 
regardless for how long, use IR formulations (Ref. 41). Further, as 
mentioned above, opioid analgesics prescribed for chronic pain can also 
become unneeded. Therefore, FDA is considering having any mail-back 
envelope requirement apply to all opioid analgesics, including IR, ER, 
and LA formulations, used in the outpatient setting for acute or 
chronic pain that are subject to the OA REMS.
    That said, requiring that a mail-back envelope be dispensed with 
every opioid analgesic prescription could be inefficient and lead to an 
excess of dispensed mail-back envelopes. The use of algorithms to 
target mail-back envelope distribution in a thoughtful, tailored manner 
would be expected to positively impact program fidelity and outcomes 
and decrease waste. Some existing retail pharmacy programs that provide 
disposal options to patients use algorithms to target disposal options 
to certain patients or certain circumstances, such as only providing 
disposal options every 6 months to patients who continue to fill 
multiple opioid analgesic prescriptions (Refs. 33 and 34). Other 
potential algorithms

[[Page 23873]]

could target the provision of mail-back envelopes to patients filling a 
prescription for an amount of opioids generally consistent with acute 
pain treatment, or to patients with a change in dose of a recurring 
opioid analgesic prescription who may then have unused opioids. FDA 
recognizes that the upfront effort to implement algorithms could be 
complicated but expects that the use of algorithms would be more 
efficient and would reduce the long-term burden on the healthcare 
delivery system by targeting the distribution of mail-back envelopes to 
patients most likely to have unused opioids. FDA would appreciate input 
on appropriate optimal algorithm design for a potential targeted mail-
back envelope provision. We would also expect, regardless of the 
algorithm used, that mail-back envelopes would be provided to any 
patient or caregiver who requests one. Additionally, we would expect 
that if a given patient does not want the mail-back envelope, they 
could decline the offer.
    Multiple studies we reviewed indicated that unused opioids are 
often stored in unsecure locations (Ref. 10) and that patients were 
reluctant to dispose of unused opioid analgesics for various reasons, 
including the patient's belief that they might need the unused opioids 
in the future (Refs. 32, 42, and 43). In the studies that we reviewed, 
patient and caregiver education about disposal was often provided with 
an at-home disposal option during counseling about care after a 
procedure, and patients were reminded about disposal during followup 
contacts. For example, one study found that combining an in-home 
disposal option with patient education focused on the importance of 
disposal increased the disposal rate versus simply providing an in-home 
disposal option or patient education (Ref. 23). Accordingly, we believe 
that patient and caregiver education that explains the importance of 
safe storage and proper disposal and addresses patients' reluctance to 
dispose of opioids would be an integral component of any mail-back 
envelope REMS requirement. We also believe that take-home educational 
materials on proper disposal, as well as followup reminders (e.g., 
automated text messages), are likely to have a positive reinforcing 
effect on patient counseling provided by the pharmacist at the time of 
dispensing.
    There are multiple ways a mail-back envelope REMS requirement could 
be designed and operationalized. We describe two possibilities here, 
and welcome input on others. One option would be to require that drug 
manufacturers subject to the OA REMS make mail-back envelopes available 
to outpatient pharmacies at no cost and allow pharmacies to provide 
mail-back envelopes and counseling on disposal according to their own 
policies and procedures. Additionally, to encourage patient education, 
FDA may also require manufacturers to create educational materials to 
assist pharmacists in counseling patients on safe storage and proper 
disposal. However, this option would not require that pharmacies 
actually provide mail-back envelopes, counseling on disposal, or take-
home educational materials. As such, this option would ultimately rely 
on pharmacy policies and procedures to drive the use of mail-back 
envelopes and counseling on safe disposal.
    Alternatively, FDA could require manufacturers to only distribute 
opioids to outpatient pharmacies certified in the REMS. Certification 
could require that mail-back envelopes, patient counseling, take-home 
materials, and followup reminders (e.g., text messages) be provided 
according to the terms of the REMS, and that all of these activities be 
conducted and appropriately documented. Again, manufacturers would 
supply mail-back envelopes to pharmacies at no cost. Certification of 
pharmacies could include requiring pharmacy staff to complete specified 
training on how to counsel patients on safe storage and proper 
disposal. As with the first option, FDA may also require manufacturers 
to create educational materials to assist pharmacies with patient 
counseling.
    For any mail-back envelope REMS requirement, FDA would intend for 
the program to increase the quantity of unused opioids properly 
disposed of, and, therefore, to decrease the quantity of unused opioids 
available for nonmedical use, accidental exposure, and overdose. FDA 
anticipates the potential for greater impact with the second option 
than the first but acknowledges that the second option would impose 
greater burdens on the healthcare system.
    The potential burdens associated with a mail-back envelope REMS 
requirement on pharmacies and pharmacists would include, depending on 
the program design: (1) Completion of any REMS-mandated training and 
certification; (2) implementation of REMS-compliant processes in 
pharmacies; and (3) documentation of compliance with REMS requirements 
by pharmacies. These efforts are in addition to existing State and 
Federal pharmacy requirements associated with dispensing opioids (e.g., 
checking prescription drug monitoring programs). A mail-back envelope 
REMS requirement is likely to be more effective under the second 
scenario described above. However, the more requirements the REMS 
imposes, the more likely that relevant stakeholders, particularly 
pharmacies, will have challenges complying with the requirements. 
Ensuring the requirements are met may necessitate remediation steps, 
such as reeducation, or even decertification, if a pharmacy fails to 
comply. Declining to certify or decertifying a pharmacy could affect 
patients' access to appropriately prescribed opioid analgesics.
    Accordingly, the ability of potential OA REMS disposal requirements 
to be integrated into healthcare providers' existing workflow is an 
important consideration in FDA's decision making. The Agency is seeking 
input on the design of a potential mail-back envelope REMS requirement 
that strikes the right balance between positive impact on unused opioid 
analgesic disposal and burden on pharmacies and other stakeholders.

F. Other Considerations for Requiring Provision of Mail-Back Envelopes 
With Opioid Analgesics

    Current DEA and USPS regulations and policies require mail-back 
envelopes to be nondescript, i.e., they must not include any markings 
or other information that might indicate that the package contains 
controlled substances.\11\ These specifications help alleviate concerns 
that mail-back envelopes can easily be identified for diversion while 
in transit. However, if a potential mail-back envelope REMS requirement 
were implemented, it could be expected to greatly increase the number 
of mail-back envelopes in circulation. The USPS has informed the Agency 
that the existing regulatory scheme, as well as USPS' rigorous 
monitoring and policing mechanisms, should be adequate to accommodate 
an increase in mail-back envelope utilization. We welcome other 
stakeholder views on this issue, including how any potential adverse 
consequences could be mitigated.
---------------------------------------------------------------------------

    \11\ 21 CFR 1317.70(c)(1); USPS Publication 52, Mail-back 
programs.
---------------------------------------------------------------------------

    FDA expects that a mail-back envelope OA REMS requirement would 
provide patients with an additional disposal option that complements 
disposal options already available through ongoing public and private 
efforts. The Agency understands mail-back envelopes will not be the 
preferred disposal option for all patients. FDA's expectation is that 
existing disposal

[[Page 23874]]

programs (e.g., provision of in-home disposal options by many 
pharmacies, including most major chain pharmacies) will continue, such 
that a mail-back envelope mandate would provide patients with an 
additional disposal option without affecting other existing disposal 
options. We are seeking input on how a mail-back envelope OA REMS 
requirement could be designed and operationalized to complement 
existing disposal efforts and programs.

G. Other Actions That Could Complement a Mail-Back Envelope REMS 
Mandate

    FDA is considering additional actions that may be necessary or 
appropriate if we were to impose a mail-back envelope disposal 
requirement under the OA REMS. For example, FDA would need to amend 
recommendations in the ``Remove the Risk'' campaign on safe disposal of 
opioids to include information on the availability and use of mail-back 
envelopes (Ref. 44). Likewise, FDA would need to amend the information 
on disposal in FDA-approved prescriber and patient labeling for opioids 
that would be subject to the mail-back envelope REMS requirement, as 
this labeling currently does not mention mail-back envelopes. FDA is 
also considering whether it might be appropriate to have a large media 
campaign aimed at increasing public awareness of the importance of 
promptly disposing unused opioids and how to safely dispose of them. 
FDA welcomes input on these and any other potential actions that could 
increase the effectiveness of a mail-back envelope disposal requirement 
under the OA REMS.

III. Additional Request for Comments And Information

    FDA is soliciting comments from stakeholders regarding all aspects 
of the potential mail-back envelope REMS mandate described in this 
document. The Agency is particularly interested in comments on the 
following topics:
    1. The potential safety advantages and public health impacts of 
providing mail-back envelopes with opioid analgesics dispensed in an 
outpatient setting.
    2. Whether there are specific opioid analgesic drug products for 
which requiring mail-back envelopes is more important from a public 
health perspective and, if so, which products.
    3. How pharmacies could identify those patients who are most likely 
to have unused opioids to optimize provision of mail-back envelopes to 
these patients and potentially positively impact the share of mail-back 
envelopes that are utilized to safely dispose of opioid analgesics.
    4. How pharmacies could develop and implement algorithms to 
determine when to provide a mail-back envelope, including how feasible 
or practical it would be for pharmacies to do so.
    5. Whether requiring provision of mail-back envelopes under the OA 
REMS should also include a requirement for patient counseling and/or 
provision of take-home materials on safe disposal at the point of 
dispensing.
    6. What key educational messages regarding secure storage and safe 
disposal should be included in any patient education component of the 
potential OA REMS requirement described in this notice, including 
educational messages to increase uptake and use of mail-back envelopes, 
as well as what form that education should take (e.g., handouts, 
pharmacist counseling of patients).
    7. How a mail-back envelope requirement could be designed and 
implemented to help ensure that the disposal requirement minimizes 
burden on pharmacies while still providing the public health benefit. 
As discussed in the document, there is a tradeoff between the potential 
effectiveness of a mail-back envelope REMS requirement and the level of 
burden imposed on those pharmacies involved in implementing the 
requirement.
    8. Possible challenges, including technical and logistical 
challenges, with the potential REMS mandate described in this notice, 
and what factors could impact manufacturers' ability to provide mail-
back envelopes to pharmacies, or the ability of pharmacies to dispense 
mail-back envelopes and provide appropriate disposal education to 
consumers.
    9. The impact of a mail-back envelope REMS requirement on other 
stakeholders, including manufacturers, prescribers, payers, and 
patients.
    10. How a mail-back envelope REMS requirement could be designed and 
operationalized to provide another option for patients that would 
complement current pharmacy disposal programs, policies, and 
procedures, as well as Federal, State, local, and private sector 
efforts on proper opioid disposal.
    11. Possible negative impacts of a potential mail-back envelope 
REMS mandate, including whether there is a risk that it could diminish 
the impact of other public and private efforts around safe disposal. 
For example, could it be the case that for some patients, provision of 
a mail-back envelope together with another commercially available in-
home disposal product, and education on how to use both, could be 
overwhelming and lead to less comprehension and utilization of either 
option?
    12. How manufacturers and FDA could best assess the effectiveness 
of a mail-back envelope OA REMS requirement. Assessing the impact of a 
mail-back envelope requirement in a REMS is likely to be challenging 
because, among other reasons, current DEA regulations prohibit mail-
back envelopes from being opened prior to destruction, preventing a 
direct inventory of contents; and some of the opioids disposed of in 
mail-back envelopes would presumably be disposed of using another 
disposal option if the mail-back envelope were not provided.
    13. How patients and others may perceive the environmental impact 
of a potential mail-back envelope requirement, including the potential 
for such envelopes to reduce the amount of medications flushed or 
disposed of in landfills.
    14. Any existing programs that provide mail-back envelopes, 
especially programs that provide patient counseling on disposal and 
that operate in retail pharmacies, including any data on the 
effectiveness of these programs.
    15. Section 3032 of the SUPPORT Act authorizes the Agency to use 
its REMS authority to require that a safe disposal packaging or safe 
disposal system for the purposes of rendering the drug nonretrievable 
be dispensed to certain patients with drugs that pose a serious risk of 
abuse or overdose if, among other things, FDA determines that such safe 
disposal packaging or system may mitigate such risks and is 
sufficiently available (21 U.S.C. 355-1(e)(4)). We recognize that the 
approach described in this document is only one potential use of the 
Agency's REMS authority concerning disposal. Comment on other possible 
uses of the Agency's REMS authority concerning disposal, including 
providing any data or information about whether other disposal 
packaging or disposal systems we might consider mandating, such as 
commercially available in-home disposal products, would satisfy the 
statutory requirements at 21 U.S.C. 355-1(e)(4).
    16. Discuss other actions FDA could take in addition to, and in 
support of, a mail-back envelope disposal REMS requirement to increase 
safe disposal of unused opioid analgesics.

IV. References

    The following references marked with an asterisk (*) are on display 
at the Dockets Management Staff (see ADDRESSES) and available for 
viewing by

[[Page 23875]]

interested persons between 9 a.m. and 4 p.m., Monday through Friday; 
they also are available electronically at https://www.regulations.gov. 
References without asterisks are not on public display at https://www.regulations.gov because they have copyright restriction. Some 
references may be available at the website address, if listed. 
References without asterisks are available for viewing only at the 
Dockets Management Staff. FDA has verified the web addresses, as of the 
date this document publishes in the Federal Register, but websites are 
subject to change over time.

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2021.

    Dated: April 13, 2022.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2022-08372 Filed 4-20-22; 8:45 am]
BILLING CODE 4164-01-P


