Notice2022-24874
Safety and Effectiveness of Certain Naloxone Hydrochloride Drug Products for Nonprescription Use; Request for Comments
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Published
November 16, 2022
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA, the Agency, or we) is announcing our preliminary assessment that certain types of naloxone hydrochloride ("naloxone") drug products may be approvable as safe and effective for nonprescription use. It is our preliminary opinion at this time that naloxone nasal spray up to 4 milligrams (mg), and naloxone autoinjector for intramuscular (IM) or subcutaneous (SC) use up to 2 mg, have the potential to be safe and effective for use as directed in nonprescription drug labeling without the supervision of a healthcare practitioner. We believe the prescription requirement for these naloxone products might not be necessary for the protection of the public health. However, we need additional data such as product- specific data on the nonprescription user interface design, including packaging and labeling, to make a conclusive determination in this respect. The Federal Food, Drug, and Cosmetic Act (FD&C Act) does not permit the simultaneous marketing of the same drug with the same active ingredient as both a prescription and nonprescription product, absent a clinically meaningful difference between them. Therefore, if and when FDA has sufficient data to support approval of a nonprescription naloxone product (e.g., through submission and approval of an application for a nonprescription naloxone product or a supplemental application to switch an FDA-approved naloxone product from prescription to nonprescription status), currently marketed naloxone products labeled as "Rx only" with no clinically meaningful difference from the approved nonprescription products will be considered misbranded.
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<title>Federal Register, Volume 87 Issue 220 (Wednesday, November 16, 2022)</title>
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[Federal Register Volume 87, Number 220 (Wednesday, November 16, 2022)]
[Notices]
[Pages 68702-68713]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2022-24874]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2022-N-2673]
Safety and Effectiveness of Certain Naloxone Hydrochloride Drug
Products for Nonprescription Use; Request for Comments
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice; request for comments.
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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is
announcing our preliminary assessment that certain types of naloxone
hydrochloride (``naloxone'') drug products may be approvable as safe
and effective for nonprescription use. It is our preliminary opinion at
this time that naloxone nasal spray up to 4 milligrams (mg), and
naloxone autoinjector for intramuscular (IM) or subcutaneous (SC) use
up to 2 mg, have the potential to be safe and effective for use as
directed in nonprescription drug labeling without the supervision of a
healthcare practitioner. We believe the prescription requirement for
these naloxone products might not be necessary for the protection of
the public health. However, we need additional data such as product-
specific data on the nonprescription user interface design, including
packaging and labeling, to make a conclusive determination in this
respect. The Federal Food, Drug, and Cosmetic Act (FD&C Act) does not
permit the simultaneous marketing of the same drug with the same active
ingredient as both a prescription and nonprescription product, absent a
clinically meaningful difference between them. Therefore, if and when
FDA has sufficient data to support approval of a nonprescription
naloxone product (e.g., through submission and approval of an
application for a nonprescription naloxone product or a supplemental
application to switch an FDA-approved naloxone product from
prescription to nonprescription status), currently marketed naloxone
products labeled as ``Rx only'' with no clinically meaningful
difference from the approved nonprescription products will be
considered misbranded.
DATES: Either electronic or written comments on the notice must be
submitted by January 17, 2023.
ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. The <a href="https://www.regulations.gov">https://www.regulations.gov</a> electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of January 17, 2023. Comments
received by mail/hand delivery/courier (for written/paper submissions)
will be considered timely if they are received on or before that date.
Electronic Submissions
Submit electronic comments in the following way:
<bullet> Federal eRulemaking Portal: <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to <a href="https://www.regulations.gov">https://www.regulations.gov</a>
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
[[Page 68703]]
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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
<bullet> 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:
<bullet> 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.
<bullet> 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-2673 for ``Safety and Effectiveness of Certain Naloxone
Hydrochloride Drug Products for Nonprescription Use; 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a> or at the Dockets Management Staff between 9 a.m.
and 4 p.m., Monday through Friday, 240-402-7500.
<bullet> 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
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: <a href="https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf</a>.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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, 240-402-7500.
FOR FURTHER INFORMATION CONTACT: Ayako Sato, Center for Drug Evaluation
and Research, Food and Drug Administration, 10903 New Hampshire Ave.,
Bldg. 51, Rm. 6206, Silver Spring, MD 20993, 240-402-4191.
SUPPLEMENTARY INFORMATION:
I. Background
A. FDA's Current Regulatory Framework
Two regulatory pathways to bring a nonprescription drug product to
market in the United States are: (1) the over-the-counter (OTC) drug
review process under section 505G of the FD&C Act (21 U.S.C. 355h) with
respect to OTC monograph drugs and (2) the application process under
section 505 of the FD&C Act (21 U.S.C. 355) or, for a biological
product, under section 351 of the Public Health Service Act (PHS Act)
(42 U.S.C. 262).
Under the OTC drug review process, a nonprescription drug product
may be marketed without an application approved under section 505 of
the FD&C Act if the nonprescription drug product meets the requirements
of section 505G of the FD&C Act, and other applicable requirements. In
addition, FDA approves drugs under section 505 of the FD&C Act and, for
biological products, under section 351 of the PHS Act, as either
prescription or nonprescription drug products.
An applicant may submit a new drug application (NDA) for a
nonprescription drug product using the pathways described in section
505(b)(1) or (2) of the FD&C Act to market a new drug product. A
section 505(b)(1) NDA includes full reports of investigations to
demonstrate that the proposed drug product is safe and effective under
the conditions prescribed, recommended, or suggested in its proposed
labeling (see sections 505(d) and (b)(1) of the FD&C Act). An NDA
submitted pursuant to section 505(b)(2) of the FD&C Act also includes
information to demonstrate that the proposed drug product is safe and
effective under the conditions prescribed, recommended, or suggested in
its proposed labeling, but at least some of the information required
for approval comes from studies not conducted by or for the applicant
and for which the applicant has not obtained a right of reference or
use. An NDA for a nonprescription drug product must include, among
other things, information to demonstrate that consumers can
appropriately self-select \1\ the proposed drug product and use the
drug product safely and effectively without the supervision of a
healthcare practitioner.
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\1\ E.g., 21 CFR 201.5. Because nonprescription drugs are
available to consumers without the supervision of a healthcare
provider, nonprescription labeling must on its own be able to
effectively communicate to a general consumer the information
required for the safe and effective use of the product. Therefore,
``self-select'' means that a consumer can apply the label
information to their personal medical situation and make correct
decisions about whether it is appropriate for them to use or not use
the drug product. In some cases, nonprescription products may be
selected and purchased by someone else, such as a family member or
caregiver and administered to another family member or individual,
such as to a child or elderly person.
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Applicants may submit an abbreviated new drug application (ANDA)
using the pathway described in section 505(j) of the FD&C Act for a
drug product that is a generic version of a previously approved drug
product (typically an approved brand-name drug). An ANDA for a
nonprescription drug product generally references a nonprescription
drug product previously approved under section 505(c) of the FD&C Act
(known as the reference listed drug (``RLD'')) and relies on the
Agency's finding that the RLD is safe and effective. An ANDA generally
must contain information to show that the proposed generic product: (1)
is the same as the RLD with respect to the active ingredient(s), route
of administration, dosage form, strength, labeling (with certain
permissible differences) and (2) is bioequivalent to the RLD. The
procedures and requirements for the submission and approval of NDAs,
ANDAs, and supplements to those applications are set forth in 21 CFR
part 314.
Section 503(b)(1) of the FD&C Act (21 U.S.C. 353(b)(1)) requires
that certain drug products be dispensed only upon prescription of a
practitioner licensed to administer such drug product. The
[[Page 68704]]
prescription requirement applies to any drug product which: (1) because
of its toxicity or other potentiality for harmful effect, or the method
of its use, or the collateral measures necessary to its use, is not
safe for use except under the supervision of a practitioner licensed by
law to dispense such drug product or (2) is limited by an approved
application under section 505 of the FD&C Act to use under the
professional supervision of a practitioner licensed by law to
administer such drug product. If the approved drug product does not
meet the criteria for prescription-only dispensing, it may be marketed
as nonprescription, provided other applicable requirements are met.
Under section 503(b)(4)(A) of the FD&C Act, the label of a drug
product that is subject to the prescription dispensing provisions of
section 503(b)(1) (i.e., a prescription drug product) must bear, at a
minimum, the ``Rx only'' symbol, or else it is misbranded. Section
503(b)(4)(B) of the FD&C Act provides that a drug product to which the
prescription provisions of the FD&C Act do not apply (i.e., a
nonprescription drug product) will be deemed to be misbranded if at any
time before dispensing, the label of the drug product bears the ``Rx
only'' symbol. FDA has interpreted the language in section 503(b)(4) of
the FD&C Act to allow simultaneous marketing of drug products with the
same active ingredient as prescription in one case and nonprescription
in another if some clinically meaningful difference, such as a
difference in indication, strength, route of administration, dosage
form, or patient population, exists between the drug products that
makes the prescription product safe and effective only under the
supervision of a healthcare practitioner licensed by law to administer
the drug product (see 83 FR 13994, April 2, 2018; see also 70 FR 52050,
September 1, 2005). This effectively means that, absent a clinically
meaningful difference between the products that makes the prescription
product safe and effective only under the supervision of a licensed
healthcare practitioner, simultaneous marketing of two drug products
with the same active ingredient as, respectively, a prescription and a
nonprescription drug product, would result in the prescription drug
product being misbranded.
Although the OTC drug review process under section 505G of the FD&C
Act and the application process under section 505 of the FD&C Act or,
for a biological product regulated as a drug, under section 351 of the
PHS Act, are the primary ways in which an applicant brings a
nonprescription drug product to market, a drug originally approved as a
prescription drug may be switched to nonprescription status if FDA
finds that prescription requirement for such drug is not necessary for
the protection of the public health.\2\ For a drug product to switch
from prescription to nonprescription status, FDA must also determine
there are sufficient data demonstrating that the drug product can be
used safely and effectively by consumers without the supervision of a
licensed healthcare practitioner.\3\
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\2\ See 21 CFR 310.200(b).
\3\ Id.
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As discussed below, such information may include evidence from a
range of studies (e.g., label comprehension study, human factors study,
and/or actual use study). Usually, manufacturers seeking authorization
to market such a prescription product as nonprescription are
responsible for conducting these studies to show that their product can
be used safely and effectively without the supervision of a healthcare
practitioner. Generally, manufacturers of nonprescription drug products
must also label and package their products such that the consumer can
use the drug product safely for the purposes for which it is intended.
This includes complying with applicable labeling requirements under 21
CFR part 201, including the format and content requirements for
nonprescription drug product labeling under Sec. 201.66 (21 CFR
201.66). Labeling created to satisfy the requirements in Sec. 201.66
is commonly referred to as the Drug Facts labeling (DFL). The DFL is
intended to enable consumers to self-select appropriately and use the
nonprescription drug product safely and effectively. In addition to the
DFL, for a nonprescription drug product that requires an approved
application under section 505, FDA may approve additional labeling to
help ensure safe and appropriate use.
B. Naloxone
1. General Background on Naloxone
The opioid crisis, which encompasses misuse, abuse, and overdose
deaths involving illicit and prescription opioids, was declared a
public health emergency (Opioid PHE) in 2017 (Ref. 1). Since 2017, the
Opioid PHE declaration has been renewed multiple times. More than
80,000 people died of opioid-involved overdose deaths in the 12-month
period ending in January 2022, representing 75 percent of all drug
overdose deaths. The number of opioid-involved overdose deaths
increased from 71,000 deaths in the preceding year (Ref. 2).\4\
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\4\ Among deaths with drug overdose as the underlying cause,
using predicted provisional number of deaths for opioids (ICD-10
multiple cause-of-death codes for illicit and prescription opioids:
T40.0-T40.4, T40.6).
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Naloxone is a critical tool to help reduce opioid overdose deaths
and address this public health crisis. Opioid overdose is characterized
by life threatening respiratory and central nervous system (CNS)
depression that, if not immediately treated, may lead to significant
morbidity and mortality. Naloxone is a nonselective opioid receptor
antagonist that reverses the effects of respiratory depression and
sedation by displacing opioids from the mu-opioid receptor in the CNS.
Timely administration of naloxone, usually within minutes of the first
signs of an opioid overdose, can counter the overdose effects.
a. Approval history for prescription naloxone products. There are
currently no naloxone products approved by FDA for nonprescription use.
Naloxone is available as a prescription drug in several strengths,
dosage forms, and routes of administration. It was first approved in
the United States in 1971 with the tradename NARCAN. NARCAN, as
originally approved, was an injectable naloxone product that could be
delivered via the intravenous (IV), IM, or SC routes of administration,
and was available in vials or ampules.\5\ It was widely used by both
hospital and first responder personnel. As opioid use and overdoses
increased, naloxone was increasingly used by non-healthcare
professionals. Multiple initiatives across the United States provided
naloxone and instructions for its use to populations at risk of opioid
overdose and their family, friends and/or caregivers. These programs
were effective at getting naloxone into the hands of those who might
witness an overdose (see section C of this document). However, because
the injectable naloxone products at the time were only available in
glass vials and ampules, they needed to be distributed with syringes
and needles for manual injection, or with syringes and atomizers for
nasal administration. These products required additional preparation or
assembly before administration and were sometimes packaged as
improvised naloxone kits. Hence, there was a public health need
[[Page 68705]]
for naloxone products that did not require additional preparation or
assembly before administration and could be administered quickly and
safely by a layperson.
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\5\ NARCAN (naloxone hydrochloride) injection (NDA 016636) for
IV, IM, SC use has been discontinued. However, generic naloxone
hydrochloride injection products continue to be marketed.
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In 2014, FDA approved EVZIO, a 0.4 milligram (mg) prefilled,
single-use auto-injector naloxone drug product for IM or SC use,
followed shortly thereafter by FDA approval of NARCAN, a 4 mg,
prefilled, single-dose nasal spray in 2015. More recently, two higher
dose \6\ naloxone products were approved: KLOXXADO, an 8 mg, prefilled,
single-dose nasal spray, approved on April 29, 2021, and ZIMHI, a 5 mg
single-dose, prefilled syringe with an integrated needle for IM or SC
use, approved October 15, 2021. These prescription naloxone products do
not need additional supplies or additional assembly prior to use (e.g.,
the drug product is already prefilled in the device for
administration), and they represent an effort to develop and market
products that could potentially be administered by individuals without
medical training (i.e., laypersons) in community settings (i.e.,
``community-use'' naloxone products) in the interest of public health.
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\6\ For this notice, ``higher dose'' naloxone products refer to
products with dosage strengths above 4 mg for IM naloxone products
and above 2 mg for IM/SC/IV.
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b. Approval standard for prescription naloxone products. \7\
Applicants proposing novel naloxone products (including nonprescription
naloxone products) need to demonstrate sufficient systemic absorption
of naloxone as well as rapidity of onset compared to an approved
naloxone product, particularly in the early critical period after drug
administration. This is in addition to any other studies needed to
support approval of the product (e.g., human factors study).
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\7\ The approval standard for prescription naloxone products as
described in this section was discussed extensively at the October
5, 2016, joint meeting of the Anesthetic and Analgesic Drug Products
Advisory Committee and the Drug Safety and Risk Management Advisory
Committee. See website at <a href="https://wayback.archive-it.org/7993/20170111202120/http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndAnalgesicDrugProductsAdvisoryCommittee/ucm486848.htm">https://wayback.archive-it.org/7993/20170111202120/http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndAnalgesicDrugProductsAdvisoryCommittee/ucm486848.htm</a>.
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FDA has determined that it is not necessary for applicants to
conduct clinical efficacy trials with novel naloxone products, as
effective doses have already been established (Ref. 3). Clinical
efficacy trials present significant logistical and ethical challenges,
as approved naloxone products are already available for treatment of
opioid overdose, which, if not immediately treated, could result in
substantial morbidity and mortality. Therefore, historically, efficacy
has been based on information known about other naloxone products and
supported by a relative bioavailability study conducted in healthy
volunteers. In addition to the bioavailability studies conducted by
applicants to support their proposed naloxone doses/products,
applicants may also need to provide additional data, such as literature
reviews, to support the safety and effectiveness of their products if
the exposure is different. As newer products with higher doses and/or
exposures have been proposed, the importance of such literature support
has increased.
c. Layperson use of naloxone: ``community-use'' naloxone products
and improvised naloxone kits. Since 2014, FDA has approved several
prescription naloxone drug-device combination products for the
emergency treatment of a known or suspected opioid overdose, including
EVZIO, NARCAN, KLOXXADO, and ZIMHI. These specific FDA-approved
prescription products are referred to in this notice as ``community-
use'' naloxone products. ``Community-use'' products are specifically
designed to facilitate use by laypersons, without the need for
additional supplies or assembly before use. Because ``community-use''
naloxone products, such as prefilled auto-injectors (Ref. 9), nasal
sprays (Ref. 10), and syringes with an integrated needle presentation,
do not require other medical supplies prior to administration, safe and
effective use by laypersons in the community may be facilitated. In
addition, as part of the approval process, data were required to
demonstrate that these ``community use'' naloxone products administered
using the integrated device can achieve naloxone blood levels
appropriate to reverse an opioid overdose.
In addition to ``community-use'' naloxone products, other naloxone
formulations may be used by laypersons in community settings (e.g.,
naloxone in vial, ampule, and some prefilled syringe presentations).
However, these products were not specifically designed to be used in
the community setting. Nevertheless, it is important to emphasize that
all FDA-approved prescription naloxone products, regardless of whether
they were specifically designed to be ``community-use'' naloxone
products, may be considered options for community distribution to
laypersons for use outside of the healthcare setting (Ref. 4).\8\
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\8\ FDA has previously stated that all FDA-approved naloxone
products ``may be considered as options for community distribution
and use by individuals with or without medical training to stop or
reverse the effects of an opioid overdose'' (Ref. 4).
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Because some naloxone products in vial, ampule, and some prefilled
syringe presentations may require other medical supplies and additional
preparation prior to administration (e.g., transfer to a syringe,
measurement of a specific dose, attachment to an atomizer or needle,
etc.), there may be added complexity to administration of the products
and increased risk for medication errors when used by laypersons. When
distributed by community-based naloxone distribution programs, for
example, additional items are often packaged along with the naloxone in
improvised naloxone kits, and these kits may contain a syringe, needle,
or atomizer, as well as, but not limited to, alcohol pads, bag valve
masks, rubber gloves, and instructional or educational materials on
naloxone use and overdose prevention (Ref. 5). Even with these
additional materials, these improvised naloxone kits may be difficult
for some laypersons to use, and there are reports of administration and
dosing errors associated with laypersons using improvised naloxone kits
(Refs. 6 to 8). In addition, the blood levels of naloxone achieved with
administration using various improvised naloxone kits may not be known
(see Ref. 11).
d. Recent naloxone sales and prescription data. Since the
introduction of ``community-use'' naloxone products EVZIO, NARCAN,
KLOXXADO, and ZIMHI to the market, the opioid epidemic has evolved and
naloxone use has increased. Based on FDA's analyses using proprietary
databases, nationally estimated sales \9\ and dispensed prescriptions
\10\ for naloxone products increased across all healthcare settings
from 2017 to 2021, largely due to a substantial increase in naloxone
nasal spray distribution. The estimated number of naloxone units sold
increased by 81 percent from approximately 5.1 million units in 2017 to
approximately 9.3 million units in 2021. Injectable and nasal spray
sales to hospitals increased by more than 50 percent, and sales to
retail pharmacies tripled during this time period. In 2017,
approximately half of naloxone sales to retail pharmacies were for the
nasal spray, and by 2021 over 90 percent of sales were for the nasal
spray. The volume of naloxone products sold to
[[Page 68706]]
other healthcare settings (e.g., to clinics or in prisons and
universities) also increased. Similar to sales to healthcare settings,
the estimated number of naloxone prescriptions dispensed from
pharmacies increased from under half a million prescriptions in 2017 to
1.5 million prescriptions in 2021. In 2021, over 95 percent of naloxone
prescriptions dispensed from U.S. outpatient retail, mail-order, and
long-term care pharmacies were for the nasal spray.
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\9\ IQVIA. National Sales Perspectives<SUP>TM</SUP>. Data
extracted January 2022. Sales were measured in volume of ``units''
sold, representing the number of vials, auto-injectors, nasal
sprays, and syringes.
\10\ Symphony Health. Metys<SUP>TM</SUP>. Data extracted January
2022.
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It is important to note that the proprietary databases used for
these analyses underestimate total availability and distribution of
naloxone products in the United States because donations from
manufacturers and most direct sales to community-based naloxone
distribution programs are not well represented in the data above. These
donations and direct sales may be a substantial source of naloxone to
individuals with opioid use. Some sources cite that community-based
naloxone distribution programs received over 2 million injectable
naloxone doses donated by manufacturers or purchased in bulk at low
cost between 2017 and 2021 (Refs. 12 and 13). While the analyses showed
a decrease in injectable naloxone dispensed from retail pharmacies from
2017 to 2021, distribution patterns by product formulation from
community-based naloxone distribution programs may differ from the FDA
analyses using data from proprietary databases. Furthermore, some
naloxone sold to hospitals may also be distributed to settings such as
outpatient clinics and emergency medical services (EMS). Although the
analyses show an increased number of prescriptions dispensed from
retail pharmacies and an overall increase in naloxone sales over the
past 5 years, the increases in overdose deaths reflect a need for
increased access and availability of naloxone products particularly for
non-healthcare settings.
2. Benefit-Risk Considerations for Naloxone Products
FDA-approved prescription naloxone products have a favorable
benefit-risk profile. Naloxone is not a controlled substance and has no
known abuse potential. Naloxone is a potentially life-saving treatment
when used together with other appropriate measures (e.g., calling
911).\11\ Current evidence suggests that increasing access to naloxone
has the potential to reduce opioid overdose deaths. Results from
multiple observational studies show that naloxone distribution and
overdose education targeted to populations likely to observe an
overdose is an effective intervention strategy (Refs. 14 to 17). For
example, studies of community-based overdose education and naloxone
distribution programs report high rates of successful opioid overdose
reversal attempts, reflecting numerous lives saved (Refs. 15 and 16).
Similarly, results from modeling efforts (Refs. 18 to 21) suggest that
increased distribution and use of naloxone could contribute to a
decrease in overall deaths related to opioid overdose. A systems
modeling study funded by FDA estimates that nearly 20,000 deaths were
averted due to layperson naloxone administration from 1999 to 2020,
particularly in more recent years (Ref. 20). This modeling research
also projects that increasing naloxone distribution (beyond EMS
providers) would have among the largest and most immediate future
effects on reducing opioid overdose deaths among 11 broad strategies
tested (Ref. 21). Although there are important limitations to each
study, results consistently show overall lives saved with increased
naloxone distribution and use, especially when distributed to those
most likely to observe an opioid overdose.
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\11\ It is imperative that individuals administering naloxone
call 911 for prompt assistance. Naloxone is a temporary treatment,
so repeat doses may be required. Management options for overdose or
any naloxone adverse events may be different in non-healthcare
settings (e.g., verbal deescalation, rescue breathing, chest
compressions) than they are in healthcare settings (e.g.,
medications for specific adverse events, supplemental oxygen,
cardiac defibrillator).
---------------------------------------------------------------------------
As with all drugs, the risks associated with naloxone use also need
to be considered. It is well-known that among patients with physical
dependence to opioids, naloxone use may result in acute-onset,
precipitated opioid withdrawal (precipitated withdrawal),\12\ referred
to in the labeling for currently marketed naloxone products as
``Precipitation of Severe Opioid Withdrawal'' (Refs. 22 to 25). As
noted in the labeling for currently approved naloxone products,
naloxone-induced precipitated withdrawal may also be associated with
other clinically serious adverse events such as pulmonary edema,
cardiac arrythmias, and agitation--these and other adverse events are
labeled in the context of postoperative opioid reversal (Refs. 22 to
25) but could also occur among opioid-dependent populations (Refs. 24
to 28). The incidence of such naloxone-induced adverse events in the
community setting may be influenced by factors such as naloxone dose,
underlying patient comorbidities, and concomitant medications or co-
exposures, including intentional or unintentional polysubstance use. In
situations involving multiple substance exposure, naloxone use may
result in unmasking the effects of non-opioid substance(s), such as
other sedating drugs or stimulants (Refs. 29 and 30). The rise in
intentional polysubstance use and unintentional exposure to
contamination in the illicit drug supply (Ref. 31) make reversing
overdoses in the current environment more complex than in previous
times. Furthermore, respiratory and CNS depression may recur after the
first dose of naloxone because of the difference in duration of action
between naloxone and the opioid. Hence, it is highly important that
users of naloxone products activate emergency medical services.
---------------------------------------------------------------------------
\12\ Precipitated withdrawal, resulting from administration of
an opioid antagonist, should be considered mechanistically and
clinically distinct from withdrawal resulting from cessation, or
significant reduction in opioid use. In an adult opioid-dependent
person, precipitated withdrawal would be expected to result in more
rapid onset signs and symptoms of greater severity, while withdrawal
resulting from cessation would be expected to occur more gradually,
with symptoms that, while uncomfortable, may not necessarily require
urgent medical attention.
---------------------------------------------------------------------------
Despite these potential risks, the benefit of broader use of
naloxone in reversing potentially fatal events is significant, even as
surveillance for and mitigation of risks are important. We believe that
the public health impacts associated with a serious adverse reaction to
naloxone, as concerning as they may be, are still far less than the
public health impacts of opioid overdose death. The public health
benefits of FDA-approved prescription naloxone products in preventing
overdose deaths clearly outweigh potential serious adverse reactions
associated with naloxone administration.
As we consider how the favorable benefit-risk profile for
prescription naloxone products may translate to nonprescription
naloxone products, FDA will need to ensure that products developed for
nonprescription use are appropriately designed to support intended
users' needs for their intended use in intended environments without
the supervision of a healthcare practitioner.
Additionally, we would encourage community programs and other
stakeholders to offer training to help further reduce the risks
described above with administration of naloxone to further benefit the
public health. Such programs could communicate critical information and
educate on topics such as:
[[Page 68707]]
<bullet> Prompt activation of EMS (e.g., calling 911)
<bullet> Opioid overdose recognition
<bullet> Alternate etiologies of unresponsiveness
<bullet> Respiratory support prior to naloxone administration and onset
if naloxone is not immediately available
<bullet> Naloxone administration
<bullet> Awareness of possible adverse events related to naloxone
administration
<bullet> Dose titration to the lowest effective dose for appropriate
clinical endpoints
<bullet> Appropriate interventions supplemental to naloxone
administration (e.g., physical stimulus, positioning, rescue breathing,
chest compressions, defibrillation)
3. FDA's Efforts To Increase Naloxone Availability and Accessibility
In light of the important role that naloxone can play in reversing
opioid overdose, FDA is committed to increasing access and broadening
distribution of naloxone products as one strategy to help address the
current opioid overdose crisis. Over the last several years, FDA has
taken a number of steps to improve availability of naloxone products,
including: encouraging manufacturers to pursue development of
nonprescription naloxone products; requiring drug manufacturers for all
opioid pain relievers and medicines to treat opioid use disorder to add
new recommendations about naloxone to the prescribing information of
their respective opioid products; approving new naloxone products,
including generics; approving the extension of the shelf life of
naloxone nasal spray from 24 months to 36 months; and issuing an
immediately-in-effect guidance to industry clarifying the scope of the
public health emergency exclusion and exemption under the Drug Supply
Chain Security Act as they apply to the distribution of FDA-approved
naloxone products.
FDA has also held public meetings to solicit scientific and
regulatory input on naloxone. On October 5, 2016, the Agency held a
joint meeting of the Anesthetic and Analgesic Drug Products Advisory
Committee and the Drug Safety and Risk Management Advisory Committee to
discuss what is known about the safety of using naloxone and the risk
of precipitating an acute opioid withdrawal syndrome, issues specific
to dosing in pediatric patients, the clinical pharmacology of naloxone,
and information about the use of naloxone.\13\ We asked the advisory
committee members for advice on whether the pharmacokinetic standard
for the approval of naloxone products based on a demonstration of
comparable or greater naloxone levels compared to 0.4 mg of naloxone
given intramuscularly is sufficient, and if higher doses are
recommended, how to weigh the need for effectiveness against the risk
of precipitating an acute withdrawal syndrome. The Agency also sought
feedback about naloxone dosing for pediatric patients as well as
whether there is benefit in having different doses for the same or
different products and how a clinician can determine which product to
prescribe.
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\13\ Meeting materials are available on the FDA website at
<a href="https://wayback.archive-it.org/7993/20170111202120/http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndAnalgesicDrugProductsAdvisoryCommittee/ucm486848.htm">https://wayback.archive-it.org/7993/20170111202120/http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndAnalgesicDrugProductsAdvisoryCommittee/ucm486848.htm</a>.
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On December 17 and 18, 2018, the Agency also held a joint meeting
of the Anesthetic and Analgesic Drug Products Advisory Committee and
the Drug Safety and Risk Management Advisory Committee (December 2018
AC Meeting) to discuss ways in which the Agency could increase the
availability of naloxone products intended for use outside of the
healthcare setting (see Ref. 3). The topic of nonprescription naloxone
was also discussed at this meeting, and participants suggested
switching prescription naloxone to nonprescription status. Some
participants stated that FDA approval of a nonprescription naloxone
product would increase access to and availability of naloxone. Others
commented that having naloxone available as a nonprescription product
and on store shelves would help increase naloxone use because it would
overcome the stigma associated with opioid use and the need for
interaction with a pharmacist to obtain prescription naloxone for
possible opioid overdoses. Others added that even though some States
have naloxone access laws that would allow an individual to obtain
naloxone without a patient-specific prescription, these State laws have
not significantly expanded access to naloxone in the same way that
nonprescription naloxone might. A few participants also noted that
eliminating the prescription status for naloxone could make it easier
to purchase naloxone in bulk and reduce legal and non-legal barriers
that exist for distribution programs that require third-party
prescribing.
Although the meeting was specifically focused on increasing
naloxone availability, pricing and cost concerns over naloxone products
were voiced by several commentors. We heard from the public that the
retail price of the currently approved naloxone products can be high.
Others expressed concern regarding insurance coverage for naloxone
products if such products were switched from prescription to
nonprescription status.
Echoing some of the comments provided about barriers to naloxone
availability and access during the December 2018 AC Meeting, common
barriers reported in a limited review of published studies included
fear of stigma and discrimination when obtaining naloxone from
physicians or pharmacists and cost (Refs. 32 and 33). Studies report
participants' past negative experiences at a pharmacy impacting
confidence for obtaining naloxone through a pharmacy (Ref. 33) and a
feeling of judgment by doctors toward people who use drugs nonmedically
(Ref. 32). Studies identified that naloxone nasal spray had high costs,
pharmacies did not have naloxone in stock, and, despite State naloxone
access laws, naloxone was unavailable without a patient-specific
prescription (Refs. 34 to 36).
4. FDA's Efforts To Facilitate Development of Nonprescription Naloxone
In the face of the increasing incidence of opioid overdose in the
United States and in an effort to increase potential naloxone
availability in the community, FDA developed an innovative strategy to
accelerate development of potential nonprescription naloxone products.
Sponsors interested in bringing a naloxone drug product to market via a
nonprescription development pathway had cited the development of a
nonprescription drug label as a major barrier in bringing their
products to market. Thus, FDA took the unprecedented steps of
developing a model naloxone DFL and assessing consumers' ability to
understand it.
Drugs that do not contain adequate directions for safe and
effective use are considered misbranded.\14\ ``Adequate directions for
use'' means directions under which a layperson can use a drug safely
and effectively and for the purposes for which it is intended.\15\
Prescription drugs, by definition, cannot bear adequate directions for
use by a layperson; FDA regulations provide an exemption from the
requirement to bear adequate directions for use by a layperson for FDA-
approved
[[Page 68708]]
prescription drugs that bear their FDA-approved labeling.\16\ For
prescription products, the prescribing information is written for
healthcare professionals. It must include all information necessary for
a healthcare professional to evaluate the appropriateness of the drug
for a particular patient. For nonprescription products, the labeling
needs to be adequately understood by the general public, regardless of
prior experience with the drug in question and across a broad range of
literacy, including those with limited literacy.\17\ Nonprescription
drug label development may be time and resource intensive and requires:
(1) identifying the essential elements of the prescribing information,
which are necessary for the proper and safe use of the medication; (2)
using these elements to create a consumer friendly DFL; and (3)
verifying with extensive consumer testing that consumers can comprehend
the DFL and use the product appropriately without the help of a
healthcare professional.
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\14\ 21 U.S.C. 352(f)(1).
\15\ 21 CFR 201.5.
\16\ 21 CFR 201.100 and 201.115.
\17\ See, e.g., 21 U.S.C. 352(c).
---------------------------------------------------------------------------
As mentioned above and as previously communicated in a 2019 Federal
Register notice (84 FR 8728), FDA has taken the unprecedented step of
designing and assessing comprehension of two versions of a model
naloxone DFL for use by industry to support a nonprescription drug
application (Ref. 37). Future sponsors of nonprescription naloxone
products using the model DFL without changes to the previously tested
portions may avoid performing a comprehensive Label Comprehension Study
(LCS) for the portions previously tested. Required testing would be
limited to any minor modifications of the DFL and the information
necessary to evaluate device-specific information (such as how to use a
particular injector or spray device).
As a foundation for creating the model naloxone DFL, FDA used the
prescribing information for the two prescription products that had been
designed for ``community use'' as of 2016: (1) EVZIO, a prefilled auto-
injector and (2) NARCAN, an intranasal spray. FDA clinicians, in
consultation with experts on the treatment of addiction, distilled the
prescribing information for naloxone into what were deemed to be the
critical elements in instructions for emergency use. They took the
relatively lengthy prescription labeling and condensed it to fit the
succinct content and format of a nonprescription DFL.
An independent research contractor conducted qualitative testing of
small segments of the DFL comprising indepth, sequential, one-on-one
interviews of 36 subjects to determine the clearest and simplest
presentation of important consumer information. This was followed by
pilot testing the revised label in another 36 subjects. Enhancement of
the label to improve readability included adding white space, boldface
type, and ``chunking'' the information (i.e., breaking up information
into small units that make it easier to notice). Additionally,
pictograms were incorporated adjacent to the written text to clarify
the stepwise directions.
The finalized version of the model DFL was tested in a pivotal LCS.
The prespecified research design of the pivotal study included
structured interviews in over 700 participants (including 33 percent
with limited literacy, as defined by a score of 60 or less on the REALM
(Rapid Estimate of Adult Literacy in Medicine)) across a wide range of
potential nonprescription naloxone users. These participants included
three groups: (1) those who had recently used opioids and their family
and friends; (2) the general adult population not screened for opioid
use; and (3) an adolescent population not screened for opioid use.
Comprehension was tested by making sure that participants could answer
open-ended questions to apply their understanding of the following
elements or ``critical tasks'' necessary for safe use: (1) how to
identify a person who might have an opioid overdose; (2) call 911; (3)
stay with the person until 911 personnel arrive; and (4) recognize the
signs of possible naloxone side effects that are to be expected. An FDA
review team that was not involved in the design or conduct of the study
reviewed the study report and determined that the model DFL
comprehension results were adequate for all groups including those with
limited literacy.
If applicants elect to use the model naloxone DFL created by FDA,
the main piece of the DFL that would still need to be tested by the
applicant are the device-specific instructions. The device-specific
instructions may be added to the model DFL and evaluated in a simulated
Human Factors (HF) validation study designed to evaluate whether the
user interface can be used safely and effectively by intended users for
the intended use under expected environment(s) of use. The HF
validation study focuses on the collection of qualitative data and
generally requires far fewer test participants as compared to a pivotal
LCS, which is statistically powered. An applicant who starts with the
FDA model naloxone DFL should only make changes to the DFL that are
related to device-specific instructions. Assuming that the DFL has not
been altered in a substantial fashion, applicants then test just those
added device-specific instructions in a simulated HF validation study,
and if successful, have the opportunity to shorten the time of
development of a potential nonprescription naloxone product. It is
important to note that LCS and HF studies address, among other things,
labeling and consumer behavior testing requirements; however, an
applicant would still need to submit other data (e.g., bioavailability,
stability, reliability of drug-device combination, non-clinical,
justification for treatment of pediatric population, etc.) to support
an application for a nonprescription product.
5. Other Considerations for Nonprescription Naloxone
The Agency is aware of concerns that are not directly related to
the safe and effective use of nonprescription naloxone products, such
as potential consequences of switching naloxone from prescription to
nonprescription status, which have been raised by the public in
multiple venues.
It is unclear how a switch to nonprescription naloxone would affect
the distribution and supply of naloxone. One study published in 2019
estimates that naloxone pharmacy purchases could increase by 15 to 179
percent with a prescription-to-nonprescription switch of naloxone based
on prior experience with nonprescription switches for nicotine gums and
patches (Ref. 38). During the December 2018 AC Meeting, committee
members discussed that drug shortages may be a problem and that
capacity will need to be expanded dramatically to meet the needs of any
expansion in naloxone distribution.
The committees also noted that if changes to the market were made,
consideration should be given to ensure those who need naloxone are
still able to get the drug at a reasonable cost. For example, the
committees recommended that FDA ensure that a switch to nonprescription
naloxone will not divert supplies away from community-based naloxone
distribution programs and hospitals to settings where patients may be
at less risk for experiencing an opioid overdose. Further, it is
possible that even if the Agency could determine that certain naloxone
products would be safe and effective for nonprescription use, which
would require all manufacturers of such products to switch their
products from prescription to nonprescription absent a clinically
[[Page 68709]]
meaningful difference, a firm may opt to stop marketing its product
altogether rather than make the nonprescription switch, which could
potentially contribute to a drug shortage.
We recognize that these concerns, although they may be outside of
the Agency's drug approval considerations, may have significant impacts
on naloxone availability and accessibility, and we will continue to
work with our Federal partners to address them. We welcome comments
from the public on any potential consequences of a switch from
prescription to nonprescription status for naloxone products, which we
will consider to the extent they may be address within our current
authorities.
C. Factors Indicating That the Prescription Requirements for Certain
Naloxone Products May Not Be Necessary
At this time, we believe that the prescription requirements for
certain naloxone products may not be necessary for the protection of
the public health, and we believe that these naloxone products have the
potential to be safe and effective for use as directed in
nonprescription drug labeling without the supervision of a healthcare
practitioner.
Naloxone, as a prescription product, has been used for many years
(since 1971) to treat opioid overdose and has a favorable benefit-risk
profile. The benefit-risk profile for naloxone takes into account
naloxone's effectiveness in helping to reduce opioid overdose deaths.
Timely administration of naloxone, usually within minutes of the first
signs of an opioid overdose, can counter the overdose effects. Although
naloxone administration is not without risks, as discussed above, the
risks associated with opioid overdose and overdose-related deaths pose
an even greater public health concern.
Moreover, community-based naloxone distribution programs have been
providing naloxone to populations at risk of overdose without patient-
specific prescriptions. These programs have provided naloxone to people
who are likely to witness an opioid overdose and use naloxone (Refs. 15
and 16). In addition, these programs may also provide overdose
education or other support for appropriate use of naloxone. Some
examples of community-based naloxone distribution programs are the Drug
Overdose and Prevention Education (DOPE) program and the Massachusetts
Overdose Education and Naloxone Distribution program. The DOPE program
in San Francisco distributed 2,500 improvised naloxone kits to
participants from 2010 to 2013. Of the 702 overdose reversal attempts
reported to the DOPE program, over 95 percent were known to have
survived (Ref. 16). In Massachusetts from 2006 to 2010, approximately
4,900 participants received improvised naloxone kits with mucosal
atomization devices, and among those reporting use of the naloxone and
the outcomes (n=359), 97 percent reported successfully reversing the
overdose (Ref. 15). The high percentage of successful reversals in both
programs should be interpreted cautiously as they represent reports
from a select population reporting back to the program. Targeted
naloxone distribution programs, such as distribution to those in opioid
treatment programs, have been also shown to be effective methods of
distribution (Refs. 39 to 45). Data are less clear on the effectiveness
of a ``universal precaution'' approach whereby all patients prescribed
opioid analgesics are also prescribed naloxone (Ref. 46).
Naloxone access laws (NAL) provide additional information on the
distribution of naloxone to end-users without a patient-specific
prescription. As of 2020, all 50 states and the District of Columbia
have some form of NAL (Ref. 47). These laws are intended to increase
naloxone availability for use in individuals experiencing an opioid
overdose. With a prescription drug, a pharmacist would generally
dispense the drug pursuant to a patient-specific prescription. However,
naloxone differs from other prescription drugs due in part to its
approved indication. As an emergency treatment for the reversal of
overdose, naloxone may not necessarily be dispensed to the patient who
experiences an overdose or administered by the patient who receives the
prescription. Because naloxone may be acquired without a patient-
specific prescription and may be administered to someone other than the
person for whom the naloxone was dispensed, naloxone faces some
challenges that may inadvertently hinder wider access to the drug. For
example, prescribers may be hesitant to prescribe naloxone to a third
party for fear of liability (Ref. 48). NALs are meant to address these
challenges by facilitating naloxone access outside of the traditional
prescriber-patient relationship.
NALs vary from State to State and have changed over time, but
generally, many have one or more of the following features: third-party
provisions that allow a prescriber to prescribe naloxone to someone not
directly at risk of overdose (e.g., caregiver, family member); standing
order provisions that allow for non-patient specific prescriptions; and
civil and/or criminal immunity provisions for prescribers and
dispensers (Ref. 49). Studies have reported that NALs are associated
with favorable public health outcomes (Ref. 13). These studies have
reported increased distribution of naloxone, reductions in overdose
deaths, and positive outcomes for emergency department events involving
opioid overdose (Ref. 49). Naloxone obtained without a patient-specific
prescription, as a result of NALs, has been administered by laypersons
with little or no professional training and with evidence of some
effectiveness at reversing opioid overdose (Refs. 15 to 17 and 50).
Notwithstanding these positive findings, barriers to access (e.g.,
stigma associated with illicit drug use) continue to persist despite
NALs (Ref. 51). For example, based on a preliminary review, knowledge
gaps regarding the details of State NALs may be contributing to
pharmacies not making naloxone available for dispensing (Refs. 52 to
54). Specifically, some pharmacy staff working in pharmacies
participating in State standing order programs did not fully understand
the requirements under their State NAL and incorrectly stated that a
patient-specific prescription or identification was required to obtain
naloxone or that third parties (i.e., individuals other than the person
at risk of an opioid overdose) could not obtain naloxone (Refs. 52 to
54). In California, although significant improvement to naloxone access
has been achieved since the State's NAL first went into effect,
naloxone continues to not be dispensed due to knowledge gaps regarding
the State NAL (Ref. 54). The number of pharmacies reporting that they
were willing to dispense naloxone without a patient-specific
prescription increased by 80 percent from 2018 to 2020 (Ref. 54).
However, fewer than half of all pharmacies interviewed were still
willing to dispense naloxone without a patient-specific prescription,
which indicates that improvements to access could still be realized
(Ref. 54). A nonprescription naloxone option may provide another means
to further increase naloxone availability (Ref. 54).
In summary, these models (i.e., community-based naloxone
distribution programs and NALs) help to inform the potential public
health benefit of nonprescription naloxone use by laypersons and have
factored into our initial assessment that naloxone may be used safely
and effectively for nonprescription use. The current availability of
naloxone without a patient-specific prescription represents
[[Page 68710]]
some useful general information that a naloxone product could
potentially be used safely and effectively on a nonprescription basis.
Despite the useful information obtained through these models, they
do not necessarily inform us on whether a layperson could, on their
own, safely and effectively administer such product to a person
experiencing an overdose without the supervision of a licensed
practitioner and relying on the DFL. This is because, as mentioned
above, improvised naloxone kits that are distributed by community-based
naloxone distribution programs may include other items that accompany
the drug (e.g., atomizer, instructions for safe use), and those
distributing these improvised naloxone kits directly to the end user
may be providing additional counseling on safe naloxone use. We are
also aware that some State NALs require pharmacists to provide patient
counseling before dispensing naloxone, which may include further
information on naloxone safety, risks of opioid overdose, and resources
on substance use disorder. We do not know to what extent these factors
contribute to the safe and effective use of naloxone without the
intervention of a learned intermediary, which may occur if a layperson
obtains naloxone through one of these methods.
Moreover, even if such products are accompanied by educational or
other materials to facilitate use, naloxone products distributed and
dispensed through these models may be more challenging to administer
(e.g., requiring assembly). Thus, in order to provide a meaningful
expansion in naloxone availability, an FDA-approved nonprescription
naloxone product would need to be supported by LCS and HF studies and
other data. Additionally, as described above, challenges associated
with naloxone distributed through community-based naloxone distribution
programs and naloxone acquired through NALs persist and providing
another naloxone option--nonprescription naloxone products--with clear
and understandable DFL instructions and not hampered by the patient-
prescription requirements, may provide important value in addressing
opioid overdoses.
D. Scope of the Notice
As discussed in section C of this document, we believe that certain
naloxone products have the potential to be safe and effective for use
as directed in nonprescription drug labeling without the supervision of
a healthcare practitioner. However, more direct, specific data would be
needed to support a formal Agency determination that any particular
form of naloxone (e.g., 4 mg naloxone nasal spray) is safe and
effective as a nonprescription drug, due to factors such as the way
naloxone is delivered in combination with a device and its associated
DFL. Specific data are usually submitted in an application proposing
approval of a nonprescription product, which may include, among other
things, a LCS, HF study, and/or actual use study.
While we have defined the scope of this notice as applying to
naloxone hydrochloride, nasal spray up to 4 mg and naloxone
hydrochloride, autoinjector for IM or SC use up to 2 mg, FDA believes
it is also important to consider other naloxone products for
nonprescription use and welcomes comments from the public that could
provide additional information related to the nonprescription use of
these products.
While naloxone has been in use since 1971, two ``community-use''
naloxone products, EVZIO, a 2 mg prefilled auto-injector and NARCAN
nasal spray, a 4 mg intranasal spray, have been in use for
approximately 6 years, and may provide the best models to inform the
public health decisions for layperson use. As discussed above, these
products were designed to facilitate use by laypersons, without medical
training or the need for additional supplies or assembly before use.
Although two higher dose naloxone products, ZIMHI, a 5 mg single-
dose, prefilled syringe with an integrated needle for IM or SC use, and
KLOXXADO, an 8 mg nasal spray, are also considered ``community use''
products and have begun marketing more recently (March 2022 and August
2021, respectively), we have limited postmarketing experience to
meaningfully inform whether they may be appropriate for nonprescription
use. When considering risk, it is biologically plausible that there may
be an association between increasing naloxone doses and the severity of
precipitated withdrawal. An observational study reported that the
initial dose of naloxone patients received for opioid overdose has a
positive association with their likelihood to experience opioid
withdrawal symptoms (Ref. 55). Causality cannot be established based on
the study, however, due to concerns that differences in the opioid-
dependence status and severity of opioid overdose between patients
receiving a low or high initial naloxone dose were not well adjusted
for in the analyses.\18\ The available literature does not inform on a
threshold naloxone dose above which the risk for severe adverse events
would outweigh treatment benefit. Better understanding this dose-
response relationship could help inform decisions about specific
naloxone formulations and dosages, like higher dose naloxone, to make
available for treatment in the nonprescription setting, where naloxone
is unlikely to be administered by trained medical personnel. Further,
ZIMHI's FDA-approved labeling includes a warning of the risk of
accidental needlestick injury after use, because the needle is exposed
until the safety guard is deployed (Ref. 24). For these reasons, we do
not believe we have sufficient data to support a preliminary assessment
that these higher dose naloxone products could be safely used in a
nonprescription setting.
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\18\ The comparison of opioid withdrawal risk between patients
who received ``low'' (<=0.15 mg) and ``high'' (>=0.15 mg) initial
naloxone dose did not account for whether the patient was opioid-
dependent. While the study matched the two groups by respiratory
rate before naloxone use and adjusted for Glasgow coma scale (as a
categorical variable), overdose severity might still not be well-
balanced between the two groups, given that patients in the low-dose
group were less likely to have a low Glasgow coma scale (<=8) and
they were more likely to receive their initial naloxone dose in the
emergency department, instead of having to be treated before
arriving to the emergency department.
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With respect to naloxone supplied in other presentations including
vials, ampules, or syringes without integrated needles, at this time we
do not have enough data or information to support a preliminary
assessment that these naloxone products have the potential to be safe
and effective for use as directed in nonprescription drug labeling
without the supervision of a healthcare practitioner. The Agency is
aware that community-based naloxone distribution programs have
distributed these presentations of naloxone to laypeople. The
availability of naloxone supplied in presentations to include vials,
ampules, or syringes without integrated needles \19\ for use outside of
a healthcare setting through this distribution method cannot be
interpreted to mean that these products are safe and effective as a
nonprescription product. As discussed above, when community-based
naloxone distribution programs provide naloxone to the public, it is
often provided in an improvised naloxone kit whose contents can vary
from one program to another. These kits may contain additional
materials and
[[Page 68711]]
instructions, such as educational materials on naloxone use, which may
be a contributing factor to the safe and effective use of these
products. We have no data to support that naloxone supplied in vials,
ampules, or syringes without integrated needles and not accompanied by
such additional materials could be safely and effectively used as
directed in nonprescription drug labeling without the supervision of a
healthcare practitioner.
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\19\ It is our preliminary view that these presentations
generally constitute a clinically meaningful difference from the
naloxone hydrochloride, autoinjector for IM or SC use up to 2 mg.
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FDA's preliminary assessment that naloxone products may be
approvable as safe and effective for nonprescription use is limited to
the following naloxone products:
<bullet> Naloxone hydrochloride, nasal spray up to 4 mg; and
<bullet> Naloxone hydrochloride, autoinjector for IM or SC use up
to 2 mg.
To help facilitate increased access to and availability of safe and
effective naloxone products, FDA believes it is important to consider
the safety and effectiveness of all naloxone products for potential
nonprescription use. Therefore, we welcome comments from the public
(see Section III, Request for Additional Information and Comments) with
information that may inform the safe and effective use of naloxone for
nonprescription use for the following products:
<bullet> Naloxone hydrochloride, injection for IV, IM, or SC use,
including products greater than 2 mg; and
<bullet> Naloxone hydrochloride, nasal spray greater than 4 mg.
E. Simultaneous Marketing of Prescription and Nonprescription Naloxone
As explained above, FDA has interpreted the language in section
503(b)(4) of the FD&C Act to allow simultaneous marketing of drug
products with the same active ingredient as prescription in one case
and nonprescription in another only if some clinically meaningful
difference, such as a difference in indication, strength, route of
administration, dosage form, or patient population, exists between the
drug products that makes the prescription product safe and effective
only under the supervision of a healthcare practitioner licensed by law
to administer the drug. Absent a clinically meaningful difference
between the products, simultaneous marketing of two drug products with
the same active ingredient as, respectively, a prescription and a
nonprescription drug product would result in one of the two products
being misbranded.
At this time, we do not believe that any clinically meaningful
differences could exist between currently approved prescription and
potential nonprescription naloxone nasal spray products (up to 4 mg),
or between currently approved prescription and potential
nonprescription naloxone autoinjector products (up to 2 mg). For
example, we do not believe that a difference in the dosage strengths
within naloxone nasal spray products (i.e., 2 mg, 4 mg) by itself would
be sufficient to distinguish prescription and nonprescription versions
of a naloxone product without further support demonstrating that one
(or more) dosage strength(s) should remain prescription because
intervention of a healthcare professional is necessary for safe and
effective use of the product. Additionally, naloxone nasal spray
products with the dosage strengths 2 mg and 4 mg have the same
indication and minor, nonmeaningful label differences. We also do not
foresee a clinically meaningful distinction between currently approved
prescription and potential nonprescription naloxone products based on
indication because we do not anticipate that the indication for a
nonprescription naloxone product would differ from a prescription
naloxone product. Additionally, the Agency does not believe there is a
clinically meaningful distinction between currently approved
prescription and potential nonprescription naloxone products based on
differences in population because in the development of the model DFL,
FDA tested the labeling across a wide range of potential
nonprescription naloxone users, including adults who have and have not
used opioids as well as adolescents.
It is possible that there is a potential clinically meaningful
difference based on dosage strength with respect to naloxone nasal
spray products (up to 4 mg) or naloxone autoinjector product (up to 2
mg) and higher dose versions of those products that would allow for
simultaneous marketing of nonprescription naloxone nasal spray and
prescription higher dose naloxone nasal spray, or simultaneous
marketing of nonprescription autoinjector naloxone and prescription
higher dose autoinjector naloxone. As discussed above, we lack data on
the safety of higher dose naloxone products for nonprescription use,
and we also noted that there may be an association between higher doses
of naloxone and precipitated withdrawal; although at this time, we have
found no causal association.
II. Notice to Current Application Holders
In this document, we provide notice of the Agency's preliminarily
assessment that prescription requirements for certain naloxone products
described above may no longer be necessary for the protection of the
public health and that they may be safe and effective for use as
directed in nonprescription labeling. As noted above, the Agency needs
additional data, including product-specific data on nonprescription
user interface design, including packaging and labeling, to make a
conclusive determination in this respect. Additionally, we have
tentatively determined that it is unlikely that any clinically
meaningful differences exist between a prescription and a potential
nonprescription naloxone nasal spray product (up to 4 mg) or between a
prescription and a potential nonprescription autoinjector naloxone
product (up to 2 mg). Section 503(b) of the FD&C Act does not permit
the simultaneous marketing of drug products with the same active
ingredient as prescription and nonprescription unless there is a
clinically meaningful difference between the products. If FDA makes a
determination that naloxone products described in this notice are safe
and effective for use without a prescription, such products would be
misbranded if they bear labeling with the ``Rx only'' symbol. At that
time, an efficacy supplement that includes product-specific data to
support the nonprescription user interface design, including packaging
and labeling, will need to be submitted to an approved application for
a prescription naloxone product if an application holder plans to
switch its naloxone product covered under the application to
nonprescription marketing status in its entirety without a change in
the previously approved dosage form or route of administration. The
Agency strongly encourages application holders of prescription naloxone
products described in this notice to contact FDA as early as possible
to initiate a discussion about a possible switch.
III. Request for Additional Information and Comments
In considering additional approaches to facilitate access to
naloxone, FDA is soliciting comments and information from the public in
the following areas:
(1) Data to support the safe and effective use of nonprescription
naloxone hydrochloride injection for IV, IM, or SC use.
[[Page 68712]]
(2) Data to support the safe and effective use of higher dose
nonprescription naloxone hydrochloride products, such as naloxone
hydrochloride, nasal spray greater than 4 mg.
(3) Any potential consequences of a switch from prescription to
nonprescription status for naloxone products, and actions that FDA
could consider to address them, including but not limited to, impacts
on community-based naloxone distribution programs and consumers, drug
shortages, and the distribution and supply of naloxone.
IV. References
The following references marked with an asterisk (*) are on display
at the Dockets Management Staff (see ADDRESSES) and available for
viewing by interested persons between 9 a.m. and 4 p.m., Monday through
Friday; they also are available electronically at <a href="https://www.regulations.gov">https://www.regulations.gov</a>. References without asterisks are not on public
display at <a href="https://www.regulations.gov">https://www.regulations.gov</a> because they have copyright
restriction. Some 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.
1. *``Renewal of Determination that a Public Health Emergency Exists
Nationwide as the Result of the Continued Consequences of the Opioid
Crisis'' (renewed September 29, 2022), available at <a href="https://www.phe.gov/emergency/news/healthactions/phe/Pages/default.aspx">https://www.phe.gov/emergency/news/healthactions/phe/Pages/default.aspx</a>.
2. *Ahmad, F.B., J.A. Cisewski, L.M. Rossen, and P. Sutton, 2022,
``Provisional Drug Overdose Death Counts,'' National Center for
Health Statistics, available at <a href="https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm">https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm</a> (accessed July 7, 2022).
3. *Division of Anesthesia, Analgesia, and Addiction Products
(DAAAP) Director Memorandum dated November 19, 2018, for the AADPAC/
DSaRM meeting to discuss strategies to increase the availability of
naloxone products intended for use in the community, available at
<a href="https://www.fda.gov/media/121182/download">https://www.fda.gov/media/121182/download</a>.
4. *FDA statement on the continued efforts to increase availability
of all forms of naloxone to help reduce opioid overdose deaths
(September 20, 2019), available at <a href="https://www.fda.gov/news-events/press-announcements/statement-continued-efforts-increase-availability-all-forms-naloxone-help-reduce-opioid-overdose">https://www.fda.gov/news-events/press-announcements/statement-continued-efforts-increase-availability-all-forms-naloxone-help-reduce-opioid-overdose</a>.
5. ``Fact Sheet: How to Assemble Naloxone Kits,'' National Harm
Reduction Coalition, available at <a href="https://harmreduction.org/issues/overdose-prevention/naloxone-kits-materials/">https://harmreduction.org/issues/overdose-prevention/naloxone-kits-materials/</a>.
6. Alwasiyah, D., C.A. Carlson, T. Cook, and W.P. Kearns,
``Layperson Naloxone Administration: Pulp Fiction Style,'' Abstracts
from the 2016 American College of Medical Toxicology (ACMT) Annual
Scientific Meeting, 2016, Journal of Medical Toxicology, abstract
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7. Das, S., N. Shah, and M. Ghadiali, 2017, ``Intravenous Use of
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38(1):18-21.
8. Brenner, D.S., A.I. Stolbach, J. Zschoche, and L. Bright, 2021,
``Severe Prolonged Agitation due to Intranasal Naloxone
Overexposure,'' American Journal of Emergency Medicine, 42:261.e1-
261.e2.
9. Edwards, E.T., E.S. Edwards, E. Davis, et al., 2015,
``Comparative Usability Study of a Novel Auto-Injector and an
Intranasal System for Naloxone Delivery,'' Pain and Therapy,
4(1):89-105.
10. Krieter, P., N. Chiang, S. Gyaw, et al., 2016, ``Pharmacokinetic
Properties and Human Use Characteristics of an FDA-Approved
Intranasal Naloxone Product for the Treatment of Opioid Overdose,''
Journal of Clinical Pharmacology, 56(10):1243-1253.
11. Krieter, P.A., C.N. Chiang, S. Gyaw, and D.J. McCann, 2019,
``Comparison of the Pharmacokinetic Properties of Naloxone Following
the Use of FDA-Approved Intranasal and Intramuscular Devices Versus
a Common Improvised Nasal Naloxone Device,'' Journal of Clinical
Phramacology, 59(8):1078-1084.
12. Direct Relief, ``Pfizer to Donate 1 Million Naloxone Doses to
Direct Relief for Life-Saving Opioid Overdose Reversal,'' April 15,
2021, available at <a href="https://www.directrelief.org/2021/04/pfizer-to-donate-1-million-naloxone-doses-to-direct-relief-for-life-saving-opioid-overdose-reversal/">https://www.directrelief.org/2021/04/pfizer-to-donate-1-million-naloxone-doses-to-direct-relief-for-life-saving-opioid-overdose-reversal/</a>.
13. Wheeler, E. and M. Doe-Simkins, ``Harm Reduction Programs
Distribute One Million Doses of Naloxone in 2019,'' January 2, 2020,
available at <a href="https://medium.com/@ejwharmreduction/harm-reduction-programs-distribute-one-million-doses-of-naloxone-in-2019-4884d3535256">https://medium.com/@ejwharmreduction/harm-reduction-programs-distribute-one-million-doses-of-naloxone-in-2019-4884d3535256</a>.
14. Wheeler, E., T.S. Jones, M.K. Gilbert, and P.J. Davidson, 2015,
``Opioid Overdose Prevention Programs Providing Naloxone to
Laypersons--United States, 2014,'' MMWR Morbidity and Mortality
Weekly Report, 64(23):631-635.
15. Doe-Simkins, M., E. Quinn, Z. Xuan, et al., 2014, ``Overdose
Rescues by Trained and Untrained Participants and Change in Opioid
Use Among Substance-Using Participants in Overdose Education and
Naloxone Distribution Programs: A Retrospective Cohort Study,'' BMC
Public Health, 14(1):297.
16. Rowe, C., G.M. Santos, E. Vittinghoff, et al., 2015,
``Predictors of Participant Engagement and Naloxone Utilization in a
Community[hyphen]Based Naloxone Distribution Program,'' Addiction,
110(8):1301-1310.
17. Walley, A.Y., Z. Xuan, H.H. Hackman, et al., 2013, ``Opioid
Overdose Rates and Implementation of Overdose Education and Nasal
Naloxone Distribution in Massachusetts: Interrupted Time Series
Analysis,'' British Medical Journal, 346:f174.
18. Pitt, A.L., K. Humphreys, and M.L. Brandeau, 2018, ``Modeling
Health Benefits and Harms of Public Policy Responses to the US
Opioid Epidemic,'' American Journal of Public Health, 108(10):1394-
1400, epub ahead of print August 23, 2018, doi: 10.2105/
AJPH.2018.304590.
19. Irvine, M.A., D. Oller, J. Boggis, et al., 2022, ``Estimating
Naloxone Need in the USA Across Fentanyl, Heroin, and Prescription
Opioid Epidemics: A Modelling Study,'' Lancet Public Health,
7(3):e210-e218, Epub ahead of print February 10, 2022, doi: 10.1016/
S2468-2667(21)00304-2.
20. Lim, T.Y., E.J. Stringfellow, C.A. Stafford, et al., 2022,
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21. Stringfellow, E.J., T.Y. Lim, K. Humphreys, et al., 2022,
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22. *EVZIO labeling (October 2016), available at <a href="https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/209862lbl.pdf">https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/209862lbl.pdf</a>.
23. *NARCAN Nasal Spray labeling (March 2020), available at <a href="https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208411Orig1s004lbl.pdf">https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208411Orig1s004lbl.pdf</a>.
24. *ZIMHI labeling (October 2021), available at <a href="https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212854s000lbl.pdf">https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212854s000lbl.pdf</a>.
25. *KLOXXADO labeling (April 2021), available at <a href="https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212045s000lbl.pdf">https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212045s000lbl.pdf</a>.
26. Brenner, D.S., A.I. Stolbach, J. Zschoche, and L. Bright, 2021,
``Severe Prolonged Agitation Due to Intranasal Naloxone
Overexposure,'' American Journal of Emergency Medicine, 42:261.e1-
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27. Lameijer, H., N. Azizi, J.J.M. Ligtenberg, and J.C. Ter Maaten,
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28. Kummer, R.L., R.R. Kempainen, T.D. Olives, et al., 2022,
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29. Farkas, A., M.J. Lynch, R. Westover, et al., 2020, ``Pulmonary
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Emergency
[[Page 68713]]
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30. Merigian, K.S., 1993, ``Cocaine-Induced Ventricular Arrhythmias
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31. Mattson, C.L., L.J. Tanz, K. Quinn, et al., 2021, ``Trends and
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32. Allen, S.T., S.M. Grieb, A. O'Rourke, et al., 2019,
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33. Donovan, E., P. Case, J.P. Bratberg, et al., 2019, ``Beliefs
Associated with Pharmacy-Based Naloxone: A Qualitative Study of
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34. Bhardwaj, S.B., G. Cochran, and J. Kmiec, 2019, ``Opioid
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35. Guadamuz, J.S., G.C. Alexander, T. Chaudhri, et al., 2019,
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36. Whittington, R., K. Whittington, J. Whittington, et al., 2018,
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37. *Information about Naloxone, Naloxone Model DFL With Nasal Spray
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(DRAFT), available at <a href="https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/information-about-naloxone">https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/information-about-naloxone</a>.
38. Murphy, S.M., J.R. Morgan, P.J. Jeng and B.R. Schackman, 2019,
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52. Graves, R.L., E. Andreyeva, J. Perrone, et al., 2019, ``Naloxone
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54. Puzantian, T., J.J. Gasper, and C.M. Ramirez, 2021, ``Pharmacist
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55. Purssell, R., J. Godwin, J. Moe, et al., ``Comparison of Rates
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print May 13, 2020, doi: 10.1080/15563650.2020.1758325.
Dated: November 9, 2022.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2022-24874 Filed 11-15-22; 8:45 am]
BILLING CODE 4164-01-P
</pre></body>
</html>Indexed from Federal Register on November 16, 2022.
This is legal information, not legal advice. Laws vary by jurisdiction and change frequently. Always verify current law with official sources and consult a licensed attorney in your jurisdiction for advice on your specific situation.