Document ID: FDA-2022-N-2673-0001
Agency: fda
Document Type: Notice
Title: Safety and Effectiveness of Certain Naloxone Hydrochloride Drug Products for Nonprescription Use; Request for Comments
Posted Date: 2022-11-16T05:00Z

[Federal Register Volume 87, Number 220 (Wednesday, November 16, 2022)]
[Notices]
[Pages 68702-68713]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[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 https://www.regulations.gov 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:
     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

[[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 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-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 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, 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 https://wayback.archive-it.org/7993/20170111202120/http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndAnalgesicDrugProductsAdvisoryCommittee/ucm486848.htm.
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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 PerspectivesTM. 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. MetysTM. 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).
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    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.
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    \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.
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    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]]

 Prompt activation of EMS (e.g., calling 911)
 Opioid overdose recognition
 Alternate etiologies of unresponsiveness
 Respiratory support prior to naloxone administration and onset 
if naloxone is not immediately available
 Naloxone administration
 Awareness of possible adverse events related to naloxone 
administration
 Dose titration to the lowest effective dose for appropriate 
clinical endpoints
 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.
---------------------------------------------------------------------------

    \13\ Meeting materials are available on the FDA website at 
https://wayback.archive-it.org/7993/20170111202120/http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndAnalgesicDrugProductsAdvisoryCommittee/ucm486848.htm.
---------------------------------------------------------------------------

    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.
---------------------------------------------------------------------------

    \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.
---------------------------------------------------------------------------

    \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.
---------------------------------------------------------------------------

    FDA's preliminary assessment that naloxone products may be 
approvable as safe and effective for nonprescription use is limited to 
the following naloxone products:
     Naloxone hydrochloride, nasal spray up to 4 mg; and
     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:
     Naloxone hydrochloride, injection for IV, IM, or SC use, 
including products greater than 2 mg; and
     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 https://www.regulations.gov. References without asterisks are not on public 
display at https://www.regulations.gov 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 https://www.phe.gov/emergency/news/healthactions/phe/Pages/default.aspx.
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 https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm (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 
https://www.fda.gov/media/121182/download.
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 https://www.fda.gov/news-events/press-announcements/statement-continued-efforts-increase-availability-all-forms-naloxone-help-reduce-opioid-overdose.
5. ``Fact Sheet: How to Assemble Naloxone Kits,'' National Harm 
Reduction Coalition, available at https://harmreduction.org/issues/overdose-prevention/naloxone-kits-materials/.
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 
120, 12, 3-47, https://doi.org/10.1007/s13181-016-0538-8.
7. Das, S., N. Shah, and M. Ghadiali, 2017, ``Intravenous Use of 
Intranasal Naloxone: A Case of Overdose Reversal,'' Substance Abuse, 
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 
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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 
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12. Direct Relief, ``Pfizer to Donate 1 Million Naloxone Doses to 
Direct Relief for Life-Saving Opioid Overdose Reversal,'' April 15, 
2021, available at https://www.directrelief.org/2021/04/pfizer-to-donate-1-million-naloxone-doses-to-direct-relief-for-life-saving-opioid-overdose-reversal/.
13. Wheeler, E. and M. Doe-Simkins, ``Harm Reduction Programs 
Distribute One Million Doses of Naloxone in 2019,'' January 2, 2020, 
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14. Wheeler, E., T.S. Jones, M.K. Gilbert, and P.J. Davidson, 2015, 
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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 
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16. Rowe, C., G.M. Santos, E. Vittinghoff, et al., 2015, 
``Predictors of Participant Engagement and Naloxone Utilization in a 
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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-
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19. Irvine, M.A., D. Oller, J. Boggis, et al., 2022, ``Estimating 
Naloxone Need in the USA Across Fentanyl, Heroin, and Prescription 
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``Reducing Opioid Use Disorder and Overdose in the United States: A 
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22. *EVZIO labeling (October 2016), available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/209862lbl.pdf.
23. *NARCAN Nasal Spray labeling (March 2020), available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208411Orig1s004lbl.pdf.
24. *ZIMHI labeling (October 2021), available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212854s000lbl.pdf.
25. *KLOXXADO labeling (April 2021), available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212045s000lbl.pdf.
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``Severe Prolonged Agitation Due to Intranasal Naloxone 
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27. Lameijer, H., N. Azizi, J.J.M. Ligtenberg, and J.C. Ter Maaten, 
2014, ``Ventricular Tachycardia After Naloxone Administration: A 
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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 
Complications of Opioid Overdose Treated With Naloxone,'' Annals of 
Emergency

[[Page 68713]]

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52. Graves, R.L., E. Andreyeva, J. Perrone, et al., 2019, ``Naloxone 
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Community Pharmacies Under the Massachusetts Statewide Standing 
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54. Puzantian, T., J.J. Gasper, and C.M. Ramirez, 2021, ``Pharmacist 
Furnishing of Naloxone in California: A Follow-Up Analysis,'' 
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55. Purssell, R., J. Godwin, J. Moe, et al., ``Comparison of Rates 
of Opioid Withdrawal Symptoms and Reversal of Opioid Toxicity in 
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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