[Federal Register Volume 89, Number 157 (Wednesday, August 14, 2024)]
[Rules and Regulations]
[Pages 65991-65993]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2024-18087]


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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Part 1308

[Docket No. DEA1258]


Schedules of Controlled Substances: Placement of Zuranolone in 
Schedule IV

AGENCY: Drug Enforcement Administration, Department of Justice.

ACTION: Final rule.

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SUMMARY: This final rule adopts, without change, an interim final rule 
with request for comments published in the Federal Register on October 
31, 2023, placing zuranolone (chemically known as 1-[2-
[(3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethyl-
2,4,5,6,7,8,9,10,11,12,14,15,16,17-tetradecahydro-1H-
cyclopenta[a]phenanthren-17-yl]-2-oxoethyl]pyrazole-4-carbonitrile) and 
its salts in schedule IV of the Controlled Substances Act. With the 
issuance of this final rule, the Drug Enforcement Administration 
maintains zuranolone, including its salts, in schedule IV of the 
Controlled Substances Act.

DATES: Effective September 13, 2024.

FOR FURTHER INFORMATION CONTACT: Terrence L. Boos, Ph.D., Chief, Drug 
and Chemical Evaluation Section, Diversion Control Division, Drug 
Enforcement Administration; Telephone: (571) 362-3249.

SUPPLEMENTARY INFORMATION:

Background and Legal Authority

    Under the Controlled Substances Act (CSA), as amended in 2015 by 
the Improving Regulatory Transparency for New Medical Therapies Act 
(section 2(b) of Pub. L. 114-89), when the Drug Enforcement 
Administration (DEA) receives notification from the Department of 
Health and Human Services (HHS) that the Secretary has approved a 
certain new drug and HHS recommends control in the CSA schedule II-V, 
DEA is required to issue an interim final rule (IFR), with opportunity 
for public comment and to request a hearing, controlling the drug 
within a specified 90-day timeframe and subsequently to issue a final 
rule.\1\ When controlling a drug pursuant to subsection 811(j), DEA 
must apply the scheduling criteria of 21 U.S.C. 811(b) through (d), and 
812(b).\2\
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    \1\ 21 U.S.C. 811(j).
    \2\ 21 U.S.C. 811(j)(3).
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    On August 4, 2023, the U.S. Food and Drug Administration (FDA) 
approved the New Drug Application (commonly referred to as NDA) for 
zuranolone to be marketed as a prescription drug (ZURZUVAE, capsule) 
for the treatment of post-partum depression. DEA received notification 
that FDA approved the NDA on the same date. Pursuant to its FDA-
approved prescription drug labeling, ZURZUVAE, 50 mg, is to be 
administered orally once in the evening with fat-consuming food for 14 
days. The dose may be reduced for patients who cannot tolerate 50 mg. 
In addition, on July 12, 2023, HHS recommended that DEA place 
zuranolone and its salts in schedule IV of the CSA.
    On October 31, 2023, DEA, pursuant to 21 U.S.C. 811(j), published 
an IFR in the Federal Register to make zuranolone (including its salts) 
a schedule IV controlled substance.\3\ The IFR provided an opportunity 
for interested persons to submit comments, as well as file a request 
for a hearing or waiver of a hearing, on or before November 30, 2023. 
DEA did not receive any requests for a hearing or waiver of a hearing.
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    \3\ Schedules of Controlled Substances: Placement of Zuranolone 
in Schedule IV, 88 FR 74347 (Oct. 31, 2023).
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Comment Received

    DEA received one comment on the IFR to control zuranolone in 
schedule IV of the CSA. The commenter briefly expressed that schedule 
IV was the appropriate schedule for zuranolone based on the similarity 
of this substance to substances in schedule IV and requested 
information on what surveillance and reporting systems exist to ensure 
proper use of zuranolone due to its documented abuse potential.
    DEA Response: DEA determined in the IFR, and re-affirms in this 
final rule, that zuranolone meets the criteria under 21 U.S.C. 
812(b)(4) for schedule IV control. As described by HHS, and in DEA's 
September 2023 eight-factor analysis, zuranolone demonstrated abuse 
potential similar to schedule IV

[[Page 65992]]

depressants. DEA appreciates the support for this rulemaking.
    In response to the request of information regarding surveillance 
and reporting systems in place, DEA notes that diversion and illicit 
trafficking of zuranolone will be monitored by DEA's National Forensic 
Laboratory Information System (NFLIS)-Drug.\4\ NFLIS-Drug is a national 
forensic laboratory reporting system that systematically collects 
results from drug chemistry analyses conducted by state and local 
forensic laboratories in the United States.
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    \4\ NFLIS-Drug represents an important resource in monitoring 
illicit drug trafficking, including the diversion of legally 
manufactured pharmaceuticals into illegal markets. NFLIS is a 
comprehensive information system that includes data from forensic 
laboratories that handle more than 96 percent of an estimated 1 
million distinct annual state and local drug analysis cases. NFLIS 
includes drug chemistry results only from completed analyses. 
Although NFLIS-Drug data are not direct evidence of abuse, they can 
lead to an inference that a drug has been diverted and abused. See 
Schedules of Controlled Substances: Placement of Carisoprodol Into 
Schedule IV, 76 FR 77330, 77332 (Dec. 12, 2011).
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    DEA also notes that the monitoring of adverse effects for any new 
drug products, including abuse potential, largely falls under the 
purview of HHS, including FDA. FDA monitors the adverse events for all 
drugs through a postmarketing pharmacovigilance program.\5\
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    \5\ https://www.fda.gov/drugs/surveillance/postmarketing-adverse-event-reporting-compliance-program.
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    DEA is aware that in the publicly available NDA letter,\6\ FDA 
noted reporting information under sections ``Reporting Requirements'' 
and ``Requested Pharmacovigilance.'' Specifically, the sponsor of the 
zuranolone drug product ZURZUVAE must follow standard reporting 
guidance as described in 21 CFR 314.80(c)(1) (e.g., 15-day alert 
reports), submit standard periodic (including quarterly) adverse drug 
experience reports as described in 21 CFR 314.80(c)(2), and submit 
standard annual reports as described in 21 CFR 314.81(b)(2). Further, 
the sponsor must submit additional reports as described in the letter, 
including ``all serious and nonserious domestic and foreign adverse 
drug experience reports of Central Nervous System (CNS) depressant 
effects including adverse sequelae of the CNS depressant effects, such 
as motor vehicle accidents, falls, loss of consciousness, respiratory 
depression, or impairment of the ability to care for a child as a 15-
day `Alert report' (described under 21 CFR 314.80(c)(1)), from any 
source, including information derived from reports in the scientific 
literature and postmarketing studies (whether or not conducted under an 
investigational new drug application), through the 5th year following 
initial U.S. approval.'' DEA notes that additional information about 
published alerts, as well as the drug labeling and approval process, 
can be found at ``Drugs@FDA: FDA-Approved Drugs'' on FDA's website.\7\ 
Importantly, drug labeling is used to communicate to both healthcare 
providers and patients any potential risks associated with the product, 
including abuse-related risks, if any, and is updated over time.
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    \6\ https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2023/217369Orig2s000Corrected_ltr.pdf.
    \7\ https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm.
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    Additionally, adverse effects can be reported to FDA's Adverse 
Event Reporting System (FAERS). FDA has a publicly available FAERS 
dashboard,\8\ which states ``[t]he intention of this tool is to expand 
access of FAERS data to the general public to search for information 
related to human adverse events reported to the FDA by the 
pharmaceutical industry, healthcare providers and consumers.''
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    \8\ https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard.
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    Based on the rationale set forth in the IFR, DEA adopts the IFR, 
without change.

Requirements for Handling Zuranolone

    As indicated above, zuranolone has been a schedule IV controlled 
substance by virtue of an IFR issued by DEA in October 2023. Thus, this 
final rule does not alter the regulatory requirements applicable to 
handlers of zuranolone that have been in place since that time. 
Nonetheless, for informational purposes, we restate here those 
requirements. Zuranolone is subject to the CSA's schedule IV regulatory 
controls and administrative, civil, and criminal sanctions applicable 
to the manufacture, distributing, dispensing, importing, exporting, 
research, and conduct of instructional activities, including the 
following:
    1. Registration. Any person who handles (manufactures, distributes, 
reverse distributes, dispenses, imports, exports, engages in research, 
or conducts instructional activities or chemical analysis with, or 
possesses) zuranolone must be registered with DEA to conduct such 
activities pursuant to 21 U.S.C. 822, 823, 957, and 958, and in 
accordance with 21 CFR parts 1301 and 1312. These registration 
requirements, however, are not applicable to patients (end users) who 
possess zuranolone pursuant to a lawful prescription.
    2. Disposal of Stocks. Any person unwilling or unable to obtain a 
schedule IV registration must surrender all quantities of currently 
held zuranolone, or may transfer all quantities of currently held 
zuranolone to a person registered with DEA. Zuranolone is required to 
be disposed of in accordance with 21 CFR part 1317, in addition to all 
other applicable federal, state, local, and tribal laws.
    3. Security. Zuranolone is subject to schedule III-V security 
requirements for DEA registrants and must be handled and stored in 
accordance with 21 CFR 1301.71-1301.77. Non-practitioners handling 
zuranolone must also comply with the employee screening requirements of 
21 CFR 1301.90-1301.93. These requirements, however, are not applicable 
to patients (end users) who possess zuranolone pursuant to a lawful 
prescription.
    4. Labeling and Packaging. All labels and packaging for commercial 
containers of zuranolone must comply with 21 U.S.C. 825 and 958(e), and 
be in accordance with 21 CFR part 1302.
    5. Inventory. Since October 31, 2023, every DEA registrant who 
possesses any quantity of zuranolone must have an initial inventory of 
all stocks of controlled substances (including zuranolone) on hand on 
the date the registrant first engages in the handling of controlled 
substances, pursuant to 21 U.S.C. 827, and in accordance with 21 CFR 
1304.03, 1304.04, and 1304.11.
    Any person who registers with DEA to handle zuranolone must take an 
initial inventory of all stocks of controlled substances (including 
zuranolone) on hand on the date the registrant first engages in the 
handling of controlled substances, pursuant to 21 U.S.C. 827 and 
958(e), and in accordance with 21 CFR 1304.03, 1304.04, and 1304.11(a) 
and (b).
    After the initial inventory, every DEA registrant must take 
inventory of all controlled substances (including zuranolone) on hand 
every two years, pursuant to 21 U.S.C. 827, and in accordance with 21 
CFR 1304.03, 1304.04, and 1304.11. These requirements, however, are not 
applicable to patients (end users) who possess zuranolone pursuant to a 
lawful prescription.
    6. Records and Reports. DEA registrants must maintain records and 
submit reports for zuranolone, pursuant to 21 U.S.C. 827, 832(a), and 
958(e), and in accordance with 21 CFR 1301.74(b) and (c) and parts 
1304, 1312, and in accordance with 21 CFR 1301.74(b) and

[[Page 65993]]

(c), and 1301.76(b), and parts 1304, 1312, and 1317.
    7. Prescriptions. All prescriptions for zuranolone, or products 
containing zuranolone, must comply with 21 U.S.C. 829, and be issued in 
accordance with 21 CFR parts 1306 and 1311, subpart C.
    8. Manufacturing and Distributing. In addition to the general 
requirements of the CSA and DEA regulations that are applicable to 
manufacturers and distributors of schedule IV controlled substances, 
such registrants should be advised that (consistent with the foregoing 
considerations) any manufacturing or distribution of zuranolone may 
only be for the legitimate purposes consistent with the drug's 
labeling, or for research activities authorized by the Federal Food, 
Drug, and Cosmetic Act (FDCA), as applicable, and the CSA.
    9. Importation and Exportation. All importation and exportation of 
zuranolone must be in compliance with 21 U.S.C. 952, 953, 957, and 958, 
and in accordance with 21 CFR part 1312.
    10. Liability. Any activity involving zuranolone not authorized by, 
or in violation of, the CSA or its implementing regulations, is 
unlawful, and may subject the person to administrative, civil, and/or 
criminal sanctions.

Regulatory Analyses

Administrative Procedure Act

    This final rule, without change, affirms the IFR that is already in 
effect. Section 553 of the APA (5 U.S.C. 553) generally requires notice 
and comment for rulemakings. However, 21 U.S.C. 811(j) provides that in 
cases where a certain new drug is (1) approved by HHS, under section 
505(c) of the FDCA, and (2) HHS recommends control in CSA schedule II-
V, DEA shall issue an IFR scheduling the drug within 90 days. 
Additionally, subsection 811(j) specifies that the rulemaking shall 
become immediately effective as an IFR without requiring DEA to 
demonstrate good cause. DEA issued an IFR on October 31, 2023, and 
solicited public comments on that rule. Subsection (j) further provides 
that after giving interested persons the opportunity to comment and to 
request a hearing, the Attorney General, as delegated to the 
Administrator of DEA, shall issue a final rule in accordance with the 
scheduling criteria of 21 U.S.C. 811(b) through (d) and 812(b). As 
stated above, DEA received one comment and no requests for a hearing or 
waiver of a hearing. DEA is now issuing the final rule in accordance 
with subsection (j).

Executive Orders 12866, 13563, and 14094, Regulatory Review

    In accordance with 21 U.S.C. 811(a), this scheduling action is 
subject to formal rulemaking procedures performed ``on the record after 
opportunity for a hearing,'' which are conducted pursuant to the 
provisions of 5 U.S.C. 556 and 557. The CSA sets forth the procedures 
and criteria for scheduling a drug or other substance. Such actions are 
exempt from review by the Office of Management and Budget pursuant to 
section 3(d)(1) of Executive Order (E.O.) 12866 and the principles 
reaffirmed in E.O. 13563. E.O. 14094 modernizes the regulatory review 
process to advance policies that promote the public interest and 
address national priorities.

Executive Order 12988, Civil Justice Reform

    This meets the applicable standards set forth in sections 3(a) and 
3(b)(2) of E.O. 12988 to eliminate drafting errors and ambiguity, 
minimize litigation, provide a clear legal standard for affected 
conduct, and promote simplification and burden reduction.

Executive Order 13132, Federalism

    This rulemaking does not have federalism implications warranting 
the application of E.O. 13132. The proposed rule does not have 
substantial direct effects on the states, on the relationship between 
the national government and the states, or on the distribution of power 
and responsibilities among the various levels of government.

Executive Order 13175, Consultation and Coordination With Indian Tribal 
Governments

    This rule does not have tribal implications warranting the 
application of E.O. 13175. It does not have substantial direct effects 
on one or more Indian tribes, on the relationship between the Federal 
government and Indian tribes, or on the distribution of power and 
responsibilities between the Federal government and Indian tribes.

Paperwork Reduction Act

    This proposed action does not impose a new collection of 
information requirement under the Paperwork Reduction Act, 44 U.S.C. 
3501-3521.

Regulatory Flexibility Act

    The Regulatory Flexibility Act (RFA) (5 U.S.C. 601-612) applies to 
rules that are subject to notice and comment under section 553(b) of 
the APA. As noted in the above discussion regarding the applicability 
of the APA, DEA is not required to publish a general notice of proposed 
rulemaking. Consequently, the RFA does not apply to this final rule.

Unfunded Mandates Reform Act of 1995

    In accordance with the Unfunded Mandates Reform Act (UMRA) of 1995, 
2 U.S.C. 1501 et seq., DEA has determined and certifies that this 
proposed action would not result in any Federal mandate that may result 
``in the expenditure by State, local, and tribal governments, in the 
aggregate, or by the private sector, of $100,000,000 or more (adjusted 
annually for inflation) in any 1 year * * *.'' Therefore, neither a 
Small Government Agency Plan nor any other action is required under 
UMRA of 1995.

Congressional Review Act

    This rule is not a major rule as defined by the Congressional 
Review Act (CRA), 5 U.S.C. 804. However, pursuant to the CRA, DEA is 
submitting a copy of this final rule to both Houses of Congress and to 
the Comptroller General.

Signing Authority

    This document of the Drug Enforcement Administration was signed on 
August 6, 2024, by Administrator Anne Milgram. That document with the 
original signature and date is maintained by DEA. For administrative 
purposes only, and in compliance with requirements of the Office of the 
Federal Register, the undersigned DEA Federal Register Liaison Officer 
has been authorized to sign and submit the document in electronic 
format for publication, as an official document of DEA. This 
administrative process in no way alters the legal effect of this 
document upon publication in the Federal Register.

List of Subjects in 21 CFR Part 1308

    Administrative practice and procedure, Drug traffic control, 
Reporting and recordkeeping requirements.

PART 1308--SCHEDULES OF CONTROLLED SUBSTANCES

0
Accordingly, the interim rule amending 21 CFR part 1308, published 
October 31, 2023, at 88 FR 74347, is adopted as a final rule without 
change.

Heather Achbach,
Federal Register Liaison Officer Drug Enforcement Administration.
[FR Doc. 2024-18087 Filed 8-13-24; 8:45 am]
BILLING CODE 4410-09-P