Rule2024-18087
Schedules of Controlled Substances: Placement of Zuranolone in Schedule IV
Primary source
Metadata and text below are from the Federal Register, a public-domain U.S. government work. Always verify the official published version before relying on it for any legal matter.
Published
August 14, 2024
Effective
September 13, 2024
Issuing agencies
Justice DepartmentDrug Enforcement Administration
Abstract
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.
Full Text
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<title>Federal Register, Volume 89 Issue 157 (Wednesday, August 14, 2024)</title>
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[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 [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[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
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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\ <a href="https://www.fda.gov/drugs/surveillance/postmarketing-adverse-event-reporting-compliance-program">https://www.fda.gov/drugs/surveillance/postmarketing-adverse-event-reporting-compliance-program</a>.
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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\ <a href="https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2023/217369Orig2s000Corrected_ltr.pdf">https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2023/217369Orig2s000Corrected_ltr.pdf</a>.
\7\ <a href="https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm">https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm</a>.
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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\ <a href="https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard">https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard</a>.
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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
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(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
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</html>Indexed from Federal Register on August 14, 2024.
This is legal information, not legal advice. Laws vary by jurisdiction and change frequently. Always verify current law with official sources and consult a licensed attorney in your jurisdiction for advice on your specific situation.