Schedules of Controlled Substances: Placement of Zuranolone in Schedule IV, 74347-74352 [2023-23982]

Agencies

• Drug Enforcement Administration
• Department of Justice

[Federal Register Volume 88, Number 209 (Tuesday, October 31, 2023)]
[Rules and Regulations]
[Pages 74347-74352]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2023-23982]


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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: Interim final rule; request for comments.

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SUMMARY: On August 4, 2023, the United States Food and Drug 
Administration approved a new drug application for ZURZUVAE 
(zuranolone) capsules for the treatment of post-partum depression. The 
Department of Health and Human Services provided the Drug Enforcement 
Administration (DEA) with a scheduling recommendation to place 
zuranolone and its salts in schedule IV of the Controlled Substances 
Act (CSA). In accordance with the CSA, as amended by the Improving 
Regulatory Transparency for New Medical Therapies Act, DEA is hereby 
issuing an interim final rule placing zuranolone, including its salts, 
in schedule IV of the CSA. This action facilitates the public 
availability of zuranolone as a schedule IV controlled substance.

DATES: This rule is effective October 31, 2023. Comments must be 
submitted electronically or postmarked on or before November 30, 2023.
    Requests for hearing and waivers of an opportunity for a hearing or 
to participate in a hearing, together with a written statement of 
position on the matters of fact and law asserted in the hearing, must 
be received on or before November 30, 2023.

ADDRESSES: Interested persons may file written comments on this 
rulemaking in accordance with 21 U.S.C. 811(j)(3) and 21 CFR 
1308.43(g). The electronic Federal Docket Management System will not 
accept comments after 11:59 p.m. Eastern Time on the last day of the 
comment period. To ensure proper handling of comments, please reference 
``Docket No. DEA1258'' on all correspondence, including any 
attachments.
     Electronic comments: The Drug Enforcement Administration 
(DEA) encourages commenters to submit comments electronically through 
the Federal eRulemaking Portal, which provides the ability to type 
short comments directly into the comment field on the web page or 
attach a file for lengthier comments. Please go to https://www.regulations.gov and follow the online instructions at that site for 
submitting comments. Upon completion of your submission, you will 
receive a Comment Tracking Number for your comment. Submitted comments 
are not instantaneously available for public view on Regulations.gov. 
If you have received a Comment Tracking Number, your comment has been 
successfully submitted and there is no need to resubmit the same 
comment.
     Paper comments: Paper comments that duplicate electronic 
submissions are not necessary. Should you wish to mail a paper comment 
in lieu of an electronic comment, it should be sent via regular or 
express mail to: Drug Enforcement Administration, Attn: DEA Federal 
Register Representative/DPW, 8701 Morrissette Drive, Springfield, VA 
22152.
     Hearing requests: All requests for hearing and waivers of 
participation, together with a written statement of position on the 
matters of fact and law asserted in the hearing, must be filed with the 
DEA Administrator, who will make the determination of whether a hearing 
will be needed to address such matters of fact and law in the 
rulemaking. Such requests must be sent to: Drug Enforcement 
Administration, Attn: Administrator, 8701 Morrissette Drive, 
Springfield, Virginia 22152. For informational purposes, a courtesy 
copy of requests for hearing and waivers of participation should also 
be sent to: (1) Drug Enforcement Administration, Attn: Hearing Clerk/
OALJ, 8701 Morrissette Drive, Springfield, Virginia 22152; and (2) Drug 
Enforcement Administration, Attn: DEA Federal Register Representative/
DPW, 8701 Morrissette Drive, Springfield, Virginia 22152.

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

SUPPLEMENTARY INFORMATION:

Posting of Public Comments

    Please note that all comments received in response to this docket 
are considered part of the public record. DEA will make comments 
available for public inspection online at https://www.regulations.gov. 
Such information includes personal or business identifying information 
(such as name, address, State or Federal identifiers, etc.) voluntarily 
submitted by the commenter. In general, all information voluntarily 
submitted by the commenter, unless clearly marked as Confidential 
Information in the method described below, will be publicly posted. 
Comments may be submitted anonymously. The Freedom of Information Act 
applies to all comments received.
    Commenters submitting comments which include personal identifying 
information (PII), confidential, or proprietary business information 
that the commenter does not want made publicly available should submit 
two copies of the comment. One copy must be marked ``CONTAINS 
CONFIDENTIAL INFORMATION'' and should clearly identify all PII or 
business information the commenter does not want to be made publicly 
available, including any supplemental materials. DEA will review this 
copy, including the claimed PII and confidential business information, 
in its consideration of comments. The second copy should be marked ``TO 
BE PUBLICLY POSTED'' and must have all claimed confidential PII and 
business information already redacted. DEA will post only the redacted 
comment on https://www.regulations.gov for public inspection.
    For easy reference, an electronic copy of this document and 
supplemental information to this interim final rule (IFR) are available 
at https://www.regulations.gov.

Request for Hearing or Appearance; Waiver

    Pursuant to 21 U.S.C. 811(a), this action is a formal rulemaking 
``on the record after opportunity for a hearing.'' Such proceedings are 
conducted pursuant to the provisions of the Administrative Procedure 
Act (APA), 5 U.S.C. 551-559.\1\ Interested persons, as defined in 21 
CFR 1300.01(b), may file requests for a hearing in conformity with the 
requirements of 21 CFR 1308.44(a) and 1316.47(a), and such requests 
must:
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    \1\ 21 CFR 1308.41-1308.45; 21 CFR part 1316, subpart D.
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    (1) state with particularity the interest of the person in the 
proceeding;
    (2) state with particularity the objections or issues concerning 
which the person desires to be heard; and

[[Page 74348]]

    (3) state briefly the position of the person with regarding to the 
objections or issues.
    Any interested person may file a waiver of an opportunity for a 
hearing or to participate in a hearing in conformity with the 
requirements of 21 CFR 1308.44(copyright), together with a written 
statement of position on the matters of fact and law involved in any 
hearing.\2\
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    \2\ 21 CFR 1316.49.
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    All requests for hearings and waivers of participation, together 
with a written statement of position on the matters of fact and law 
involved in such hearing, must be sent to DEA using the address 
information provided above. The decision whether a hearing will be 
needed to address such matters of fact and law in the rulemaking will 
be made by the Administrator. If a hearing is needed, DEA will publish 
a notice of hearing on the proposed rulemaking in the Federal 
Register.\3\ Further, once the Administrator determines a hearing is 
needed to address such matters of fact and law in rulemaking, she will 
then designate an Administrative Law Judge (ALJ) to preside over the 
hearing. The ALJ's functions shall commence upon designation, as 
provided in 21 CFR 1316.52.
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    \3\ 21 CFR 1308.44(b), 1316.53.
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    In accordance with 21 U.S.C. 811 and 812, the purpose of a hearing 
would be to determine whether zuranolone meets the statutory criteria 
for placement in schedule IV.

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), DEA is required to commence an 
expedited scheduling action with respect to certain new drugs approved 
by the Food and Drug Administration (FDA). As provided in 21 U.S.C. 
811(j), this expedited scheduling is required where both of the 
following conditions apply: (1) The Secretary of the Department of 
Health and Human Services (HHS) has advised DEA that a New Drug 
Application (NDA) has been submitted for a drug that has a stimulant, 
depressant, or hallucinogenic effect on the central nervous system 
(CNS), and that it appears that such drug has an abuse potential; and 
(2) the Secretary of HHS recommends that DEA control the drug in 
schedule II, III, IV, or V pursuant to 21 U.S.C. 811(a) and (b). In 
these circumstances, DEA is required to issue an interim final rule 
(IFR) controlling the drug within 90 days.
    Subsection 811(j)(2) states that the 90-day timeframe starts the 
later of (1) the date DEA receives HHS's scientific and medical 
evaluation/scheduling recommendation, or (2) the date DEA receives 
notice of the NDA approval by HHS. Subsection 811(j)(3) specifies that 
the rulemaking shall become immediately effective as an IFR without 
requiring DEA to demonstrate good cause therefore. Thus, the purpose of 
subsection 811(j) is to speed the process by which DEA schedules newly 
approved drugs that are currently either in schedule I or not 
controlled (but which have sufficient abuse potential to warrant 
control) so that such drugs may be marketed without undue delay 
following FDA approval.\4\
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    \4\ Given the parameters of subsection 811(j), in DEA's view, it 
would not apply to a reformulation of a drug containing a substance 
currently in schedules II through V for which an NDA has recently 
been approved.
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    Subsection 811(j)(3) further provides that the IFR shall give 
interested persons the opportunity to comment and to request a hearing. 
After the conclusion of such proceedings, DEA must issue a final rule 
in accordance with the scheduling criteria of 21 U.S.C. 811(b) through 
(d), and 812(b).
    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) is 
a new molecular entity with CNS activity. Zuranolone is a positive 
allosteric modulator of gamma-aminobutyric acid type A 
(GABAA) receptors and an inhibitory neurosteroid substance 
that shares structural features and a pharmacological mechanism of 
action with progesterone, alfaxalone (schedule IV), and brexanolone 
(allopregnanolone, schedule IV).
    On December 5, 2022, Sage Therapeutics, Inc. submitted an NDA for 
zuranolone to FDA. On August 4, 2023, FDA approved the 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.

Determination To Schedule Zuranolone

    On July 12, 2023, DEA received from HHS a scientific and medical 
evaluation entitled ``Basis for the Recommendation to Control 
Zuranolone and its Salts in Schedule IV of the Controlled Substances 
Act'' and a scheduling recommendation. Pursuant to 21 U.S.C. 811(b) and 
(c), this document contained an eight-factor analysis of the abuse 
potential, legitimate medical use, and dependence liability of 
zuranolone, along with HHS's recommendation to control zuranolone and 
its salts under schedule IV of the CSA.
    In response, DEA reviewed the scientific and medical evaluation and 
scheduling recommendation provided by HHS, along with all other 
relevant data, and completed its own eight-factor review pursuant to 21 
U.S.C. 811(c). DEA concluded that zuranolone meets the 21 U.S.C. 
812(b)(4) criteria for placement in schedule IV of the CSA.
    Pursuant to subsection 811(j), and based on HHS's scheduling 
recommendation, the approval of the NDA by HHS/FDA, and DEA's 
determination, DEA is issuing this IFR to schedule zuranolone as a 
schedule IV controlled substance under the CSA.
    Included below is a brief summary of each factor as analyzed by HHS 
and DEA, and as considered by DEA in its scheduling action. Please note 
that both DEA and HHS analyses are available in their entirety under 
``Supporting Documents'' in the public docket for this IFR at https://www.regulations.gov, under Docket Number ``DEA1258.'' Full analysis of, 
and citations to, the information referenced in the summary may also be 
found in the supporting and related material.

1. Its Actual or Relative Potential for Abuse

    Zuranolone is a new molecular entity that has not been marketed in 
the United States or any country. Thus, evidence regarding its 
diversion, illicit manufacturing, or deliberate ingestion is currently 
lacking. DEA notes that there are no reports of law enforcement 
encounters of zuranolone in the National Forensic Laboratory 
Information System (NFLIS)-Drug database.\5\ Zuranolone has sedative 
effects and is likely to have abuse potential, similar to schedule IV 
sedatives such as alprazolam. Thus, it is reasonable to assume that 
zuranolone may be diverted from legitimate channels, used contrary to 
or without

[[Page 74349]]

medical advice, and capable of creating hazards to the users and to the 
safety of the community. In human abuse potential studies, zuranolone 
produced positive subjective responses that are similar to those 
produced by alprazolam (schedule IV). Zuranolone produces rewarding 
effects that are comparable to those produced by schedule IV sedatives; 
therefore, zuranolone is likely to be abused for its sedative effects 
contrary to medical advice.
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    \5\ NFLIS-Drug is a comprehensive information system that 
includes data from forensic laboratories that handle more than 96% 
of an estimated 1 million distinct annual State and local drug 
analysis cases. NFLIS-Drug includes drug chemistry results from 
completed analyses only. While NFLIS-Drug data is not direct 
evidence of abuse, it can lead to an inference that a drug has been 
diverted and abused. See 76 FR 77330, 77332 (Dec. 12, 2011). NFLIS 
data were queried on August 30, 2023.
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2. Scientific Evidence of Its Pharmacological Effects, If Known

    Zuranolone is a selective neuroactive steroid that potentiates 
synaptic ([gamma] subunit-containing) and extra synaptic ([delta]-
subunit containing) GABAA receptor activity. Zuranolone acts 
on GABAA receptors to enhance the effects of GABA, a major 
inhibitory neurotransmitter in the CNS. Zuranolone acts directly 
through the GABAA receptor-channel complex to increase the 
probability that the channel will enter into naturally occurring open 
states of relatively long duration and allow the influx of chloride. 
Zuranolone was found to potentiate GABA-evoked current in cells 
expressing human GABAA receptor subtypes. HHS noted that 
these data are consistent with a mechanism of action of zuranolone that 
is similar to other schedule IV neurosteroids (e.g., brexanolone) as a 
positive allosteric modulator of GABAA sites.
    In animal studies, zuranolone's effect on the general behavioral 
profile in male rats showed that it produced behavioral activities, 
such as decreased activity, ataxia, hypersensitivity to touch and/or 
sound, and impaired righting reflex at supratherapeutic plasma 
concentrations. The observations were generally limited to the highest 
dose test (22.5 mg/kg), although some animals exhibited slight 
impairments at the lower doses tested (3 and 10 mg/kg).
    In a drug discrimination study using male rats trained to 
discriminate midazolam and saline, intraperitoneally administered 
zuranolone (0.1, 0.3, 0.5, 1, and 3 mg/kg) produced dose-dependent 
effects and full substitution to midazolam discriminative stimulus 
effect at the highest dose tested when considering lever presses over 
the entire session and not just the first reinforcer (75 percent). 
However, 3 mg/kg zuranolone produced behavioral impairment, such that 
only five of ten rodents completed the session. In female rats, 
intraperitoneally administered zuranolone (0.1, 0.3, 0.5, 1, and 2 mg/
kg) also produced dose-dependent effects and full substitution to 
midazolam discriminative stimulus effect at the highest dose tested 
when considering lever presses over the entire session and not just the 
first reinforcer (72.5 percent).
    Zuranolone reinforcing properties were assessed by determining 
whether self-administration behavior was maintained when the drug was 
substituted for cocaine (schedule II). As stated by HHS in their 
scientific and medical evaluation, the study found that the selected 
doses of zuranolone did not maintain robust self-administration in 
animals with a previous history of cocaine self-administration.
    In clinical trials, zuranolone produced significantly greater mean 
drug liking than placebo. The low (30 mg) and middle (60 mg) doses of 
zuranolone produced significantly less mean drug liking scores than 
both alprazolam (schedule IV) doses (1.5 and 3 mg). However, the 
highest dose of zuranolone produced mean drug liking scores that were 
similar to both doses of alprazolam (schedule IV).
    Zuranolone produced euphoria-related adverse events that are 
supportive of zuranolone having an abuse potential. However, the abuse-
related treatment emergent AE profile of zuranolone was slightly lower 
than that of alprazolam (a schedule IV benzodiazepine) at a 
supratherapeutic dose of zuranolone.
    Zuranolone produced incidence of euphoria-related adverse events 
supportive of its abuse potential in animals and humans similar to 
those of benzodiazepines in schedule IV. These data are consistent with 
the fact that both drugs share a common mechanism of action involving 
positive allosteric modulation of the GABAA receptors.

3. The State of Current Scientific Knowledge Regarding the Drug or 
Other Substance

    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, is 
a new molecular entity.
    Zuranolone is a drug product formulated as 20, 25, and 30 mg 
colored hard-gelatin capsules. The powder is white to off-white in 
color. Zuranolone is available as an immediate-release formulation and 
is absorbed with a time to maximum effect of approximately 6 hours and 
a half-life of 20 hours.
    As discussed in the background section, zuranolone has an accepted 
medical use in the United States.

4. Its History and Current Pattern of Abuse

    There is no information on the history and current pattern of abuse 
for zuranolone, since it has not been marketed, legally or illegally, 
in the United States or any other country. There is no evidence of 
diversion of zuranolone that has been distributed for research, such as 
for clinical trials. Data from preclinical and clinical studies 
indicate that the abuse potential of zuranolone is similar to that of 
schedule IV sedatives, including benzodiazepines. Consistent with the 
fact that zuranolone is a new molecular entity, the NFLIS-Drug database 
had no records of encounters by law enforcement.
    In summary, pharmacological data on zuranolone show that it 
produces abuse-related effects and has an abuse potential similar to 
that of schedule IV CNS depressants.

5. The Scope, Duration, and Significance of Abuse

    A search by DEA of the NFLIS-Drug database found no evidence of law 
enforcement encounters of zuranolone in the United States. Data from 
preclinical and clinical studies showed that zuranolone has an abuse 
potential that is similar to that of schedule IV sedatives, including 
benzodiazepines. Upon availability of zuranolone in the market, it is 
likely to be abused.

6. What, if any, Risk There Is to the Public Health

    Zuranolone's abuse potential, similar to that of schedule IV 
sedatives, is an indication of its public health risk. As such, upon 
availability for marketing, it is likely to pose risk to public health 
comparable to schedule IV positive allosteric modulators of the 
GABAA receptor such as brexanolone and benzodiazepines. 
According to evaluation of public health risks conducted by HHS, the 
most observed adverse effects were somnolence, dizziness, and sedation. 
An overdose of zuranolone could result in sedation with or without 
respiratory depression or other severe adverse effects. Two simulated 
driving studies demonstrated impairment approximately 9 hours after 
nighttime administration.
    Concomitant use with other CNS depressants such as alcohol may 
potentiate the impairment of psychomotor performance and cognition. HHS 
noted that zuranolone is not recommended for chronic administration; it 
is intended for a 14-day treatment course. This may lessen some public 
health risks compared to

[[Page 74350]]

other drugs that are prescribed for longer durations or in larger 
quantities.

7. Its Psychic or Physiological Dependence Liability

    Zuranolone's psychic and physiological dependence liability was 
assessed using data from animal physical dependence studies and 
clinical evaluations of physical dependence, including measures of 
withdrawal. As described by HHS, data from a physiologic dependence 
study conducted in rats demonstrated zuranolone did not induce 
significant withdrawal-related phenotypes at the doses tested; however, 
zuranolone produced significant toxic effects in dogs, including 
convulsions and death in the dog toxicity studies. HHS noted the toxic 
effects in dogs, such as the early mortalities, may be consistent with 
withdrawal-type effects observed after cessation of chronic dosing of 
sedative-hypnotic benzodiazepines.
    In clinical trials, when zuranolone was administered at therapeutic 
doses (<=50 mg/day) for a minimum of five days, it produced mild-to-
moderate withdrawal-related effects in healthy individuals upon abrupt 
drug discontinuation, including the following: insomnia, palpitations, 
decreased appetite, nightmare, nausea, hyperhidrosis, and paranoia. 
Similar effects were not evident in the patient population. HHS 
provided caveats for why this may be the case, such as the withdrawal 
effects may have been obscured by the symptoms of the underlying 
condition (post-partum depression and major depressive disorder) or 
inadequate assessment of withdrawal in the various Phase 3 studies. 
However, based on available data provided by HHS, the withdrawal-
related symptoms produced by zuranolone after abrupt drug 
discontinuation are similar to those that are clinically known for 
benzodiazepines in schedule IV.
    The data taken together suggest that zuranolone maybe produce 
physical dependence, and the risk of physical dependence and withdrawal 
syndrome upon drug discontinuation is expected to be more severe for 
individuals who take a higher than the therapeutic dose of zuranolone 
for an extended period of time, which may include convulsions based on 
the dog toxicity studies.

8. Whether the Substance Is an Immediate Precursor of a Substance 
Already Controlled Under the CSA

    Zuranolone is not an immediate precursor of any controlled 
substance, as defined by 21 U.S.C. 802(23).
    Conclusion: After considering the scientific and medical evaluation 
and scheduling recommendation provided by HHS, and its own eight-factor 
analysis, DEA has determined that these facts and all relevant data 
constitute substantial evidence of potential for abuse of zuranolone. 
As such, DEA hereby schedules zuranolone as a controlled substance 
under the CSA.

Determination of Appropriate Schedule

    The CSA lists the findings required to place a drug or other 
substance in any particular schedule (I, II, III, IV, or V).\6\ After 
consideration of the analysis and recommendation of the Assistant 
Secretary for Health of HHS and review of all available data, the 
Administrator of DEA, pursuant to 21 U.S.C. 812(b)(4), finds that:
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    \6\ 21 U.S.C. 812(b).
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    (1) Zuranolone has a potential for abuse similar to the drugs or 
other substances in schedule IV.
    Zuranolone, a neuroactive steroid, is a positive allosteric 
modulator of GABAA receptors and produces sedation in 
general behavioral studies. In a drug discrimination study in animals, 
zuranolone produced dose-dependent substitution for midazolam (schedule 
IV) when considering the full session (partial substitution when 
considering the first reinforcer), demonstrating it has GABA agonist 
properties. Zuranolone produced positive subjective responses and 
euphoria-related adverse events similar to that of alprazolam (schedule 
IV), and greater than that of placebo in a human abuse potential study.
    Furthermore, data from other clinical studies show that zuranolone 
produced incidence of euphoria-like adverse events in 5 percent of 
healthy individuals, including euphoric mood, feeling drunk, feeling of 
relaxation, feeling abnormal, and inappropriate effect compared to no 
incidence following placebo. Therefore, zuranolone has the potential 
for abuse similar to alprazolam, midazolam, methohexital, and other 
substances in schedule IV.
    (2) Zuranolone has a currently accepted medical use in treatment in 
the United States.
    FDA approved the NDA for ZURZUVAE (zuranolone) as a treatment for 
post-partum depression. Thus, zuranolone has a currently accepted 
medical use in treatment in the United States.
    (3) Abuse of zuranolone may lead to limited physical dependence or 
psychological dependence relative to the drugs or other substances in 
schedule III but similar to other substances in schedule IV.
    Zuranolone shares a similar pharmacology profile with brexanolone 
(schedule IV) and benzodiazepines (schedule IV). Data from a rat 
physical dependence study demonstrated that discontinuation of chronic 
administration of zuranolone at the doses tested did not produce 
physical dependence or withdrawal syndrome. In a dog toxicity study, 
drug discontinuation after chronic administration at supratherapeutic 
doses produced convulsions similar to that of benzodiazepines. Further, 
upon abrupt discontinuation in humans at the therapeutic dose (<=50 mg 
per day), zuranolone produced mild to moderate withdrawal-like effects 
in healthy individuals no worse than what is clinically known for 
schedule IV benzodiazepines. HHS concluded that there would be higher 
risk of developing physical dependence and withdrawal syndrome and more 
severe effects after abrupt drug discontinuation in individuals that 
took more than the therapeutic dose or for an extended duration. 
Withdrawal symptoms from physical dependence may include convulsions. 
Zuranolone produced positive subjective responses and euphoria-related 
adverse events and may produce psychic dependence. Zuranolone may lead 
to physical or psychological dependence similar to benzodiazepines in 
schedule IV.
    Based on these findings, the Administrator concludes that 
zuranolone warrants control in schedule IV of the CSA.\7\
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    \7\ 21 U.S.C. 812(b)(4).
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Requirements for Handling Zuranolone

    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.

[[Page 74351]]

    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, pursuant to 21 U.S.C. 823, 821, 
871(b). 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. 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 (c) 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

    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. As stated 
in the legal authority section, the 90-day time frame is the later of: 
(1) the date DEA receives HHS's scientific and medical evaluation/
scheduling recommendation, or (2) the date DEA receives notice of the 
NDA approval by HHS. Additionally, subsection 811(j) specifies that the 
rulemaking shall become immediately effective as an IFR without 
requiring DEA to demonstrate good cause.

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 IFR.

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

[[Page 74352]]

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 IFR to both Houses of Congress and to the 
Comptroller General.

Signing Authority

    This document of the Drug Enforcement Administration was signed on 
October 25, 2023, 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.

Scott Brinks,
Federal Register Liaison Officer, Drug Enforcement Administration.

List of Subjects in 21 CFR Part 1308

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

    For the reasons set out above, DEA amends 21 CFR part 1308 as 
follows:

PART 1308--SCHEDULES OF CONTROLLED SUBSTANCES

0
1. The authority citation for 21 CFR part 1308 continues to read as 
follows:

    Authority: 21 U.S.C. 811, 812, 871(b), 956(b) unless otherwise 
noted.


0
2. In Sec.  1308.14:
    a. Add a new paragraph (c)(60) to read as follows:


Sec.  1308.14  Schedule IV.

* * * * *
    (c) * * *

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                                * * * * *
(60) Zuranolone..............................................       2420
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* * * * *
[FR Doc. 2023-23982 Filed 10-30-23; 8:45 am]
BILLING CODE 4410-09-P