Federal Register / Vol. 88, No. 209 / Tuesday, October 31, 2023 / Rules and Regulations 74347 

1 21 CFR 1308.41–1308.45; 21 CFR part 1316, 

subpart D. 

Nonmetallic Safety Cans for Flammable 

and Combustible Liquids, Tenth 

Edition, dated April 29, 2022. 

(2) [Reserved] 

Alberta E. Mills, 

Secretary, Consumer Product Safety 

Commission. 

[FR Doc. 2023–23655 Filed 10–30–23; 8:45 am] 

BILLING CODE 6355–01–P 

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. 

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: 

(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 


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74348 Federal Register / Vol. 88, No. 209 / Tuesday, October 31, 2023 / Rules and Regulations 

2 21 CFR 1316.49. 

3 21 CFR 1308.44(b), 1316.53. 

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. 

5NFLIS-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 NFLISDrug 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. 

(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©, together with a written 

statement of position on the matters of 

fact and law involved in any hearing.2

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. 

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

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-dimethyl2,4,5,6,7,8,9,10,11,12,14,15,16,17- 

tetradecahydro-1Hcyclopenta[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 


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Federal Register / Vol. 88, No. 209 / Tuesday, October 31, 2023 / Rules and Regulations 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. 

2. Scientific Evidence of Its 

Pharmacological Effects, If Known 

Zuranolone is a selective neuroactive 

steroid that potentiates synaptic (g 

subunit-containing) and extra synaptic 

(d-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 dosedependent 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 dosedependent 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 euphoriarelated adverse events that are 

supportive of zuranolone having an 

abuse potential. However, the abuserelated 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-dimethyl2,4,5,6,7,8,9,10,11,12,14,15,16,17- 

tetradecahydro-1Hcyclopenta[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 abuserelated 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 


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74350 Federal Register / Vol. 88, No. 209 / Tuesday, October 31, 2023 / Rules and Regulations 

6 21 U.S.C. 812(b). 7 21 U.S.C. 812(b)(4). 

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 sedativehypnotic 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 withdrawalrelated 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: 

(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

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. 


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Federal Register / Vol. 88, No. 209 / Tuesday, October 31, 2023 / Rules and Regulations 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 


lotter on DSK11XQN23PROD with RULES1
74352 Federal Register / Vol. 88, No. 209 / Tuesday, October 31, 2023 / Rules and Regulations 

1 88 FR 22955 (Apr. 14, 2023). 

2 21 U.S.C. 802(34). 

3 Id. 

4 85 FR 20822 (Apr. 15, 2020). 

5 Id. 

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 

■ 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. 

■ 2. In § 1308.14: 

a. Add a new paragraph (c)(60) to read 

as follows: 

§ 1308.14 Schedule IV. 

* * * * * 

(c) * * * 

* * * * * 

(60) Zuranolone ............................ 2420 

* * * * * 

[FR Doc. 2023–23982 Filed 10–30–23; 8:45 am] 

BILLING CODE 4410–09–P 

DEPARTMENT OF JUSTICE 

Drug Enforcement Administration 

21 CFR Part 1310 

[Docket No. DEA–1098] 

Designation of Halides of 4- 

Anilinopiperidine as List I Chemicals 

AGENCY: Drug Enforcement 

Administration, Department of Justice. 

ACTION: Final rule. 

SUMMARY: The Drug Enforcement 

Administration (DEA) is finalizing the 

modification of the listing of the list I 

chemical, N-phenylpiperidin-4-amine 

(also known as 4-anilinopiperidine; Nphenyl-4-piperidinamine; 4–AP) 

(hereinafter referred to as 4- 

anilinopiperidine), to include halides of 

4-anilinopiperidine. This rule finalizes 

the modification of the listing of 4- 

anilinopiperidine as a list I chemical. 

DATES: This rule is effective November 

30, 2023. Persons currently 

manufacturing, distributing, importing, 

or exporting halides of 4- 

anilinopiperidine or a chemical mixture 

containing halides of 4- 

anilinopiperidine, if they are not 

already registered to handle list I 

chemicals, must apply on or before 

November 30, 2023, to continue their 

business pending final action by DEA 

on their application. 

FOR FURTHER INFORMATION CONTACT: 

Terrence L. Boos, Drug and Chemical 

Evaluation Section, Diversion Control 

Division, Drug Enforcement 

Administration; Telephone: (571) 362– 

3249. 

SUPPLEMENTARY INFORMATION: The Drug 

Enforcement Administration (DEA) is 

extremely concerned with the recent 

increase in the illicit manufacture and 

distribution of fentanyl and fentanyl 

analogues. Therefore, on April 14, 2023, 

DEA published a Notice of Proposed 

Rulemaking (NPRM) to include halides 

of 4-anilinopiperidine as list I 

chemicals.1 This rulemaking finalizes 

that NPRM. 

This action subjects handlers of 

halides of 4-anilinopiperidine to the 

regulatory provisions of the Controlled 

Substances Act (CSA) and its 

implementing regulations regarding list 

I chemicals. This rulemaking does not 

establish a threshold for domestic and 

international transactions of halides of 

4-anilinopiperidine. As such, all 

transactions involving halides of 4- 

anilinopiperidine, regardless of size, 

shall be regulated and are subject to 

control under the CSA. In addition, 

chemical mixtures containing halides of 

4-anilinopiperidine are not exempt from 

regulatory requirements at any 

concentration. Therefore, all 

transactions of chemical mixtures 

containing any quantity of halides of 4- 

anilinopiperidine shall be regulated 

pursuant to the CSA as list I chemicals. 

Legal Authority 

The CSA gives the Attorney General 

the authority to specify, by regulation, 

chemicals as list I chemicals.2 A ‘‘list I 

chemical’’ is a chemical that is used in 

manufacturing a controlled substance in 

violation of the CSA and is important to 

the manufacture of the controlled 

substances.3 The current list of all listed 

chemicals is published at 21 CFR 

1310.02(a). Pursuant to 28 CFR 0.100(b), 

the Attorney General has delegated his 

authority to designate list I chemicals to 

the Administrator of DEA 

(Administrator). The DEA regulations 

set forth the process by which DEA may 

add a chemical as a listed chemical. As 

set forth in 21 CFR 1310.02(c), the 

agency may do so by publishing a final 

rule in the Federal Register following a 

published notice of proposed 

rulemaking with at least 30 days for 

public comments. 

Background 

DEA previously found that 4- 

anilinopiperidine is used in the illicit 

manufacture of the controlled substance 

fentanyl (a schedule II substance under 

the CSA) and fentanyl analogues 

controlled in schedule I of the CSA, and 

is important to the manufacture of the 

controlled substance fentanyl and 

fentanyl analogues, because it cannot be 

replaced by other chemicals in its 

respective synthetic pathways that are 

used in the illicit manufacture of 

fentanyl and fentanyl analogues.4 On 

this basis, DEA previously specified that 

4-anilinopiperidine is a list I chemical.5

DEA has now found that halides of 4- 

anilinopiperidine are also used in the 

illicit manufacture of schedule I 

controlled substances, such as parafluorofentanyl, ortho-fluorofentanyl, 

and para-chlorofentanyl. Accordingly, 

this action adds halides of 4- 

anilinopiperidine to the prior listing of 

4-anilinopiperidine and thereby subjects 

handlers of halides of 4- 

anilinopiperidine to the regulatory 

provisions of the CSA and its 

implementing regulations. 


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