[Federal Register Volume 84, Number 116 (Monday, June 17, 2019)]
[Rules and Regulations]
[Pages 27938-27943]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-12721]


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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Part 1308

[Docket No. DEA-503]


Schedules of Controlled Substances: Placement of Brexanolone in 
Schedule IV

AGENCY: Drug Enforcement Administration, Department of Justice.

ACTION: Interim final rule, with request for comments.

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SUMMARY: On March 19, 2019, the U.S. Food and Drug Administration (FDA) 
approved a new drug application for Zulresso (brexanolone). Brexanolone 
is chemically known as 3[alpha]-hydroxy-5[alpha]-pregnan-20-one and is 
also referred to as allopregnanolone. The Department of Health and 
Human Services (HHS) provided the Drug Enforcement Administration (DEA) 
with a recommendation that brexanolone be placed in schedule IV of the 
Controlled Substances Act (CSA). In accordance with the CSA, as revised 
by the Improving Regulatory Transparency for New Medical Therapies Act, 
DEA is hereby issuing an interim final rule placing brexanolone 
(including its salts, isomers, and salts of isomers whenever the 
existence of such salts, isomers, and salts of isomers is possible) in 
schedule IV of the CSA.

DATES: The effective date of this rulemaking is June 17, 2019. 
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). Electronic 
comments must be submitted, and written comments must be postmarked, on 
or before July 17, 2019. Commenters should be aware that 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.
    Interested persons may file a request for hearing or waiver of 
hearing in accordance with 21 U.S.C. 811(j)(3) and 21 CFR 1308.44. 
Requests for hearing and waivers of an opportunity for a hearing or to 
participate in a hearing must be received on or before July 17, 2019.

ADDRESSES: To ensure proper handling of comments, please reference 
``Docket No. DEA-503'' on all correspondence, including any 
attachments.
     Electronic comments: The Drug Enforcement Administration 
encourages that all comments be submitted 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 http://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. Please be aware that 
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 the 
electronic submission are not necessary and are discouraged. 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 must be sent to: Drug Enforcement Administration, Attn: 
Administrator, 8701 Morrissette Drive, Springfield, Virginia 22152. All 
requests for hearing and waivers of participation should also be sent 
to: (1) Drug Enforcement Administration, Attn: Hearing Clerk/LJ, 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: Lynnette M. Wingert, Diversion Control 
Division, Drug Enforcement Administration; Mailing Address: 8701 
Morrissette Drive, Springfield, Virginia 22152; Telephone: (202) 598-
6812.

SUPPLEMENTARY INFORMATION: 

Posting of Public Comments

    Please note that all comments received are considered part of the 
public record. They will, unless reasonable cause is given, be made 
available by the Drug Enforcement

[[Page 27939]]

Administration (DEA) for public inspection online at http://www.regulations.gov. Such information includes personal identifying 
information (such as your name, address, etc.) voluntarily submitted by 
the commenter. The Freedom of Information Act (FOIA) applies to all 
comments received. If you want to submit personal identifying 
information (such as your name, address, etc.) as part of your comment, 
but do not want it to be made publicly available, you must include the 
phrase ``PERSONAL IDENTIFYING INFORMATION'' in the first paragraph of 
your comment. You must also place all of the personal identifying 
information you do not want made publicly available in the first 
paragraph of your comment and identify what information you want 
redacted.
    If you want to submit confidential business information as part of 
your comment, but do not want it to be made publicly available, you 
must include the phrase ``CONFIDENTIAL BUSINESS INFORMATION'' in the 
first paragraph of your comment. You must also prominently identify the 
confidential business information to be redacted within the comment.
    Comments containing personal identifying information and 
confidential business information identified as directed above will 
generally be made publicly available in redacted form. If a comment has 
so much confidential business information or personal identifying 
information that it cannot be effectively redacted, all or part of that 
comment may not be made publicly available. Comments posted to http://www.regulations.gov may include any personal identifying information 
(such as name, address, and phone number) included in the text of your 
electronic submission that is not identified as directed above as 
confidential.
    An electronic copy of this document and supplemental information, 
including the complete Department of Health and Human Services and Drug 
Enforcement Administration eight-factor analyses, to this interim final 
rule are available at http://www.regulations.gov for easy reference.

Request for Hearing or Waiver of Participation in Hearing

    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. 21 CFR 1308.41-1308.45; 21 CFR part 1316, 
subpart D. Interested persons may file requests for a hearing or 
notices of intent to participate in a hearing in conformity with the 
requirements of 21 CFR 1308.44(a) or (b) and include a statement of 
interest in the proceeding and the objections or issues, if any, 
concerning which the person desires to be heard. Any interested person 
may file a waiver of an opportunity for a hearing or to participate in 
a hearing together with a written statement regarding the interested 
person's position on the matters of fact and law involved in any 
hearing as set forth in 21 CFR 1308.44(c).
    All requests for a hearing and waivers of participation must be 
sent to the DEA using the address information provided above.

Legal Authority

    Under the Improving Regulatory Transparency for New Medical 
Therapies Act (Pub. L. 114-89), which was signed into law on November 
25, 2015, the Drug Enforcement Administration (DEA) is required to 
commence an expedited scheduling action with respect to certain new 
drugs approved by the 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 
(Secretary of HHS or the Secretary) 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 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, the DEA is required to issue an interim final rule 
controlling the drug within 90 days.
    The law further states that the 90-day timeframe starts the later 
of (1) the date DEA receives the HHS scientific and medical evaluation/
scheduling recommendation or (2) the date DEA receives notice of the 
NDA approval by HHS. In addition, the law specifies that the rulemaking 
shall become immediately effective as an interim final rule without 
requiring the DEA to demonstrate good cause therefor. Thus, the purpose 
of subsection (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.\1\
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    \1\ Given the parameters of subsection (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 (j) further provides that the interim final rule 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 subsections 21 
U.S.C. 811(b), (c), and (d) and 21 U.S.C. 812(b).

Background

    Brexanolone (3[alpha]-hydroxy-5[alpha]-pregnan-20-one), also known 
as allopregnanolone, is a new molecular entity with central nervous 
system (CNS) depressant properties. Brexanolone is an inhibitory 
neurosteroidal substance structurally related to progesterone. 
Brexanolone shares a pharmacological mechanism of action with schedule 
IV substances such as diazepam and alprazolam and is a positive 
allosteric modulator of the gamma-aminobutyric acid type A (GABA-A) 
receptors.
    On April 19, 2018, Sage Therapeutics (Sponsor) submitted an NDA for 
brexanolone to the FDA. On March 19, 2019, the DEA received 
notification that HHS/FDA approved, on that date, the NDA for Zulresso 
(brexanolone) injection, for intravenous use, to treat postpartum 
depression (PPD) in adult women. Zulresso is approved with a Risk 
Evaluation and Mitigation Strategy (REMS) and is available to patients 
through a restricted distribution program where a healthcare 
professional can only administer the drug in a certified healthcare 
facility.

Determination To Schedule Brexanolone

    On March 19, 2019, the DEA received from the HHS a scientific and 
medical evaluation document (dated March 08, 2019) prepared by the FDA 
entitled ``Basis for the Recommendation to Control Brexanolone and its 
Salts in schedule IV of the Controlled Substances Act.'' Pursuant to 21 
U.S.C. 811(b), this document contained an eight-factor analysis of the 
abuse potential of brexanolone, along with the HHS's recommendation to 
control brexanolone under schedule IV of the CSA.
    In response, the DEA reviewed the scientific and medical evaluation 
and scheduling recommendation provided by the HHS, along with all other 
relevant data, and completed its own eight-factor review document 
pursuant to 21 U.S.C. 811(c). The DEA concluded that brexanolone met 
the 21 U.S.C.

[[Page 27940]]

812(b)(4) criteria for placement in schedule IV of the CSA.
    Pursuant to subsection 811(j), and based on the HHS recommendation, 
NDA approvals by HHS/FDA, and the DEA's determination, the DEA is 
issuing this interim final rule to schedule brexanolone as a schedule 
IV controlled substance under the CSA.
    Included below is a brief summary of each factor as analyzed by the 
HHS and the DEA, and as considered by the DEA in its scheduling action. 
Please note that both the DEA and the HHS analyses are available in 
their entirety under ``Supporting Documents'' in the public docket for 
this interim final rule at http://www.regulations.gov, under Docket 
Number ``DEA-503.'' 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: Brexanolone is a new 
molecular entity and is not currently available or marketed in any 
country; evidence regarding its diversion, illicit manufacturing, or 
deliberate ingestion is lacking. However, as stated by the HHS, 
brexanolone is related in action to schedule IV sedatives such as 
midazolam and alprazolam. It is thus reasonable to assume that 
brexanolone may be diverted from legitimate channels, used contrary to 
or without medical advice, and otherwise abused so as to create hazards 
to the users and to the safety of the community to an extent similar to 
that of schedule IV sedatives.
    Pre-clinical and clinical studies show that brexanolone produces 
effects that are similar to schedule IV sedative-hypnotics, such as 
midazolam and alprazolam. Data obtained from general behavioral studies 
demonstrate that brexanolone produced a sedative effect. In a drug 
discrimination study in rats, brexanolone mimicked stimulus effects of 
midazolam at certain dosages. Brexanolone produced positive subjective 
responses and euphoria-related adverse events (AEs) similar to that of 
alprazolam (schedule IV) in nondependent and healthy humans with a 
history of recreational use of CNS depressants. Thus, brexanolone 
likely has abuse potential similar to that of schedule IV sedatives, 
such as midazolam and alprazolam, and it is likely to be abused for its 
sedative effects contrary to medical advice.
    2. Scientific Evidence of Its Pharmacological Effects, if Known: 
Brexanolone, an inhibitory neurosteroid, shares a similar 
pharmacological profile to another inhibitory neurosteroid (alfaxalone, 
a schedule IV controlled substance) and schedule IV benzodiazepines 
such as alprazolam and midazolam. Brexanolone, a metabolite of 
progesterone, acts on GABA-A receptors and enhances the effects of 
GABA. GABA is the major inhibitory neurotransmitter in the CNS. The 
GABA-A receptor is a ligand-gated chloride ion channel consisting of 
five subunits and a central chloride channel. Benzodiazepines and other 
GABAergic substances enhance the opening of the ligand-gated chloride 
channel and the influx of chloride. Brexanolone's ability to bind to 
GABA-related sites is consistent with the action of other related 
neurosteroids, such as alfaxalone.
    Brexanolone, like schedule IV benzodiazepines, has sedative 
activity in animals. Acute and chronic administration of brexanolone to 
male and female rats and dogs elicited dose-dependent behaviors 
indicative of the sedative and muscle relaxation properties of the 
drug. In a drug discrimination study using male rats previously trained 
to discriminate midazolam, brexanolone produced interoceptive cues that 
are similar to those of midazolam. In human abuse potential studies, 
brexanolone produced subjective responses similar to that of alprazolam 
and may have a reinforcing effect at a higher infusion rate. The abuse-
related neuropharmacology profile of brexanolone is similar to that of 
schedule IV substances (alprazolam and midazolam) and consistent with 
its mechanism of action as a positive allosteric modulator of the GABA-
A receptors.
    3. The State of Current Scientific Knowledge Regarding the Drug or 
Other Substance: Brexanolone is a new molecular entity. It is the 
established name for allopregnanolone, chemically known as 5[alpha]-
pregnan-3[alpha]-ol-20-one (also known as 3[alpha]-hydroxy-5[alpha]-
pregnan-20-one). It is insoluble in water, very slightly soluble in n-
heptane, sparingly soluble in ethyl acetate, slightly soluble in 
methanol, soluble in 2-methyl-tetrahydrofuran, and freely soluble in 
tetrahydrofuran. Brexanolone drug product is formulated as a sterile, 
clear, colorless solution intended for dilution followed by intravenous 
infusion; and it contains brexanolone, Betadex Sulfobutyl Ether Sodium 
USP/NF (Captisol) as a solubilizer, citric acid and sodium citrate as 
buffering agents, and water for injection. The pH of the final bulk 
compounded solution is adjusted to 6.0 using either sodium hydroxide or 
hydrochloric acid.
    4. Its History and Current Pattern of Abuse: There is no 
information on the history and current pattern of abuse for 
brexanolone, since it has not been marketed, legally or illegally, in 
any country. The DEA conducted a search on the National Forensic 
Laboratory Information System (NFLIS) \2\ and STARLiMS \3\ databases 
for brexanolone encounters. Consistent with the fact that brexanolone 
is a new molecular entity, these databases had no records of encounters 
by law enforcement.
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    \2\ NFLIS 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.
    \3\ STARLiMS is a web-based, commercial laboratory information 
management system that systematically collects results from drug 
chemistry analyses conducted by the DEA laboratories. On October 1, 
2014, STARLiMS replaced the System to Retrieve Information from Drug 
Evidence (STRIDE) as the DEA laboratory drug evidence data system of 
record.
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    HHS notes that brexanolone produces abuse-related signals and abuse 
potential similar to that of schedule IV benzodiazepines. In 
particular, the pharmacological mechanism of action of brexanolone 
involving a positive allosteric modulation of the GABA-A receptors 
suggests that its pattern of abuse would be similar to schedule IV 
sedative-hypnotics with similar mechanisms of action, such as midazolam 
and diazepam.
    5. The Scope, Duration, and Significance of Abuse: As noted, 
brexanolone is not marketed, legally or illegally, in any country. 
Thus, information about the scope, duration, and significance of abuse 
for brexanolone is lacking. However, because of brexanolone's 
pharmacological similarities to certain schedule IV benzodiazepines, 
brexanolone is likely to be abused when available in the market with a 
scope, duration, and significance of abuse similar to those of schedule 
IV benzodiazepines.
    6. What, if any, Risk There Is to the Public Health: The extent of 
abuse potential of a drug is an indication of its public health risk. 
Data from preclinical and clinical studies showed that brexanolone has 
abuse potential similar to that of certain schedule IV benzodiazepines. 
Therefore, upon availability for marketing, it is likely to pose a 
public health risk to a degree similar to schedule IV benzodiazepines. 
Data from clinical trials showed that brexanolone caused excessive 
sedation with occasional loss of consciousness and amnesia. In 
addition, transient apnea occurred in one patient at a supratherapeutic 
dose. The HHS states that these adverse effects would likely occur in 
abusers of brexanolone.

[[Page 27941]]

    The brexanolone prescription product label states that concomitant 
use of opioids, antidepressants, or other CNS depressants such as 
benzodiazepines or alcohol may increase the possibility or severity of 
adverse reactions related to sedation. In addition, because of the risk 
of excessive sedation or sudden loss of consciousness, brexanolone is 
only available through a REMS program. A REMS is a drug safety program 
required by the FDA for certain medications with serious safety 
concerns to ensure the benefits of the medication outweighs its risks 
and is designed to reinforce medication use behaviors and actions that 
support the safe use of the medication.\4\
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    \4\ More information may be found at https://www.fda.gov/Drugs/DrugSafety/REMS/default.htm.
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    The abuse of brexanolone may present risks to the public health at 
a level similar to those associated with the abuse of schedule IV 
benzodiazepines, such as midazolam and alprazolam.
    7. Its Psychic or Physiological Dependence Liability: The HHS 
review states that there were no physical dependence studies conducted 
in animals or humans using brexanolone. Brexanolone is 
pharmacologically similar to benzodiazepines that are known to produce 
physical dependence. Sleep disturbances, anxiety, and convulsions can 
occur upon discontinuation of chronic administration of 
benzodiazepines. Thus, it is likely brexanolone may have a physical 
dependence potential similar to that of benzodiazepines. Data from a 
dog toxicity study demonstrated that discontinuation of chronic 
administration of brexanolone led to convulsions, similar to the effect 
from discontinuing benzodiazepines. Because brexanolone produced 
positive subjective responses and euphoria-related AEs, it is likely to 
cause psychic dependence.
    8. Whether the Substance Is an Immediate Precursor of a Substance 
Already Controlled under the CSA: Brexanolone is not an immediate 
precursor of any substance already controlled in the CSA.
    Conclusion: After considering the scientific and medical evaluation 
conducted by the HHS, the HHS's recommendation, and its own eight-
factor analysis, the DEA has determined that these facts and all 
relevant data constitute substantial evidence of a potential for abuse 
of brexanolone. As such, the DEA hereby schedules brexanolone 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). 21 U.S.C. 
812(b). After consideration of the analysis and recommendation of the 
Assistant Secretary for Health of the HHS and review of all available 
data, the Acting Administrator of the DEA, pursuant to 21 U.S.C. 
812(b)(4), finds that:
    (1) Brexanolone has a low potential for abuse relative to the drugs 
or other substances in Schedule III.
    Brexanolone, a neuroactive steroid, is a positive allosteric 
modulator of GABA-A receptors and produces sedation in general 
behavioral studies and locomotion study. In a drug discrimination study 
in animals, brexanolone was generalized to midazolam (schedule IV) at 
certain dosages, demonstrating it has GABA-A receptor agonist 
properties. In a human abuse potential (HAP) study, brexanolone 
produced positive subjective responses and euphoria-related AEs similar 
to those of alprazolam (schedule IV) in an HAP study. Furthermore, data 
from other clinical studies show that brexanolone produced abuse-
related AEs, namely somnolence and sedation. Because brexanolone is 
similar to midazolam and alprazolam (both schedule IV controlled 
substances) in its abuse potential, brexanolone has a low potential for 
abuse relative to the drugs or other substances in schedule III.
    (2) Brexanolone has a currently accepted medical use in the United 
States.
    The FDA recently approved the NDA for brexanolone as an intravenous 
treatment of PPD in adult women. Thus, brexanolone has a currently 
accepted medical use for treatment in the United States.
    (3) Abuse of Brexanolone may lead to limited physical dependence or 
psychological dependence relative to the drugs or other substances in 
schedule III.
    Brexanolone has a pharmacology profile similar to that of 
benzodiazepine drugs. Because abrupt discontinuation of benzodiazepines 
is associated with withdrawal symptoms, it is likely that brexanolone 
may have the potential to produce physical dependence similar to that 
produced by benzodiazepines. Data from a dog toxicity study 
demonstrated that discontinuation of chronic administration of 
brexanolone led to convulsions, similar to the effect from 
discontinuing benzodiazepines. In addition, because brexanolone 
produced positive subjective responses and euphoria-related AEs, it is 
likely that brexanolone can produce psychic dependence. Thus, abuse of 
brexanolone may lead to limited physical or psychological dependence 
relative to the drugs or other substances in schedule III.
    Based on these findings, the Acting Administrator of the DEA 
concludes that brexanolone, including its salts, isomers, and salts of 
isomers whenever the existence of such salts, isomers, and salts of 
isomers is possible, warrants control in schedule IV of the CSA. 21 
U.S.C. 812(b)(4).

Requirements for Handling Brexanolone

    Brexanolone is subject to the CSA's schedule IV regulatory controls 
and administrative, civil, and criminal sanctions applicable to the 
manufacture, distribution, reverse distribution, dispensing, importing, 
exporting, research, and conduct of instructional activities and 
chemical analysis with, and possession involving schedule IV 
substances, 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) brexanolone, or who desires to handle brexanolone, must be 
registered with the 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. Any person who currently handles or intends to handle 
brexanolone, and is not registered with the DEA, must submit an 
application for registration and may not continue to handle 
brexanolone, unless the DEA has approved that application for 
registration, pursuant to 21 U.S.C. 822, 823, 957, and 958, and in 
accordance with 21 CFR parts 1301 and 1312.
    2. Disposal of stocks. Any person who does not desire or is not 
able to maintain a schedule IV registration must surrender all 
quantities of currently held brexanolone or may transfer all quantities 
of brexanolone to a person registered with the DEA in accordance with 
21 CFR part 1317, in addition to all other applicable federal, state, 
local, and tribal laws.
    3. Security. Brexanolone is subject to schedule III-V security 
requirements and must be handled and stored in accordance with 21 CFR 
1301.71-1301.93.
    4. Labeling and Packaging. All labels, labeling, and packaging for 
commercial containers of brexanolone must comply with 21 U.S.C. 825 and 
958(e), and be in accordance with 21 CFR part 1302.

[[Page 27942]]

    5. Inventory. Every DEA registrant who possesses any quantity of 
brexanolone must take an inventory of all stocks of brexanolone on 
hand, pursuant to 21 U.S.C. 827 and 958(e), and in accordance with 21 
CFR 1304.03, 1304.04, and 1304.11.
    Any person who becomes registered with the DEA to handle 
brexanolone must take an initial inventory of all stocks of controlled 
substances (including brexanolone) 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.
    After the initial inventory, every DEA registrant must take an 
inventory of all controlled substances (including brexanolone) on hand 
every two years, pursuant to 21 U.S.C. 827 and 958(e), and in 
accordance with 21 CFR 1304.03, 1304.04, and 1304.11.
    6. Records and Reports. DEA registrants must maintain records and 
submit reports for brexanolone, pursuant to 21 U.S.C. 827 and 958(e), 
and in accordance with 21 CFR parts 1304, 1312, and 1317.
    7. Prescriptions. All prescriptions for brexanolone or products 
containing brexanolone 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 brexanolone 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 and the CSA.
    9. Importation and Exportation. All importation and exportation of 
brexanolone 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 brexanolone 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

    As explained above, under 21 U.S.C. 811(j), when a new drug is (1) 
approved by the Department of Health and Human Services (HHS), and (2) 
HHS recommends control in CSA schedule II-V, the DEA shall issue an 
interim final rule scheduling the drug within 90 days. Additionally, 
the law specifies that the rulemaking shall become immediately 
effective as an interim final rule without requiring the DEA to 
demonstrate good cause. Therefore, the DEA has determined that the 
notice and comment requirements of section 553 of the APA, 5 U.S.C. 
553, do not apply to this scheduling action.

Executive Orders 12866, 13563, and 13771, Regulatory Planning and 
Review, Improving Regulation and Regulatory Review, and Reducing 
Regulation and Controlling Regulatory Costs

    In accordance with Public Law 114-89, 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 (OMB) 
pursuant to section 3(d)(1) of Executive Order 12866 and the principles 
reaffirmed in Executive Order 13563.
    This interim final rule is not an Executive Order 13771 regulatory 
action pursuant to Executive Order 12866 and OMB guidance.\5\
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    \5\ Office of Mgmt. & Budget, Exec. Office of The President, 
Interim Guidance Implementing Section 2 of the Executive Order of 
January 30, 2017 Titled ``Reducing Regulation and Controlling 
Regulatory Costs'' (Feb. 2, 2017).
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Executive Order 12988, Civil Justice Reform

    This regulation meets the applicable standards set forth in 
sections 3(a) and 3(b)(2) of Executive Order 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 Executive Order 13132. The 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 Executive Order 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.

Regulatory Flexibility Act

    In accordance with 5 U.S.C. 603(a), ``[w]henever an agency is 
required by [5 U.S.C. 553], or any other law, to publish general notice 
of proposed rulemaking for any proposed rule, or publishes a notice of 
proposed rulemaking for an interpretive rule involving the internal 
revenue laws of the United States, the agency shall prepare and make 
available for public comment an initial regulatory flexibility 
analysis.'' As noted in the above discussion regarding applicability of 
the APA, the DEA has determined that the notice and comment 
requirements of section 553 of the APA, 5 U.S.C. 553, do not apply to 
this scheduling action. Consequently, the Regulatory Flexibility Act 
does not apply to this interim 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., the DEA has determined that this 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 for inflation) in any 
one year.'' Therefore, neither a Small Government Agency Plan nor any 
other action is required under UMRA of 1995.

Paperwork Reduction Act of 1995

    This action does not impose a new collection of information 
requirement under the Paperwork Reduction Act of 1995. 44 U.S.C. 3501-
3521. This action would not impose recordkeeping or reporting 
requirements on State or local governments, individuals, businesses, or 
organizations. An agency may not conduct or sponsor, and a person is 
not required to respond to, a collection of information unless it 
displays a currently valid OMB control number.

Congressional Review Act

    This rule is not a major rule as defined by the Congressional 
Review Act (CRA), 5 U.S.C. 804. This rule will not result in: An annual 
effect on the economy of $100,000,000 or more; a

[[Page 27943]]

major increase in costs or prices for consumers, individual industries, 
Federal, State, or local government agencies, or geographic regions; or 
significant adverse effects on competition, employment, investment, 
productivity, innovation, or on the ability of U.S.-based companies to 
compete with foreign based companies in domestic and export markets. 
However, pursuant to the CRA, the DEA has submitted a copy of this 
interim final rule to both Houses of Congress and to the Comptroller 
General.

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, the 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), unless otherwise noted.

0
2. Amend Sec.  1308.14 by:
0
a. Redesignating paragraphs (c)(4) through (c)(55) as (c)(5) through 
(c)(56);
0
b. Adding new paragraph (c)(4).
    The addition reads as follows:


Sec.  1308.14   Schedule IV.

* * * * *
    (c) * * *

------------------------------------------------------------------------
 
------------------------------------------------------------------------
(4) Brexanolone.................................................    2400
------------------------------------------------------------------------

* * * * *

    Dated: June 10, 2019.
Uttam Dhillon,
Acting Administrator.
[FR Doc. 2019-12721 Filed 6-14-19; 8:45 am]
 BILLING CODE 4410-09-P