[Federal Register Volume 86, Number 40 (Wednesday, March 3, 2021)]
[Rules and Regulations]
[Pages 12257-12260]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2021-04183]


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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Part 1308

[Docket No. DEA-600]


Schedules of Controlled Substances: Placement of Lemborexant in 
Schedule IV

AGENCY: Drug Enforcement Administration, Department of Justice.

ACTION: Final rule.

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SUMMARY: This final rule adopts, without change, an interim final rule 
with request for comments published in the Federal Register on April 7, 
2020, placing lemborexant ((1R,2S)-2-[(2,4-dimethylpyrimidin-5-
yl)oxymethyl]-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropane-
1-carboxamide), 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 Controlled Substances Act (CSA). With 
the issuance of this final rule, the Drug

[[Page 12258]]

Enforcement Administration maintains lemborexant, 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 final rulemaking is March 3, 2021.

FOR FURTHER INFORMATION CONTACT: Dr. Terrence L. Boos, Drug and 
Chemical Evaluation Section, Diversion Control Division, Drug 
Enforcement Administration; Mailing Address: 8701 Morrissette Drive, 
Springfield, Virginia 22152; Telephone: 571-362-3249.

SUPPLEMENTARY INFORMATION:

Background and Legal Authority

    Under the Controlled Substances Act (CSA), as amended in 2015 by 
the Improving Regulatory Transparency for New Medical Therapies Act 
(Pub. L. 114-89), when the Drug Enforcement Administration (DEA) 
receives notification from the Department of Health and Human Services 
(HHS) that the Secretary has approved a certain new drug and HHS 
recommends control in the CSA schedule II-V, DEA is required to issue 
an interim final rule, with opportunity for public comment and to 
request a hearing, controlling the drug within a specified 90-day 
timeframe and to subsequently issue a final rule. 21 U.S.C. 811(j). 
When controlling a drug pursuant to subsection (j), DEA must apply the 
scheduling criteria of 21 U.S.C. 811 (b) through (d) and 812(b). 21 
U.S.C. 811(j)(3).
    On April 7, 2020, DEA published an interim final rule to make 
lemborexant (including its salts, isomers, and salts of isomers 
whenever the existence of such salts, isomers, and salts of isomers is 
possible) a schedule IV controlled substance. 85 FR 19387. The interim 
final rule provided an opportunity for interested persons to submit 
comments as well as file a request for hearing or waiver of hearing, on 
or before May 7, 2020. DEA did not receive any requests for hearing or 
waiver of hearing.

Comments Received

    DEA received five comments in response to the interim final rule 
for the placement of lemborexant into schedule IV of the CSA. The 
submissions were from individual or anonymous commenters. Two 
commenters provided support for the interim final rule, one commenter 
opposed the rule, one commenter solely included a link to potential 
malware, and one commenter expressed views on a subject not related to 
the rule. As these final two comments were outside the scope of this 
rulemaking, DEA did not summarize or respond to them below.

Support of the Interim Final Rule

    A commenter supported controlling lemborexant as a schedule IV 
controlled substance, if such control helped to prevent abuse of, or 
the addiction to, this substance. Another commenter noted HHS, in its 
analysis, found that lemborexant had similar abuse potential to other 
schedule IV sedatives such as suvorexant and zolpidem, and therefore, 
agreed with HHS's recommendation of schedule IV control for 
lemborexant. In addition, this commenter referenced a study, conducted 
by Eisai, Inc. (the Sponsor of the new drug application for Dayvigo 
(lemborexant)), and recommended that DEA add this particular study 
analysis regarding abuse and dependency potential to DEA's final rule, 
under the ``Determination to Schedule Lemborexant'' section, to further 
support DEA's placing lemborexant in schedule IV.
    DEA Response: DEA appreciates the support for this rulemaking. DEA 
determined in the interim final rule, and re-affirms in this final 
rule, that there is substantial evidence of a potential for abuse of 
lemborexant, and lemborexant warrants control in schedule IV. Regarding 
the commenter's request that DEA include the study analysis in this 
final rule, DEA assumes that the commenter is referring to the human 
abuse potential (HAP) study conducted by Eisai, Inc. In the event the 
commenter is referencing this study, DEA asserts that the HAP study 
conducted by the Sponsor was included in both the DEA and HHS 
lemborexant eight-factor reviews and in the interim final rule located 
in the ``Determination to Schedule Lemborexant'' section in Factor 2 
and in the ``Determination of Appropriate Schedule'' in section 3 of 
the interim final rule.

Opposition to the Interim Final Rule

    A commenter claimed that DEA did not rely on the pharmacological 
data for lemborexant or follow any of the other factors required to be 
considered under 21 U.S.C. 811(c) to determine the placement of 
lemborexant in schedule IV. Instead, the commenter stated that DEA 
relied on a ``small and unrepeated sample group'' and its subjective 
responses, which matched responses to the schedule IV sedative 
suvorexant. The commenter also contended that there is a disparity in 
DEA's scheduling treatment for lemborexant (schedule IV) and Rozarem 
(non-controlled), as these both are sedatives--with the same Food and 
Drug Administration (FDA)-approved indication--that exert 
pharmacological activity by other means than binding to gamma-
aminobutyric acid (GABA) receptors. As such, the commenter considered 
DEA's decision to schedule lemborexant ``arbitrary and capricious.'' 
This commenter further stated that the placement of lemborexant in 
schedule IV of the CSA would increase the regulatory restrictions on a 
drug intended to treat insomnia, thereby causing many to resort to more 
dangerous and addictive substances such as benzodiazepines and other 
drugs that bind to the GABA receptor. Lastly, the commenter stated 
lemborexant is a new molecular entity thus evidence of actual abuse or 
potential for abuse liability does not exist. Therefore, the commenter 
asserted that DEA should either not place lemborexant in the same 
schedule as drugs with proven abuse potential, such as Xanax and 
Ambien, or delay scheduling lemborexant until evidence of actual abuse 
data can be produced using the eight-factors stipulated in 21 U.S.C. 
811(c).
    DEA Response: Regarding the commenter's point concerning the lack 
of appropriate pharmacological data in support of the abuse potential 
of lemborexant, DEA asserts that pharmacological data serves as only 
one portion of the data used to determine abuse potential and abuse 
liability. As stated in the interim final rule, while lemborexant is 
highly selective for both the orexin 1 and orexin 2 receptors and has 
little to no affinity to other central nervous system receptor sites 
associated with abuse potential, in a clinical HAP study of 
lemborexant, lemborexant produced statistically significant increases 
in positive subjective measures in the bipolar visual analog scale 
(i.e., Drug Liking, Overall Drug Liking, Good Effects, High, Stoned, 
and Take Drug Again) that were greater than placebo and statistically 
similar to other sedatives in the same drug class. Thus, in this HAP 
study, lemborexant showed potential for abuse. Following comprehensive 
evaluation of all available data, including both preclinical and 
clinical data as related to the eight-factor analysis pursuant to 21 
U.S.C. 811(c), HHS recommended schedule IV for lemborexant. Upon 
careful consideration of all available data, DEA concurred with HHS' 
recommendation that lemborexant possesses abuse potential comparable to 
other schedule IV depressants.
    Regarding the commenter's concerns that the control of lemborexant 
as a schedule IV drug would negatively impact treatment choices and 
increase addiction risks, DEA contends that there

[[Page 12259]]

is no evidence to suggest that such control of lemborexant creates 
undue regulatory restrictions increasing the risk of addiction. 
Furthermore, a HAP study of lemborexant was conducted, the results of 
which indicate that lemborexant has an abuse potential that is greater 
than placebo and statistically similar to other controlled sedatives in 
schedule IV of the CSA. Therefore, DEA asserts that by adopting the 
interim final rule placing lemborexant in schedule IV of the CSA, there 
is no ``risk of restricting its prescribing'' and limiting treatment 
options for insomnia to ``more dangerous and addictive molecules.'' 
Rather, lemborexant is being placed in a schedule with other sedative/
hypnotics that have similar abuse potential such as benzodiazepines, 
barbiturates, and muscle relaxants.
    Regarding the commenter's point that lemborexant is a new molecular 
entity with unknown actual or potential for abuse, and the commenter's 
request for DEA to either not place lemborexant in schedule IV or to 
postpone such scheduling until there is evidence showing the requisite 
abuse potential, DEA's determination of the abuse liability of 
lemborexant in the interim final rule, and again in this final rule, is 
in agreement with that of HHS. In a clinical HAP study investigating 
the abuse potential of lemborexant, HHS concluded that lemborexant 
produced subjective responses that were similar to those for the 
schedule IV sedative suvorexant. In the context of drug development, 
HAP studies are conducted as a component of the safety evaluation of a 
new molecular entity. These studies are utilized by HHS, FDA, and the 
scientific community. They are accepted as repeatable and follow 
rigorous scientific guidelines. In effect, the HAP studies are indeed 
evidence showing the requisite abuse potential of lemborexant; 
therefore, no additional studies are necessary to prove potential for 
abuse. Additionally, HHS' evaluation of a HAP study conducted by the 
Sponsor concluded that lemborexant produces positive subjective effects 
and has abuse potential similar to that of schedule IV sedatives, such 
as suvorexant and zolpidem, which were used as positive controls in the 
study. DEA asserts that when the evidence of actual abuse is not 
available, both HHS and DEA rely upon data from preclinical and 
clinical studies to inform determinations on potential for abuse of a 
given substance. Therefore, upon evaluation of the above-mentioned 
clinical studies and other preclinical data, DEA concurred with HHS' 
findings that the abuse liability of lemborexant is similar to other 
substances placed in schedule IV (i.e., benzodiazepines, barbiturates, 
and muscle relaxants) and therefore supported--and continues to support 
through this final rule--placement of lemborexant in schedule IV.
    Finally, we address the commenter's claim that the control of 
lemborexant is improper because there is another substance, that is not 
controlled, which the commenter asserts has similar pharmacological 
properties to those of lemborexant. DEA contends that while both drugs 
are classified as sedatives with similar FDA-approved indications, they 
do not share the same pharmacological mechanism of action or abuse 
liability. Even assuming this assertion were correct, this is not a 
legal basis to decline to control a substance. The CSA does not 
require, as a condition of control under 21 U.S.C. 811, that every 
other substance with similar properties be simultaneously controlled.
    Based on the rationale set forth in the interim final rule, DEA 
adopts the interim final rule without change.

Requirements for Handling Lemborexant

    As indicated above, lemborexant has been a schedule IV controlled 
substance by virtue of the interim final rule issued by DEA in April 
2020. Thus, this final rule does not alter the regulatory requirements 
applicable to handlers of lemborexant that have been in place since 
that date. Nonetheless, for informational purposes, we re-state here 
those requirements. Lemborexant 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, but not limited to, 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) lemborexant, or who desires to handle lemborexant, 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. Any person who intends to handle lemborexant, and is not 
registered with DEA, must submit an application for registration and 
may not handle lemborexant, unless DEA approves 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 obtains a schedule IV 
registration to handle lemborexant but who subsequently does not desire 
or is not able to maintain such registration must surrender all 
quantities of lemborexant, or may transfer all quantities of 
lemborexant to a person registered with DEA in accordance with 21 CFR 
part 1317, in addition to all other applicable Federal, State, local, 
and tribal laws.
    3. Security. Lemborexant is subject to schedule III-V security 
requirements and must be handled and stored in accordance with 21 CFR 
1301.71-1301.93. Non-practitioners handling lemborexant must also 
comply with the employee screening requirements of 21 CFR 1301.90-
1301.93.
    4. Labeling and Packaging. All labels, labeling, and packaging for 
commercial containers of lemborexant must comply with 21 U.S.C. 825 and 
958(f), and be in accordance with 21 CFR part 1302.
    5. Inventory. Every DEA registrant who possesses any quantity of 
lemborexant was required to keep an inventory of lemborexant on hand, 
as of April 7, 2020, 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 lemborexant, or products containing lemborexant, 
pursuant to 21 U.S.C. 827 and 958(f), and in accordance with 21 CFR 
parts 1304, 1312, and 1317.
    7. Prescriptions. All prescriptions for lemborexant or products 
containing lemborexant 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 lemborexant 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 
lemborexant 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 lemborexant not authorized 
by, or in

[[Page 12260]]

violation of, the CSA or its implementing regulations, is unlawful, and 
may subject the person to administrative, civil, and/or criminal 
sanctions.

Regulatory Analyses

Administrative Procedure Act

    This final rule, without change, affirms the amendment made by the 
interim final rule that is already in effect. Section 553 of the 
Administrative Procedure Act (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 and (2) 
HHS recommends control in CSA schedule II-V, DEA shall issue an interim 
final rule scheduling the drug within 90 days. Additionally, subsection 
(j) specifies that the rulemaking shall become immediately effective as 
an interim final rule without requiring DEA to demonstrate good cause. 
DEA issued an interim final rule on April 7, 2020, and solicited public 
comments on that rule. Subsection (j) further states that after giving 
interested persons the opportunity to comment and to request a hearing, 
the Attorney General, as delegated to the Administrator of DEA, shall 
issue a final rule in accordance with the scheduling criteria of 21 
U.S.C. 811 (b) through (d) and 812(b). DEA is now responding to the 
comments submitted by the public and issuing the final rule in 
accordance with subsection (j).

Executive Orders 12866 (Regulatory Planning and Review) and 13563 
(Improving Regulation and Regulatory Review)

    In accordance with 21 U.S.C. 811(a) and (j), 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 (E.O.) 12866 and the 
principles reaffirmed in E.O. 13563.

Executive Order 12988, Civil Justice Reform

    This regulation 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 final rule does not have federalism implications warranting 
the application of E.O. 13132. The final 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 final 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.

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 was not required to publish a general notice of 
proposed rulemaking. Consequently, the RFA does not apply.

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 
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 million 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.

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 does 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 final 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 million or more; a 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 the U.S.-based companies to compete 
with foreign-based companies in domestic and export markets. However, 
pursuant to the CRA, DEA has submitted a copy of this 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.

PART 1308--SCHEDULES OF CONTROLLED SUBSTANCES

0
Accordingly, the interim final rule (85 FR 19387) amending 21 CFR part 
1308, which published on April 7, 2020, is adopted as a final rule 
without change.

D. Christopher Evans,
Acting Administrator.
[FR Doc. 2021-04183 Filed 3-2-21; 8:45 am]
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