[Federal Register Volume 86, Number 104 (Wednesday, June 2, 2021)]
[Rules and Regulations]
[Pages 29506-29509]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2021-11512]


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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Part 1308

[Docket No. DEA-658]


Schedules of Controlled Substances: Placement of Remimazolam in 
Schedule IV

AGENCY: Drug Enforcement Administration, Department of Justice.

ACTION: Final rule.

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SUMMARY: This final rule adopts, without change, an interim final rule 
with request for comments published in the Federal Register on October 
6, 2020, placing the substance remimazolam, 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. With the issuance of this final rule, DEA 
maintains remimazolam, including its salts, isomers, and salts of 
isomers whenever the existence of such salts,

[[Page 29507]]

isomers, and salts of isomers is possible, in schedule IV of the 
Controlled Substances Act.

DATES: The effective date of this rulemaking is July 2, 2021.

FOR FURTHER INFORMATION CONTACT: Terrence L. Boos, Drug and Chemical 
Evaluation Section, Diversion Control Division, Drug Enforcement 
Administration; Telephone: 571-776-2265.

SUPPLEMENTARY INFORMATION:

Background and Legal Authority

    On October 6, 2020, the Drug Enforcement Administration (DEA), 
pursuant to 21 U.S.C. 811(j), published an interim final rule (IFR) [85 
FR 63014] to make remimazolam (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(s). See 21 CFR 
1308.14(c)(51) (DEA Controlled Substance Code 2846).
    Over time, alternative chemical names have been used to describe 
this same specific substance. In the preamble to the IFR, DEA provided 
``4H-imidazol[1,2-a][1,4]benzodiazepine-4-propionic acid, 8-bromo-1-
methyl-6-(2-pyridinyl)-(4S)-methyl ester, benzenesulfonate (1:1) and 
also, methyl 3-[(4S)-8-bromo-1-methyl-6-pyridin-2-yl-4H-imidazo[1,2-
a][1,4]benzodiazepin-4yl]propanoate benzenesulfonic acid'' \1\ as the 
chemical names of remimazolam, which refer to the benzenesulfonic acid 
salt of remimazolam. Since DEA controlled remimazolam and its salts, 
isomers, and salts of isomers in schedule IV by publication of the IFR, 
DEA believes it is more appropriate to include chemical names 
consistent with the free base of this substance, namely ``4H-
imidazol[1,2-a][1,4]benzodiazepine-4-propionic acid, 8-bromo-1-methyl-
6-(2-pyridinyl)-(4S)-methyl ester and methyl 3-[(4S)-8-bromo-1-methyl-
6-pyridin-2-yl-4H-imidazo[1,2-a][1,4]benzodiazepin-4yl]propanoate'' in 
the preamble of this final rule. It bears emphasis that the chemical 
that is the subject of this final rule is the same substance that was 
the subject of the IFR. DEA simply is using alternative chemical 
descriptions to refer to that same substance in this preamble.
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    \1\ The Department of Health and Human Services also referred to 
the substance by these chemical names in its April 2020 scientific 
and medical evaluation and scheduling recommendation.
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    Remimazolam is a new molecular entity with central nervous system 
depressant properties, and the Food and Drug Administration (FDA), in 
July 2020, approved the use of BYFAVO (Remimazolam) as an intravenous 
medication for the induction and maintenance of procedural sedation in 
adults undergoing procedures lasting 30 minutes or less. The IFR to 
schedule remimazolam provided opportunity for interested persons to 
submit comments, as well as file a request for hearing or waiver of 
hearing, on or before November 5, 2020. DEA did not receive any 
requests for hearing or waiver of hearing.

Comments Received

    In response to the IFR, DEA received three comments, from one 
individual and two anonymous sources. One commenter supported schedule 
IV placement; the second commenter suggested placement in schedule III 
instead; and the third commenter expressed views on a non-DEA 
rulemaking. DEA will not summarize or respond to this last comment as 
it was outside the scope of this rulemaking.

Schedule IV Placement

    An anonymous commenter briefly expressed that schedule IV was the 
appropriate schedule for remimazolam based on the data from clinical 
trials conducted, limited side effects, and its better performance as 
compared to similar substances such as midazolam.
    DEA Response: DEA determined in the IFR, and re-affirms in this 
final rule, that remimazolam meets the criteria under 21 U.S.C. 
812(b)(4) for schedule IV control. As described by the Department of 
Health and Human Services (HHS),\2\ and in DEA's August 2020 eight-
factor analysis, remimazolam demonstrated abuse potential similar to 
midazolam, a schedule IV depressant. DEA appreciates the support for 
this rulemaking.
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    \2\ Basis for the Recommendation to Control Remimazolam and Its 
Salts in Schedule IV of the Controlled Substances Act. Department of 
Health and Human Services. April 15, 2020. Received by DEA on July 
10, 2020.
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Schedule III Placement

    One individual commenter expressed concerns with DEA's placement of 
remimazolam in schedule IV and instead suggested placing remimazolam in 
schedule III. The commenter briefly discussed the pharmacology of 
remimazolam and noted that both HHS and DEA stated the abuse potential 
and public health risk of remimazolam is similar to schedule IV 
benzodiazepines. However, the commenter stated that remimazolam induced 
``positive euphoria related responses in [a] human abuse potential 
study leading to dependence to relative drugs in schedule III'' and 
recommended classifying remimazolam as schedule III ``due to FDA 
placing a black box warning label on benzodiazepines and the numerous 
studies illustrating [the abuse and misuse of benzodiazepines] within 
the public communities.'' The commenter noted that schedule III 
provided more restrictions and could protect the public from harm. The 
individual summarized four reference articles related to the historic 
medical use and abuse of prescription benzodiazepines, diversion and 
trafficking of licit and illicit benzodiazepines, and the serious 
adverse effects that may occur with misuse and abuse of 
benzodiazepines, including an increase in benzodiazepine-related 
deaths. Further, the commenter believed that the opioid epidemic has 
overshadowed the benzodiazepines misuse and abuse, but suggested that 
benzodiazepines and opioids are working ``in tandem wreaking havoc in 
the lives of many'' and that ``creating a strong foundation through 
classification of drugs can place precedent in ensuring the health and 
safety of American citizens.''
    DEA Response: DEA considered the commenter's position; however, 
does find placement in schedule IV to be appropriate for remimazolam. 
As discussed briefly in the background and legal authority section 
above, and in more detail in the IFR [85 FR 63014, 63015-63016], FDA 
approved the New Drug Application (NDA) for BYFAVO (remimazolam), and 
HHS provided DEA with a scientific and medical evaluation and a 
scheduling recommendation for control of remimazolam in schedule IV. 
Pursuant to 21 U.S.C. 811(j), the scheduling recommendation by HHS and 
FDA approval of the NDA necessitated DEA's review and its own 
determination for the scheduling action (to first issue the IFR and 
subsequently to issue this final rule) in accordance with 21 U.S.C. 
811(b). DEA considered HHS' scientific and medical evaluation and 
scheduling recommendation, and all other relevant data and concurred 
with HHS' recommendation that remimazolam has low potential of abuse 
relative to substances in schedule III and therefore supported--and 
continues to support through this final rule--placement of remimazolam 
in schedule IV. DEA notes that under 21 U.S.C. 811(b), HHS's 
recommendation shall be binding on the Administrator of DEA (as 
delegated by the Attorney General) as to any scientific or medical 
considerations involved in three of the eight factors specified in 21 
U.S.C. 811(c) (i.e., factors pertaining to the substance's actual or 
relative potential for abuse, its history

[[Page 29508]]

and current pattern of abuse, and the scope, duration, and significance 
of abuse). Regarding the commenter's public safety concerns with 
remimazolam's placement in schedule IV, there is still significant 
oversight for schedule IV drugs. For both the IFR and this final rule, 
DEA made the findings required under 21 U.S.C. 812(b)(4) for the 
placement of remimazolam in schedule IV.

Requirements for Handling Remimazolam

    As indicated above, remimazolam has been a schedule IV controlled 
substance by virtue of an IFR issued by DEA in October 2020. Thus, this 
final rule does not alter the regulatory requirements applicable to 
handlers of remimazolam that have been in place since that time. 
Nonetheless, for informational purposes, we restate here those 
requirements. Remimazolam is subject to the Controlled Substances Act's 
(CSA) 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) remimazolam, or who desires to handle remimazolam, 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 remimazolam, and is not 
registered with DEA, must submit an application for registration and 
may not continue to handle remimazolam unless 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. These 
registration requirements, however, are not applicable to patients (end 
users) who possess remimazolam pursuant to a lawful prescription.
    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 remimazolam or may transfer all quantities 
of remimazolam to a person registered with DEA in accordance with 21 
CFR part 1317, in additional to all other applicable Federal, State, 
local, and tribal laws.
    3. Security. Remimazolam is subject to schedule III-V security 
requirements for DEA registrants and it must be handled and stored in 
accordance with 21 CFR 1301.71-1301.77. Non-practitioners handling 
remimazolam 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 remimazolam must comply with 21 U.S.C. 825 and 
958(e), and be in accordance with 21 CFR part 1302.
    5. Inventory. Since October 6, 2020, every DEA registrant who 
possesses any quantity of remimazolam must take an inventory of 
remimazolam on hand, pursuant to 21 U.S.C. 827 and 958, 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 remimazolam, 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 1317.
    7. Prescriptions. All prescriptions for remimazolam, or products 
containing remimazolam, 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 remimazolam 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 
remimazolam 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 remimazolam not authorized 
by, or in violation of, the CSA or its implementing regulations, is 
unlawful, and may subject the person to administrative, civil, and/or 
criminal sanctions.

Regulatory Analyses

Administrative Procedure Act

    This final rule, without change, affirms the amendment made by the 
IFR 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 IFR 
scheduling the drug within 90 days. Additionally, subsection (j) 
specifies that the rulemaking shall become immediately effective as an 
IFR without requiring DEA to demonstrate good cause. DEA issued an IFR 
on October 6, 2020, and solicited public comments on that rule. 
Subsection (j) further provides that after giving interested persons 
the opportunity to comment and to request a hearing, the Attorney 
General, as delegated to the Administrator of DEA, shall issue a final 
rule in accordance with the scheduling criteria of 21 U.S.C. 811(b) 
through (d) and 812(b). 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 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 rulemaking does not have federalism implications warranting 
the application of E.O. 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.

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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.

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 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 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 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 (CRA)

    This rule is not a major rule as defined by the CRA, 5 U.S.C. 804. 
However, pursuant to the CRA, DEA is submitting a copy of this final 
rule to both Houses of Congress and to the Comptroller General.

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 IFR amending 21 CFR part 1308, which published on 
October 6, 2020 (85 FR 63014), is adopted as final without change.

D. Christopher Evans,
Acting Administrator.
[FR Doc. 2021-11512 Filed 6-1-21; 8:45 am]
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