Rule2021-11512
Schedules of Controlled Substances: Placement of Remimazolam in Schedule IV
Primary source
Metadata and text below are from the Federal Register, a public-domain U.S. government work. Always verify the official published version before relying on it for any legal matter.
Published
June 2, 2021
Effective
July 2, 2021
Issuing agencies
Justice DepartmentDrug Enforcement Administration
Abstract
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, isomers, and salts of isomers is possible, in schedule IV of the Controlled Substances Act.
Full Text
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<title>Federal Register, Volume 86 Issue 104 (Wednesday, June 2, 2021)</title>
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[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 [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[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,
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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
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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]
BILLING CODE 4410-09-P
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</html>Indexed from Federal Register on June 2, 2021.
This is legal information, not legal advice. Laws vary by jurisdiction and change frequently. Always verify current law with official sources and consult a licensed attorney in your jurisdiction for advice on your specific situation.