[Federal Register Volume 85, Number 194 (Tuesday, October 6, 2020)]
[Rules and Regulations]
[Pages 63014-63019]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-19313]


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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: Interim final rule with request for comments.

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SUMMARY: On July 2, 2020, the U.S. Food and Drug Administration 
approved a new drug application for BYFAVO (remimazolam) for 
intravenous use. Remimazolam is chemically known as 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. The 
Department of Health and Human Services provided the Drug Enforcement 
Administration (DEA) with a scheduling recommendation to place 
remimazolam and its salts in schedule IV of the Controlled Substances 
Act (CSA). In accordance with the CSA, as amended by the Improving 
Regulatory Transparency for New Medical Therapies Act, DEA is hereby 
issuing an interim final rule placing 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 CSA.

DATES: The effective date of this rulemaking is October 6, 2020. 
Interested persons may file written comments on this rulemaking in 
accordance with 21 U.S.C. 811(j)(3) and 21CFR 1308.43(g). Electronic 
comments must be submitted, and written comments must be postmarked, on 
or before November 5, 2020. 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, together with a written statement of position 
on the matters of fact and law asserted in the hearing, must be 
received on or before November 5, 2020.

ADDRESSES: To ensure proper handling of comments, please reference 
``Docket No. DEA-658'' on all correspondence, including any 
attachments.
     Electronic comments: The Drug Enforcement Administration 
(DEA) 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.

[[Page 63015]]

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: Scott A. Brinks, Regulatory Drafting 
and Policy Support Section, Diversion Control Division, Drug 
Enforcement Administration; Mailing Address: 8701 Morrissette Drive, 
Springfield, Virginia 22152; Telephone: (571) 362-3261.

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 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 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 (HHS) 
and DEA 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 a 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. Such requests or notices must conform to the requirements of 
21 CFR 1308.44(a) or (b), and 1316.47 or 1316.48, as applicable, and 
include a statement of the person's interests in the proceeding and the 
objections or issues, if any, concerning which the person desires to be 
heard. Any waiver must conform to the requirements of 21 CFR 1308.44(c) 
and may include a written statement regarding the interested person's 
position on the matters of fact and law involved in any hearing.
    All requests for a hearing and waivers of participation must be 
sent to DEA using the address information provided above.

Background and Legal Authority

    Under the CSA, as amended in 2015 by the Improving Regulatory 
Transparency for New Medical Therapies Act (section 2(b) of Pub. L. 
114-89), DEA is required to commence an expedited scheduling action 
with respect to certain new drugs approved by the Food and Drug 
Administration (FDA). As provided in 21 U.S.C. 811(j), this expedited 
scheduling is required where both of the following conditions apply: 
(1) The Secretary of HHS has advised DEA that a New Drug Application 
(NDA) has been submitted for a drug that has a stimulant, depressant, 
or hallucinogenic effect on the central nervous system (CNS), and that 
it appears that such drug has an abuse potential; and (2) the Secretary 
of HHS recommends that DEA control the drug in schedule II, III, IV, or 
V pursuant to 21 U.S.C. 811(a) and (b). In these circumstances, DEA is 
required to issue an interim final rule controlling the drug within 90 
days.
    Subsection (j)(2) states that the 90-day timeframe starts the later 
of (1) the date DEA receives HHS' scientific and medical evaluation/
scheduling recommendation, or (2) the date DEA receives notice of the 
NDA approval by HHS. Subsection (j)(3) specifies that the rulemaking 
shall become immediately effective as an interim final rule without 
requiring DEA to demonstrate good cause therefore. 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)(3) 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 21 U.S.C. 
811(b) through (d) and 812(b).
    Remimazolam (4H-imidazol[1,2-a][1,4]benzodiazepine-4-propionic 
acid, 8-bromo-1-methyl-6-(2-pyridinyl)-(4S)-methyl ester, 
benzenesulfonate (1:1) or methyl 3-[(4S)-8-bromo-1-methyl-6-pyridin-2-
yl-4H-imidazo[1,2-a][1,4]benzodiazepin-4yl]propanoate benzenesulfonic 
acid), is a new molecular entity with CNS depressant properties. 
Remimazolam is an agonist at gamma-aminobutyric acid subtype A 
(GABAA) receptors. On April 5, 2019, Cosmo Technologies, 
Ltd. (Sponsor) submitted an NDA for BYFAVO (remimazolam) to FDA with a 
proposed dose of 5.0 mg (intravenous; i.v.) with supplemental doses of 
2.6 mg (i.v.). On July 2, 2020, DEA received notification that FDA, on 
the same date, approved the NDA for BYFAVO (remimazolam), under section 
505(c) of the Federal Food, Drug, and Cosmetic Act (FDCA), to be used 
as an i.v. treatment for the induction and maintenance of

[[Page 63016]]

procedural sedation in adults undergoing procedures lasting 30 minutes 
or less. In January 2020, remimazolam was approved for marketing in 
Japan for general anesthesia.\2\
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    \2\ Keam SJ (2020). Remimazolam: First Approval. Drugs; 
80(6):625-633.
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Determination To Schedule Remimazolam

    On July 10, 2020, DEA received from HHS a scientific and medical 
evaluation (dated April 15, 2020) entitled ``Basis for the 
Recommendation to Control Remimazolam and its Salts in Schedule IV of 
the Controlled Substances Act'' and a scheduling recommendation. 
Pursuant to 21 U.S.C. 811(b) and (c), this document contained an eight-
factor analysis of the abuse potential, legitimate medical use, and 
dependence liability of remimazolam, along with HHS's recommendation to 
control remimazolam and its salts under schedule IV of the CSA.
    In response, DEA reviewed the scientific and medical evaluation and 
scheduling recommendation provided by HHS, along with all other 
relevant data, and completed its own eight-factor review pursuant to 21 
U.S.C. 811(c). DEA concluded that remimazolam meets the 21 U.S.C. 
812(b)(4) criteria for placement in schedule IV of the CSA.
    Pursuant to subsection 811(j), and based on HHS' recommendation, 
NDA approval by HHS/FDA, and DEA's determination, DEA is issuing this 
interim final rule to schedule remimazolam as a schedule IV controlled 
substance under the CSA.
    Included below is a brief summary of each factor as analyzed by HHS 
and DEA, and as considered by DEA in its scheduling action. Please note 
that both DEA and HHS analyses are available in their entirety under 
``Supporting Documents'' in the public docket for this interim final 
rule at http://www.regulations.gov, under Docket Number ``DEA-658.'' 
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

    Remimazolam is a new molecular entity that has not been marketed in 
the United States, and was approved in Japan for general anesthesia in 
January 2020. Evidence regarding its diversion, illicit manufacturing, 
or deliberate ingestions is lacking. DEA notes that there are no 
reports for remimazolam in the National Forensic Laboratory Information 
System (NFLIS),\3\ which collects drug cases submitted to and analyzed 
by state and local forensic laboratories. There were also no reports in 
STARLiMS,\4\ DEA's laboratory drug evidence data system of record.
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    \3\ NFLIS represents an important resource in monitoring illicit 
drug trafficking, including the diversion of legally manufactured 
pharmaceuticals into illegal markets. NFLIS is a comprehensive 
information system that includes data from forensic laboratories 
that handle more than 96% of an estimated 1.0 million distinct 
annual State and local drug analysis cases. NFLIS includes drug 
chemistry results from completed analyses only. While NFLIS data is 
not direct evidence of abuse, it can lead to an inference that a 
drug has been diverted and abused. See 76 FR 77330, 77332, Dec. 12, 
2011. NFLIS data were queried April 23, 2020.
    \4\ On October 1, 2014, DEA implemented STARLiMS (a web-based, 
commercial laboratory information management system) to replace the 
System to Retrieve Information from Drug Evidence (STRIDE) as its 
laboratory drug evidence data system of record. DEA laboratory data 
submitted after September 30, 2014, are reposited in STARLiMS. 
STARLiMS data were queried May 5, 2020.
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    As stated by HHS, remimazolam is so related in action to depressant 
drugs such as benzodiazepines in schedule IV that it is reasonable to 
assume that there may be comparable diversions from legitimate 
channels, use contrary to or without medical advice, and capability of 
creating hazards to the users and to the safety of the community. 
Preclinical and clinical studies show that remimazolam has similar 
pharmacological mechanism of action as an agonist at the 
GABAA receptors as midazolam. Data gathered from general 
behavior studies indicate remimazolam produces a sedative effect, and 
similar abuse-related effects in humans and in animal studies to those 
of midazolam, a schedule IV depressant. It is likely that remimazolam 
has similar abuse potential and is likely to be abused for its 
depressant effects, contrary to medical advice.

2. Scientific Evidence of Its Pharmacological Effects, if Known

    Remimazolam shares similar pharmacological mechanism of action via 
GABAA receptor agonism as schedule IV benzodiazepines, such 
as midazolam. The GABAA receptor is a ligand-gated chloride 
ion channel consisting of five subunits and a central chloride channel. 
Benzodiazepines enhance the opening of the ligand-gated chloride 
channel and the influx of chloride.
    Remimazolam, similar to schedule IV benzodiazepines, has sedative 
activity in animals. Acute administration of remimazolam in rats 
elicited dose-dependent behaviors indicative of sedative and muscle 
relaxation properties of the drug. In a drug discrimination study using 
male rats previously trained to discriminate midazolam, remimazolam 
produced interoceptive cues that are similar to those of midazolam. 
Remimazolam was self-administered variably based on session duration. 
In the shorter-access paradigm (two-hour sessions), only two of four 
monkeys tested self-administered remimazolam, whereas for the longer-
access paradigm (24-hour sessions), all four monkeys self-administered 
remimazolam at a rate higher than placebo and pentobarbital, the 
reference drug (a schedule II or III depressant).\5\
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    \5\ The HHS review of remimazolam incorrectly stated that 
pentobarbital was a schedule IV substance. FDA/Controlled Substance 
Staff through an email correspondence confirmed that it was an 
inadvertent error in the HHS review. Pentobarbital is currently 
controlled as schedule II (21 CFR 1308.12(e)), or as schedule III if 
any material, compound, mixture, or preparation containing any 
quantity of pentobarbital having a depressant effect on the central 
nervous system (21 CFR 1308.13(c)(1)), or any suppository dosage 
form and its salts that are approved by FDA for marketing only as a 
suppository (21 CFR 1308.13(c)(2)).
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    In human abuse potential studies, remimazolam, in agreement with 
its mechanism of action as a GABAA receptor agonist, 
produced subjective responses and abuse-related neuropharmacology 
profile similar to that of midazolam, a schedule IV depressant.

3. The State of Current Scientific Knowledge Regarding the Drug or 
Other Substance

    Remimazolam is a new molecular entity. It is chemically known as 
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 as methyl 3-[(4S)-8-bromo-1-methyl-6-pyridin-2-yl-4H-imidazo[1,2-
a][1,4]benzodiazepin-4yl]propanoate benzenesulfonic acid. It is a white 
to off-white powder that is freely soluble in water. In preclinical 
studies, remimazolam, an ester based drug, is rapidly hydrolyzed by 
tissue esterases, primarily in the liver by carboxylesterase-1, and 
results in one inactive metabolite. In humans, acute administration of 
the proposed therapeutic dose (5 mg, i.v.) of remimazolam resulted in 
rapid onset sedative effects (one to three minutes), fast time to 
maximal plasma concentration (Tmax, nine minutes), and a 
short half-life (twenty minutes).

4. Its History and Current Pattern of Abuse

    There is no information on the history and current pattern of abuse 
for

[[Page 63017]]

remimazolam, since it has not been marketed, legally or illegally, in 
the United States, and only recently in Japan. HHS notes that the abuse 
potential of remimazolam is similar to that of schedule IV 
benzodiazepines. Therefore, if remimazolam were available for 
marketing, it is likely to be abused in a manner similar to schedule IV 
benzodiazepines, such as midazolam.
    DEA conducted a search of NFLIS and STARLiMS databases for 
remimazolam encounters. No records of encounters by law enforcement 
were identified in these databases, which is consistent with the fact 
that remimazolam is a new molecular entity.
    The pharmacological mechanism of action of remimazolam through 
GABAA receptor agonism suggests that its pattern of abuse 
would be similar to schedule IV depressants with a similar mechanism of 
action, such as midazolam.

5. The Scope, Duration, and Significance of Abuse

    Remimazolam is not marketed in the United States, legally or 
illegally, and marketed only recently in Japan. However, because of 
remimazolam's pharmacological similarities to schedule IV 
benzodiazepines, remimazolam, similar to these schedule IV substances, 
is likely to be abused when available in the market.

6. What, If Any, Risk There Is To the Public Health

    According to HHS, the public health risk associated with 
remimazolam is due to its abuse potential and is largely borne by the 
individual. Data from preclinical and clinical studies showed that 
remimazolam has abuse potential similar to that of the schedule IV 
depressant midazolam. In clinical studies when remimazolam was given to 
healthy individuals, adverse events such as euphoric mood and 
somnolence occurred; thus, remimazolam produced rewarding and 
depressant effects, as would be expected from a benzodiazepine. 
Therefore, upon availability for marketing, it is likely to pose a 
public health risk to a degree similar to schedule IV benzodiazepines, 
such as midazolam.

7. Its Psychic or Physiological Dependence Liability

    As described in the HHS review, the Sponsor conducted a study 
related to physical dependence liability produced by remimazolam in six 
cynomolgus monkeys (0.5, 0.75, and 1.0 mg/kg/h, continuous i.v. 
infusion for 28 days) and psychic dependence liability in 39 humans 
(doses tested 5 and 10 mg, i.v.).
    During extended daily dosing administrations lasting a period of 28 
days, all monkeys showed depressant signs, such as ataxia, slowed 
motion, and hyporeactivity. During the discontinuation phase, all 
monkeys showed withdrawal signs including: Facial apprehension, 
hyperirritability, piloerection, muscle rigidity, retching and 
vomiting, tremors, restlessness, and impaired motor activity. Decreases 
in food consumption and body weights were also observed. Severe 
withdrawal symptoms such as dissociation from the environment, systemic 
convulsions, and continuously prone position for 25 hours were observed 
in one monkey, and remimazolam administration lessened this withdrawal 
syndrome in this monkey. HHS concluded that remimazolam produces 
physical dependence, as evidenced by the withdrawal syndrome observed 
after its chronic administration was discontinued.
    Remimazolam produced positive subjective responses to ratings of 
Drug Liking, Overall Drug Liking, Good Drug Effects, and Take Drug 
Again in a human abuse potential study. The responses were 
significantly higher than the placebo and similar to midazolam, a 
schedule IV depressant. HHS concluded that remimazolam can produce 
psychic dependence to a similar extent as midazolam.

8. Whether the Substance is an Immediate Precursor of a Substance 
Already Controlled Under the CSA

    Remimazolam is not an immediate precursor of any controlled 
substance, as defined by 21 U.S.C. 802(23).
    Conclusion: After considering the scientific and medical evaluation 
conducted by HHS, HHS's recommendation, and its own eight-factor 
analysis, DEA has determined that these facts and all relevant data 
constitute substantial evidence of potential for abuse of remimazolam. 
As such, DEA hereby schedules remimazolam 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 HHS and review of all available data, 
the Acting Administrator of DEA, pursuant to 21 U.S.C. 812(b)(4), finds 
that:

1. Remimazolam Has a Low Potential for Abuse Relative to the Drugs or 
Other Substances in Schedule III.

    Remimazolam, similar to that of the schedule IV drug midazolam, is 
an agonist at GABAA receptors. Remimazolam produced 
depressant effects in general behavior assessments, and generalized to 
midazolam (schedule IV) in a drug discrimination study in animals, 
demonstrating it has GABAA receptor agonist properties. In a 
human abuse potential study, remimazolam at the therapeutic and supra-
therapeutic doses produced positive subjective responses such as Drug 
Liking, Overall Drug Liking, Good Drug Effects, and Take Drug Again 
similar to those of midazolam (schedule IV) and significantly higher 
than placebo. Furthermore, data from other clinical studies show that 
remimazolam produced abuse-related adverse events, namely euphoria and 
somnolence. Because remimazolam is similar to midazolam (schedule IV) 
in its abuse potential, remimazolam has a lower potential for abuse 
relative to the drugs or other substances in schedule III.

2. Remimazolam Has a Currently Accepted Medical Use in the United 
States.

    FDA recently approved the NDA for BYFAVO (remimazolam) injection 
for use in the induction and maintenance of procedural sedation in 
adults undergoing procedures lasting 30 minutes or less. Thus, 
remimazolam has a currently accepted medical use for treatment in the 
United States.

3. Remimazolam May Lead To Limited Physical Dependence or Psychological 
Dependence Relative to the Drugs or Other Substances in Schedule III.

    Remimazolam shares a similar pharmacology profile with 
benzodiazepine drugs. Abrupt discontinuation of benzodiazepines is 
associated with withdrawal symptoms. Remimazolam produced withdrawal 
symptoms after abrupt discontinuation in monkeys, indicative of 
physical dependence, similar to that of benzodiazepines. In addition, 
remimazolam produced positive subjective responses and euphoria-related 
adverse events in a human abuse potential study. It is likely that 
remimazolam can produce psychic dependence similar to midazolam. Thus, 
abuse of remimazolam may lead to limited physical or psychological 
dependence relative to the drugs or other substances in schedule III of 
the CSA.

[[Page 63018]]

    Based on these findings, the Acting Administrator of DEA concludes 
that remimazolam warrants control in schedule IV of the CSA. 21 U.S.C. 
812(b)(4).

Requirements for Handling Remimazolam

    Remimazolam 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 intends to handle (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 currently handles or 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.
    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 and 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. 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.
    Any person who becomes registered with DEA to handle remimazolam 
must take an initial inventory of all stocks of controlled substances 
(including remimazolam) 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 a new 
inventory of all stocks of controlled substances (including 
remimazolam) 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 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 FDCA and 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

    Section 553 of the APA (5 U.S.C. 553) generally requires notice and 
comment for rulemakings. However, 21 U.S.C. 811(j) provides that in 
cases where a certain new drug is (1) approved by HHS, under section 
505(c) of the FDCA and (2) HHS recommends control in CSA schedule II-V, 
DEA shall issue an interim final rule scheduling the drug within 90 
days. As stated in the legal authority section, the 90-day time frame 
is the later of: (1) the date DEA receives HHS's scientific and medical 
evaluation/scheduling recommendation, or (2) the date DEA receives 
notice of the NDA approval by HHS. Additionally, subsection (j) 
specifies that the rulemaking shall become immediately effective as an 
interim final rule without requiring DEA to demonstrate good cause.
    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 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.
    This interim final rule is not an E.O. 13771 regulatory action 
pursuant to E.O. 12866 and OMB guidance.\6\
---------------------------------------------------------------------------

    \6\ 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).
---------------------------------------------------------------------------

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.

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

[[Page 63019]]

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. Under 21 U.S.C. 811(j), DEA is not required to publish a 
general notice of proposed rulemaking. Consequently, the RFA 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., 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 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 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 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 United States-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 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, 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), 956(b) unless otherwise 
noted.


0
2. In Sec.  1308.14:
0
a. Redesignate paragraphs (c)(51) through (c)(57) as (c)(52) through 
(c)(58); and
0
b. Add new paragraph (c)(51).
    The addition reads as follows:


Sec.  1308.14  Schedule IV.

* * * * *
    (c) * * *

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(51) Remimazolam...........................................        2846
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* * * * *

Timothy J. Shea,
Acting Administrator.
[FR Doc. 2020-19313 Filed 10-5-20; 8:45 am]
BILLING CODE 4410-09-P