Federal Register / Vol. 87, No. 67 / Thursday, April 7, 2022 / Rules and Regulations 20313 

DEPARTMENT OF JUSTICE 

Drug Enforcement Administration 

21 CFR Part 1308 

[Docket No. DEA–949] 

Schedules of Controlled Substances: 

Placement of Daridorexant in Schedule 

IV 

AGENCY: Drug Enforcement 

Administration, Department of Justice. 

ACTION: Interim final rule with request 

for comments. 

SUMMARY: On January 7, 2022, the 

United States Food and Drug 

Administration approved a new drug 

application for QUIVIVIQ (daridorexant) 

tablets for the treatment of adult 

patients with insomnia characterized by 

difficulties with sleep onset and/or 

sleep maintenance. The Department of 

Health and Human Services provided 

the Drug Enforcement Administration 

(DEA) with a scheduling 

recommendation to place daridorexant 

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 daridorexant 

in schedule IV, including its salts, 

isomers, and salts of isomers whenever 

the existence of such salts, isomers, and 

salts of such isomers is possible within 

the specific chemical designation, 

thereby facilitating the commercial 

distribution of QUIVIVIQ as a lawful 

controlled substance. 

DATES: The effective date of this rule is 

April 7, 2022. Comments must be 

submitted electronically or postmarked 

on or before May 9, 2022. 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. 

Requests for hearing and waivers of 

an opportunity for a hearing or to 

participate in a hearing must be 

received on or before May 9, 2022. 

ADDRESSES: Interested persons may file 

written comments on this rulemaking in 

accordance with 21 U.S.C. 811(j)(3) and 

21 CFR 1308.43(g). To ensure proper 

handling of comments, please reference 

‘‘Docket No. DEA–949’’ 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. 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 electronic submissions 

are not necessary and are discouraged. 

Should you wish to mail a paper 

comment in lieu of an electronic 

comment, it should be sent via regular 

or express mail to: Drug Enforcement 

Administration, Attn: DEA Federal 

Register Representative/DPW, 8701 

Morrissette Drive, Springfield, VA 

22152. 

• Hearing requests: All requests for 

hearing and waivers of participation, 

together with a written statement of 

position on the matters of fact and law 

asserted in the hearing, must be sent to: 

Drug Enforcement Administration, Attn: 

Hearing Clerk/OALJ, 8701 Morrissette 

Drive, Springfield, Virginia 22152. All 

requests for hearing and waivers of 

participation should also be sent to: (1) 

Drug Enforcement Administration, Attn: 

Administrator, 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: 

Terrence L. Boos, Drug & Chemical 

Evaluation Section, Diversion Control 

Division, Drug Enforcement 

Administration; Telephone: (571) 362– 

3249. 

SUPPLEMENTARY INFORMATION: 

Posting of Public Comments 

All comments received in response to 

this docket are considered part of the 

public record. The Drug Enforcement 

Administration (DEA) will make 

comments available, unless reasonable 

cause is given, 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 

DEA to make it 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 DEA to make 

it 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. 

DEA will generally make available in 

publicly redacted form comments 

containing personal identifying 

information and confidential business 

information identified, as directed 

above. If a comment has so much 

confidential business information or 

personal identifying information that 

DEA cannot effectively redact it, DEA 

may not make available publicly all or 

part of that comment. 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 confidential as directed 

above. 

An electronic copy of this document 

and supplemental information to this 

interim final rule (IFR) are available at 

http://www.regulations.gov for easy 

reference. 

Request for Hearing or Appearance; 

Waiver 

Pursuant to 21 U.S.C. 811(a), this 

action is a formal rulemaking ‘‘on the 

record after opportunity for a hearing’’. 

Such proceedings are conducted 

pursuant to the provisions of the 

Administrative Procedure Act (APA), 5 

U.S.C. 551–559. 21 CFR 1308.41– 

1308.45; 21 CFR part 1316, subpart D. 

Interested persons may file requests for 

a hearing or notices of intent to 

participate in a hearing in conformity 

with the requirements of 21 CFR 

1308.44(a) or (b), and such requests 

must include a statement of the person’s 

interests in the proceeding and the 


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20314 Federal Register / Vol. 87, No. 67 / Thursday, April 7, 2022 / Rules and Regulations 

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. 

2NFLIS represents an important resource in 

monitoring illicit drug trafficking, including the 

diversion of legally manufactured pharmaceuticals 

into illegal markets. It systematically collects results 

from drug chemistry analyses conducted by State 

and local forensic laboratories. NFLIS data were 

queried on January 18, 2022. 

objections or issues, if any, concerning 

which the person desires to be heard. 21 

CFR 1316.47(a). Any interested person 

may file a waiver of an opportunity for 

a hearing or to participate in a hearing 

together with a written statement 

regarding the interested person’s 

position on the matters of fact and law 

involved in any hearing as set forth in 

21 CFR 1308.44(c). 

All requests for hearings and waivers 

of participation, together with a written 

statement of position on the matters of 

fact and law involved in such hearing, 

must be sent to DEA using the address 

information provided above. 

Background and Legal Authority 

Under the Controlled Substances Act 

(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 the Department of Health 

and Human Services (HHS) has advised 

DEA that an NDA has been submitted 

for a drug that has a stimulant, 

depressant, or hallucinogenic effect on 

the central nervous system (CNS), and 

that it appears that such drug has an 

abuse potential; and (2) the Secretary 

recommends that DEA control the drug 

in schedule II, III, IV, or V pursuant to 

21 U.S.C. 811(a) and (b). In these 

circumstances, DEA is required to issue 

an IFR 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 IFR 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

Subsection (j)(3) further provides that 

the IFR 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). 

Daridorexant, chemically known as 

[(S)-2-(5-chloro-4-methyl-1Hbenzo[d]imidazol-2-yl)-2- 

methylpyrrolidin-1-yl](5-methoxy-2- 

(2H-1,2,3-triazol-2- 

yl)phenyl)methanone, is a new 

molecular entity (NME) with CNS 

activity. Daridorexant is a dual orexin 

receptor antagonist that inhibits the 

orexin neuropeptide-induced activation 

of the orexin receptor type 1 (OX1R) and 

orexin receptor type 2 (OX2R) subtypes. 

Daridorexant shares chemical structure 

and pharmacological mechanism of 

action with certain schedule IV CNS 

depressants such as suvorexant and 

lemborexant. 

On January 8, 2021, Idorsia 

Pharmaceuticals, Ltd (Sponsor) 

submitted an NDA to FDA for 

QUIVIVIQ (daridorexant) tablets for use 

as a treatment of adult patients with 

insomnia, characterized by difficulties 

with sleep onset and/or sleep 

maintenance. On January 7, 2022, DEA 

received notification that FDA, on the 

same date, approved this NDA. The 

recommended dosage is 25–50 mg once 

per night, taken orally within 30 

minutes before going to bed, with at 

least seven hours remaining prior to 

planned awakening. 

Determination To Schedule 

Daridorexant 

On December 22, 2021, DEA received 

from HHS a scientific and medical 

evaluation entitled ‘‘Basis for the 

Recommendation to Control 

Daridorexant 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 daridorexant, along with 

HHS’s recommendation to control 

daridorexant 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 daridorexant 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’ scheduling 

recommendation, the approval of the 

NDA by HHS/FDA, and DEA’s 

determination, DEA is issuing this IFR 

to schedule daridorexant 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–949.’’ 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 

Daridorexant is an NME that has not 

been marketed in the United States or 

any country; evidence regarding its 

diversion, illicit manufacturing, or 

deliberate ingestion is lacking. There are 

no reports of law enforcement 

encounters of daridorexant in the 

National Forensic Laboratory 

Information System (NFLIS) database.2

However, daridorexant is related in 

action to schedule IV depressants such 

as suvorexant and lemborexant. It is 

thus reasonable to assume that 

daridorexant may be diverted from 

legitimate channels, used contrary to or 

without medical advice, and otherwise 

abused so as to create hazards to the 

users and to the safety of the community 

to an extent similar to that of schedule 

IV CNS depressants. In clinical studies, 

daridorexant produced abuse-related 

effects in humans similar to suvorexant 

and zolpidem (schedule IV sedatives) 

and shares pharmacological mechanism 

of action similar to suvorexant and 

lemborexant; thus, it is likely to be 

abused for its sedative effects contrary 

to medical advice. 

2. Scientific Evidence of Its 

Pharmacological Effects, if Known 

Daridorexant shares pharmacological 

profiles with other dual orexin receptor 

antagonists such as suvorexant and 

lemborexant, schedule IV CNS 

depressants. Data from the orexin 

binding studies demonstrated that 

daridorexant behaved as an 

insurmountable antagonist at the dual 

orexin receptors (OXIR and OX2R). 


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Daridorexant is similar to suvorexant in 

its potency and duration of action at 

OX1R; however, it is more potent and 

has double the occupancy time as 

suvorexant at OX2R. 

In animal studies, oral doses of 

daridorexant (100, 300, and 1000 mg/kg) 

produced transient decrease in rectally 

measured body temperature and 

increased incidence of whole-body 

tremors. Dose-dependent decline in 

activity was observed in unstimulated 

rats. In a study conducted to measure 

locomotor activity following 

daridorexant administration, rats given 

single oral dose of 300 mg/kg showed 

decline in locomotor activity when 

compared to the vehicle control group. 

Daridorexant’s reinforcing properties 

were assessed by determining whether 

self-administration behavior was 

maintained when the drug was 

substituted for cocaine. Data from this 

study showed that rats self-administered 

cocaine (0.8 mg/kg/infusion), but doses 

of 0.1, 0.3, and 1 mg/kg/infusion of 

daridorexant produced a significantly 

lower mean number of active lever 

presses. 

A randomized, double-blind, doubledummy, active-and placebo-controlled, 

6-way cross-over study was conducted 

to determine the abuse potential of 

single oral doses of daridorexant. 

Suvorexant (150 mg) and Zolpidem (30 

mg) served as the positive controls. 

Subjects received daridorexant at 

therapeutic (50 mg) and 

supratherapeutic (100 and 150 mg) 

doses. Bipolar visual analog scale (VAS) 

for Drug-Liking (0–100) served as the 

primary end. A score of 0 described a 

drug-disliking response; a score of 50 

represented a neutral response, while a 

score of 100 described a strong drug 

liking. Drug liking scores following 

supratherapeutic doses (100 and 150 

mg) of daridorexant showed statistically 

significant increases as compared to 

placebo on positive subjective measures 

(VAS measures for Drug Liking, Take 

Drug Again, Overall Drug Liking, High, 

and Good Drug Effects) and were 

statistically similar to those following 

suvorexant and zolpidem. Further, 

using a Drowsiness/Alertness VAS and 

an observer assessment of alertness/ 

sedation, daridorexant’s sedative 

properties were assessed. Both measures 

demonstrate that similar to suvorexant 

and zolpidem, daridorexant elicits 

drowsiness and sedation. 

Data from Phase 1 clinical safety 

studies showed that daridorexant (5– 

200 mg) administered to 478 subjects 

produced somnolence in 52.7 percent 

(252), fatigue in 10.9 percent (52), and 

disturbances in attention in 3.8 percent 

(18) of subjects, respectively. 

Daridorexant at every dose produced 

somnolence at a rate that is 2- to 3-fold 

higher than that reported in the placebotreated group. In two Phase 2 studies 

conducted to evaluate the efficacy and 

safety of daridorexant in subjects with 

insomnia disorder (one with adults 

(aged 18–64 years) at doses of 5–50 mg 

and the other with the elderly (≥65 

years) at doses of 10–50 mg), 

daridorexant treatment led to reports of 

somnolence that exceeded reports of 

other effects that may be associated with 

abuse potential, including fatigue (5 (2.1 

percent)) and dizziness (3 (1.3 percent). 

In three Phase 3 studies, which were 

conducted as confirmatory studies in 

adults and elderly subjects with 

insomnia disorder and were similarly 

designed to the two Phase 2 studies, the 

treatment-emergent adverse effects with 

the highest number of reports were 

somnolence (38 (2.14 percent)), fatigue 

(34 (1.91 percent)), and dizziness (26 

(1.46 percent)). These types of reports 

were similar to those reported in the 

Phase 1 and 2 studies. The reported 

adverse events from the Phase 1, 2, and 

3 studies demonstrate there were no 

significant abuse-related signals in these 

studies. 

Daridorexant, similar to schedule IV 

drugs such as suvorexant and zolpidem, 

has sedative effects. In a human abuse 

potential (HAP) study, daridorexant 

produced abuse-related effects in 

humans similar to those of suvorexant 

and zolpidem. The abuse-related 

neuropharmacology profile of 

daridorexant is similar to that of 

schedule IV CNS depressants, such as 

suvorexant and lemborexant, and is 

consistent with its mechanism of action 

as a dual orexin receptors antagonist. 

3. The State of Current Scientific 

Knowledge Regarding the Drug or Other 

Substance 

Daridorexant, chemically known as 

[(S)-2-(5-chloro-4-methyl-1Hbenzo[d]imidazol-2-yl)-2- 

methylpyrrolidin-1-yl](5-methoxy-2- 

(2H-1,2,3-triazol-2- 

yl)phenyl)methanone, is an NME. It is 

soluble in acidic water and slightly 

soluble in ethanol. It has one 

stereoisomer with one chiral center. The 

drug product is manufactured in tablet 

dose strengths that contain 25 mg and 

50 mg of the active ingredient (i.e., 

daridorexant) and a series of excipients 

to aid in taste and tablet disintegration. 

The excipients in the tablet have no 

known abuse liability. Daridorexant 

plasma exposure is dose proportional 

from 25 mg to 50 mg with an absolute 

bioavailability of 62 percent, and has 

consistent pharmacokinetic profile 

following multiple-dose and single-dose 

administration with no accumulation. 

As discussed in the background 

section, daridorexant has an accepted 

medical use in the United States. 

4. Its History and Current Pattern of 

Abuse 

There is no information on the history 

and current pattern of abuse for 

daridorexant, since it has not been 

marketed, legally or illegally, in the 

United States or any country. There is 

no evidence of diversion of daridorexant 

that has been distributed for research, 

such as for clinical trials. Data from 

preclinical and clinical studies indicate 

that the abuse potential of daridorexant 

is similar to that of schedule IV CNS 

depressants such as suvorexant and 

lemborexant. Consistent with the fact 

that daridorexant is an NME; NFLIS 

database had no records of encounters 

by the law enforcement. 

The pharmacological mechanism of 

action of daridorexant as a dual orexin 

receptor antagonist suggests that its 

pattern of abuse would be similar to 

schedule IV depressants with a similar 

mechanism of action, such as 

suvorexant and lemborexant. 

5. The Scope, Duration, and 

Significance of Abuse 

Data from preclinical and clinical 

studies showed that daridorexant has an 

abuse potential similar to that of the 

schedule IV depressants such as 

suvorexant and zolpidem. Thus, 

daridorexant, similar to these schedule 

IV substances, will have low potential 

for abuse relative to drugs and 

substances in schedule III. A search by 

DEA of the NFLIS database found no 

evidence of law enforcement encounters 

of daridorexant in the United States. 

Because daridorexant has a mechanism 

of action similar to schedule IV drugs 

suvorexant and lemborexant, it is likely 

that upon availability of daridorexant in 

the market, it will be abused similar to 

these schedule IV depressants. 

6. What, if any, Risk There Is to the 

Public Health 

The public health risk associated with 

daridorexant is largely due to its abuse 

potential. Data from preclinical and 

clinical studies showed that 

daridorexant has abuse potential similar 

to that of schedule IV depressants 

zolpidem and suvorexant. Therefore, 

upon availability for marketing, it is 

likely to pose a public health risk to a 

degree similar to these schedule IV 

depressants. Data from clinical trials 

showed that daridorexant has rewarding 

and depressant effects. The abuse of 

daridorexant may present risks to the 


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20316 Federal Register / Vol. 87, No. 67 / Thursday, April 7, 2022 / Rules and Regulations 

public health at a level similar to those 

associated with the abuse of schedule IV 

CNS depressants. 

7. Its Psychic or Physiological 

Dependence Liability 

Data obtained from a HAP study 

demonstrate that similar to suvorexant 

and zolpidem, daridorexant produced 

subjective responses to measures such 

as Drug Liking, Overall Drug Liking, 

Good Drug Effects, High, and Take Drug 

Again; indicative of psychological 

effects. HHS states that the data suggest 

daridorexant can produce psychic 

dependence similar to zolpidem and 

suvorexant, schedule IV depressants. 

Results from a physiologic 

dependence study conducted in rats 

demonstrate that oral doses (0, 20, or 

200 mg/kg/day) of daridorexant 

administered for 28-days followed by a 

14-days discontinuation period did not 

produce alterations in physiological, 

neurobehavioral, or locomotor 

parameters during the discontinuation 

Phase of the study. Physical dependence 

signs were not observed in clinical 

studies after discontinuation of 

treatment in Phase 3 studies. 

Data from animal studies and clinical 

trials demonstrate that chronic 

administration of daridorexant did not 

produce withdrawal signs or symptoms 

upon discontinuation. Daridorexant 

does not produce physical dependence. 

8. Whether the Substance Is an 

Immediate Precursor of a Substance 

Already Controlled Under the CSA 

Daridorexant 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 and 

scheduling recommendation provided 

by HHS, and its own eight-factor 

analysis, DEA has determined that these 

facts and all relevant data constitute 

substantial evidence of potential for 

abuse of daridorexant. As such, DEA 

hereby schedules daridorexant 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 

Administrator of DEA (Administrator), 

pursuant to 21 U.S.C. 812(b)(4), finds 

that: 

(1) Daridorexant has a low potential 

for abuse relative to the drugs or other 

substances in Schedule III. 

Daridorexant, similar to schedule IV 

depressants such as suvorexant and 

lemborexant, is an orexin receptor 

antagonist. It produced sedation in 

general behavioral and locomotor 

studies. In a HAP study, oral 

administration of therapeutic (50 mg) 

and supratherapeutic doses (100 and 

150 mg) of daridorexant produced 

increases in positive subjective 

measures such as Drug Liking, Overall 

Drug Liking, Good Drug Effects, High, 

and Take Drug Again that were 

statistically greater than those produced 

by placebo. These subjective responses 

following daridorexant were statistically 

similar to those produced by the 

positive control drugs that are schedule 

IV depressant such as zolpidem and 

suvorexant. These data show that 

daridorexant has an abuse potential that 

is similar to the schedule IV drugs 

zolpidem and suvorexant. Because 

daridorexant is similar to suvorexant 

and zolpidem in its abuse potential, 

daridorexant has a low potential for 

abuse relative to the drugs or other 

substances in schedule III. 

(2) Daridorexant has a currently 

accepted medical use in treatment in 

the United States. 

FDA recently approved the NDA for 

daridorexant as an oral treatment for 

adult patients with insomnia 

characterized by difficulties with sleep 

onset and/or sleep maintenance. Thus, 

daridorexant has a currently accepted 

medical use in treatment in the United 

States. 

(3) Abuse of daridorexant may lead to 

limited physical dependence or 

psychological dependence relative to 

the drugs or other substances in 

schedule III. 

Data from both preclinical and 

clinical studies demonstrate that 

discontinuation of daridorexant was not 

associated with withdrawal symptoms 

indicative of physical dependence. 

Because daridorexant produced positive 

subjective responses in a HAP study 

similar to those of zolpidem and 

suvorexant (both schedule IV drugs), it 

is likely that daridorexant can produce 

psychic dependence to an extent that is 

similar to these schedule IV substances. 

Thus, abuse of daridorexant may lead to 

limited physical or psychological 

dependence relative to the drugs or 

other substances in schedule III. 

Based on these findings, the 

Administrator concludes that 

daridorexant warrants control in 

schedule IV of the CSA. 21 U.S.C. 

812(b)(4). 

Requirements for Handling 

Daridorexant 

Daridorexant is subject to the CSA’s 

schedule IV regulatory controls and 

administrative, civil, and criminal 

sanctions applicable to the manufacture, 

distribution, reverse distribution, 

dispensing, importing, exporting, 

research, and conduct of instructional 

activities and chemical analysis with, 

and possession involving schedule IV 

substances, including the following: 

1. Registration. Any person who 

handles (manufactures, distributes, 

reverse distributes, dispenses, imports, 

exports, engages in research, or 

conducts instructional activities or 

chemical analysis with, or possesses), or 

who desires to handle, daridorexant 

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 

daridorexant and is not registered with 

DEA must submit an application for 

registration and may not continue to 

handle daridorexant unless DEA has 

approved that application, 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 daridorexant pursuant to a 

lawful prescription. 

2. Disposal of stocks. Any person 

unwilling or unable to obtain a schedule 

IV registration must surrender all 

quantities of currently held 

daridorexant, or may transfer all 

quantities of currently held 

daridorexant to a person registered with 

DEA. Daridorexant is required to be 

disposed of in accordance with 21 CFR 

part 1317, in addition to all other 

applicable Federal, state, local, and 

tribal laws. 

3. Security. Daridorexant 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 daridorexant must also comply 

with the employee screening 

requirements of 21 CFR 1301.90– 

1301.93. These requirements, however, 

are not applicable to patients (end users) 

who possess daridorexant pursuant to a 

lawful prescription. 

4. Labeling and Packaging. All labels, 

labeling, and packaging for commercial 

containers of daridorexant 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 


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daridorexant must take an inventory of 

daridorexant on hand, pursuant to 21 

U.S.C. 827 and 958, and in accordance 

with 21 CFR 1304.03, 1304.04, and 

1304.11(a) and (d). 

Any person who registers with DEA to 

handle daridorexant must take an initial 

inventory of all stocks of controlled 

substances (including daridorexant) 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(a) 

and (b). 

After the initial inventory, every DEA 

registrant must take an inventory of all 

stocks of controlled substances 

(including daridorexant) 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. 

These requirements, however, are not 

applicable to patients (end users) who 

possess daridorexant pursuant to a 

lawful prescription. 

6. Records and Reports. DEA 

registrants must maintain records and 

submit reports for daridorexant, 

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 

daridorexant, or products containing 

daridorexant, 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 

daridorexant 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 (FDCA), as applicable, 

and the CSA. 

9. Importation and Exportation. All 

importation and exportation of 

daridorexant must comply with 21 

U.S.C. 952, 953, 957, and 958, and in 

accordance with 21 CFR part 1312. 

10. Liability. Any activity involving 

daridorexant 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 

IFR 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 IFR 

without requiring DEA to demonstrate 

good cause. 

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 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 

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 is not 

required to publish a general notice of 

proposed rulemaking. Consequently, the 

RFA does not apply to this IFR. 

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 

This rule is not a major rule as 

defined by the Congressional Review 

Act (CRA), 5 U.S.C. 804. However, 

pursuant to the CRA, DEA is submitting 

a copy of this IFR 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 

■ 1. The authority citation for 21 CFR 

part 1308 continues to read as follows: 


khammond on DSKJM1Z7X2PROD with RULES
20318 Federal Register / Vol. 87, No. 67 / Thursday, April 7, 2022 / Rules and Regulations 

1As set forth in a memorandum of understanding 

entered into by the Food and Drug Administration 

(FDA) and the National Institute on Drug Abuse 

(NIDA), FDA acts as the lead agency within HHS 

in carrying out the Secretary’s scheduling 

responsibilities under the CSA, with the 

concurrence of NIDA. 50 FR 9518, Mar. 8, 1985. 

The Secretary of HHS has delegated to the Assistant 

Secretary for Health of HHS the authority to make 

domestic drug scheduling recommendations. 58 FR 

35460, July 1, 1993. 

Authority: 21 U.S.C. 811, 812, 871(b), 

956(b) unless otherwise noted. 

■ 2. In § 1308.14: 

■ a. Redesignate paragraphs (c)(16) 

through (58) as (c)(17) through (59); and 

■ b. Add new paragraph (c)(16). 

■ The addition reads as follows: 

§ 1308.14 Schedule IV. 

* * * * * 

(c) * * * 

(16) Daridorexant ......................................... 2410 

* * * * * 

Anne Milgram, 

Administrator. 

[FR Doc. 2022–07322 Filed 4–6–22; 8:45 am] 

BILLING CODE 4410–09–P 

DEPARTMENT OF JUSTICE 

Drug Enforcement Administration 

21 CFR Part 1308 

[Docket No. DEA–491] 

Schedules of Controlled Substances: 

Placement of 5F-EDMB-PINACA, 5FMDMB-PICA, FUB-AKB48, 5F-CUMYLPINACA, and FUB-144 in Schedule I 

AGENCY: Drug Enforcement 

Administration, Department of Justice. 

ACTION: Final rule. 

SUMMARY: By this rule, the Drug 

Enforcement Administration 

permanently places five synthetic 

cannabinoids, as identified in this final 

rule, in schedule I of the Controlled 

Substances Act. These five substances 

are currently listed in schedule I 

pursuant to a temporary scheduling 

order. As a result of this rule, the 

regulatory controls and administrative, 

civil, and criminal sanctions applicable 

to schedule I controlled substances on 

persons who handle (manufacture, 

distribute, import, export, engage in 

research, conduct instructional 

activities or chemical analysis, or 

possess), or propose to handle these five 

specified controlled substances will 

continue to apply. 

DATES: Effective April 7, 2022. 

FOR FURTHER INFORMATION CONTACT: 

Terrence L. Boos, Drug & Chemical 

Evaluation Section, Diversion Control 

Division, Drug Enforcement 

Administration; Telephone: (571) 362– 

3249. 

SUPPLEMENTARY INFORMATION: 

In this final rule, the Drug 

Enforcement Administration (DEA) is 

permanently scheduling the following 

five controlled substances in schedule I 

of the Controlled Substances Act (CSA), 

including their salts, isomers, and salts 

of isomers whenever the existence of 

such salts, isomers, and salts of isomers 

is possible within the specific chemical 

designation: 

• Ethyl 2-(1-(5-fluoropentyl)-1Hindazole-3-carboxamido)-3,3- 

dimethylbutanoate (other name: 5FEDMB-PINACA), 

• Methyl 2-(1-(5-fluoropentyl)-1Hindole-3-carboxamido)-3,3- 

dimethylbutanoate (other names: 5FMDMB-PICA; 5F-MDMB-2201), 

• N-(Adamantan-1-yl)-1-(4- 

fluorobenzyl)-1H-indazole-3- 

carboxamide (other names: FUB-AKB48; 

FUB-APINACA; AKB48 N-(4- 

fluorobenzyl)), 

• 1-(5-Fluoropentyl)-N-(2- 

phenylpropan-2-yl)-1H-indazole-3- 

carboxamide (other names: 5F-CUMYLPINACA; SGT-25), and 

• (1-(4-Fluorobenzyl)-1H-indol-3- 

yl)(2,2,3,3- 

tetramethylcyclopropyl)methanone 

(other name: FUB-144). 

Legal Authority 

The CSA provides that issuing, 

amending, or repealing of the 

scheduling of any drug or other 

substance may be initiated by the 

Attorney General (1) on his own motion; 

(2) at the request of the Secretary of the 

Department of Health and Human 

Services (HHS); 1 or (3) on the petition 

of any interested party. 21 U.S.C. 811(a). 

The then-Acting Administrator of DEA 

(as delegated by the Attorney General to 

the Administrator of DEA) initiated this 

action on his own motion, and is 

supported by, inter alia, a 

recommendation from the then-Acting 

Assistant Secretary for Health of HHS 

and an evaluation of all relevant data by 

DEA. The regulatory controls and 

administrative, civil, and criminal 

sanctions of schedule I controlled 

substances on any person who handles 

(manufactures, distributes, imports, 

exports, engages in research, or 

conducts instructional activities or 

chemical analysis with, or possesses) or 

proposes to handle 5F-EDMB-PINACA, 

5F-MDMB-PICA, FUB-AKB48, 5FCUMYL-PINACA, and FUB-144 will 

continue to apply as a result of this 

action. 

Background 

On April 16, 2019, DEA published an 

order in the Federal Register amending 

21 CFR 1308.11(h) to temporarily place 

ethyl 2-(1-(5-fluoropentyl)-1H-indazole3-carboxamido)-3,3-dimethylbutanoate 

(trivial name: 5F-EDMB-PINACA); 

methyl 2-(1-(5-fluoropentyl)-1H-indole3-carboxamido)-3,3-dimethylbutanoate 

(trivial name: 5F-MDMB-PICA); N- 

(adamantan-1-yl)-1-(4-fluorobenzyl)-1Hindazole-3-carboxamide (trivial names: 

FUB-AKB48; FUB-APINACA; AKB48 N- 

(4-FLUOROBENZYL)); 1-(5- 

fluoropentyl)-N-(2-phenylpropan-2-yl)- 

1H-indazole-3-carboxamide (trivial 

names: 5F-CUMYL-PINACA; SGT-25); 

and (1-(4-fluorobenzyl)-1H-indol-3- 

yl)(2,2,3,3- 

tetramethylcyclopropyl)methanone 

(trivial name: FUB-144) in schedule I of 

the CSA pursuant to the temporary 

scheduling provisions of 21 U.S.C. 

811(h). 84 FR 15505. That temporary 

scheduling order took effect on the date 

of publication, and was based on 

findings by the then-Acting 

Administrator of DEA that the 

temporary scheduling of these five 

synthetic cannabinoids (SCs) was 

necessary to avoid an imminent hazard 

to the public safety pursuant to 21 

U.S.C. 811(h)(1). 

On March 30, 2021, DEA published a 

notice of proposed rulemaking (NPRM) 

in the Federal Register to permanently 

control the five SCs in schedule I of the 

CSA. 86 FR 16553. On March 31, 2021, 

DEA published an order to extend the 

temporary scheduling of the five SCs by 

one year, until April 16, 2022. 86 FR 

16669. 

DEA and HHS Eight Factor Analyses 

On February 26, 2021, HHS provided 

DEA with a scientific and medical 

evaluation and scheduling 

recommendation, prepared by the Food 

and Drug Administration (FDA), 

entitled ‘‘Basis for the Recommendation 

to Place Ethyl 2-(1-(5-fluoropentyl)-1Hindazole-3-carboxamido)-3,3- 

dimethylbutanoate [5F-EDMB-PINACA]; 

methyl 2-(1-(5-fluoropentyl)-1H-indole3-carboxamido)-3,3-dimethylbutanoate 

[5F-MDMB-PICA]; N-(adamantan-1-yl)- 

1-(4-fluorobenzyl)-1H-indazole-3- 

carboxamide [FUB-AKB48;FUBAPINACA; AKB48 N-(4-fluorobenzyl)]; 

1-(5-fluoropentyl)-N-(2-phenylpropan-2- 

yl)-1H-indazole-3-carboxamide [5FCUMYL-PINACA; SGT-25]; and (1-(4- 

fluorobenzyl)-1H-indol-3-yl)(2,2,3,3- 

tetramethylcyclopropyl)methanone 

[FUB-144; FUB-UR-144] and Their Salts, 

Isomers, and Salts of Isomers in 

Schedule I of the Controlled Substances 

Act.’’ 


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