Schedules of Controlled Substances: Placement of Suvorexant into Schedule IV, 8639-8644 [2014-03124]

Agencies

• Drug Enforcement Administration
• Department of Justice

[Federal Register Volume 79, Number 30 (Thursday, February 13, 2014)]
[Proposed Rules]
[Pages 8639-8644]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2014-03124]


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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Part 1308

[Docket No. DEA-381]


Schedules of Controlled Substances: Placement of Suvorexant into 
Schedule IV

AGENCY: Drug Enforcement Administration, Department of Justice.

ACTION: Notice of proposed rulemaking.

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SUMMARY: The Drug Enforcement Administration (DEA) proposes to place 
the substance suvorexant ([(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-
methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-
yl)phenyl]methanone), including its salts, isomers, and salts of 
isomers, into schedule IV of the Controlled Substances Act (CSA). This 
proposed scheduling action is pursuant to the CSA which requires that 
such actions be made on the record after opportunity for a hearing 
through formal rulemaking. If finalized, this action would impose the 
regulatory controls and administrative, civil, and criminal sanctions 
applicable to schedule IV controlled substances on persons who handle 
(manufacture, distribute, dispense, import, export, engage in research, 
conduct instructional activities, or possess), or propose to handle 
suvorexant.

DATES: Interested persons may file written comments on this proposal in 
accordance with 21 CFR 1308.43(g). Comments must be submitted 
electronically or postmarked on or before March 17, 2014. Commenters 
should be aware that the electronic Federal Docket Management System 
will not accept comments after midnight Eastern Time on the last day of 
the comment period.
    Interested persons, defined as those ``adversely affected or 
aggrieved by any rule or proposed rule issuable pursuant to section 201 
of the Act (21 U.S.C. 811),'' 21 CFR 1300.01, may file a request for 
hearing or waiver of participation pursuant to 21 CFR 1308.44 and in 
accordance with 21 CFR 1316.45, 1316.47, 1316.48, or 1316.49, as 
applicable. Requests for hearing, notices of appearance, and waivers of 
an opportunity for a hearing or to participate in a hearing must be 
received on or before March 17, 2014.

ADDRESSES: To ensure proper handling of comments, please reference 
``Docket No. DEA-381'' on all electronic and written correspondence. 
The 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. Go to www.regulations.gov and 
follow the on-line instructions at that site for submitting comments. 
An electronic copy of this document and supplemental information to 
this proposed rule are also available at www.regulations.gov for easy 
reference. Paper comments that duplicate electronic submissions are not 
necessary. All comments submitted to www.regulations.gov will be posted 
for public review and are part of the official docket record. Should 
you, however, wish to submit written comments, in lieu of electronic 
comments, they should be sent via regular or express mail to: Drug 
Enforcement Administration, Attention: DEA Federal Register 
Representative/ODW, 8701 Morrissette Drive, Springfield, VA 22152. All 
requests for a hearing and waivers of participation must be sent to: 
Drug Enforcement Administration, Attention: Hearing Clerk/LJ, 8701 
Morrissette Drive, Springfield, VA 22152.

FOR FURTHER INFORMATION CONTACT: Ruth A. Carter, Office of Diversion 
Control, Drug Enforcement Administration; Mailing Address: 8701 
Morrissette Drive, Springfield, VA 22152, Telephone: (202) 598-6812.

SUPPLEMENTARY INFORMATION: 

Posting of Public Comments

    Please note that all comments received in response to this docket 
are considered part of the public record and will be made available for 
public inspection online at www.regulations.gov. Such information 
includes personal identifying information (such as your name, address, 
etc.) voluntarily submitted by the commenter.
    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

[[Page 8640]]

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. If a comment 
has so much confidential business information that it cannot be 
effectively redacted, all or part of that comment may not be made 
publicly available. Comments containing personal identifying 
information or confidential business information identified as directed 
above will be made publicly available in redacted form.
    The Freedom of Information Act (FOIA) applies to all comments 
received. If you wish to personally inspect the comments and materials 
received or the supporting documentation the DEA used in preparing the 
proposed action, these materials will be available for public 
inspection by appointment. To arrange a viewing, please see the For 
Further Information Contact paragraph above.

Request for Hearing, Notice of Appearance at Hearing, or Waiver of 
Participation in Hearing

    Pursuant to the provisions of the CSA, 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. In accordance with 21 CFR 
1308.44(a)-(c), requests for a hearing, notices of appearance, and 
waivers of an opportunity for a hearing or to participate in a hearing 
may be submitted only by interested persons, defined as those 
``adversely affected or aggrieved by any rule or proposed rule issuable 
pursuant to section 201 of the Act (21 U.S.C. 811).'' 21 CFR 1300.01. 
Requests for hearing and notices of appearance 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 interest of the person 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 1316.49, including a written 
statement regarding the interested person's position on the matters of 
fact and law involved in any hearing.
    Please note that pursuant to 21 U.S.C. 811(a), the purpose and 
subject matter of a hearing held in relation to this rulemaking is 
restricted to: ``(A) find[ing] that such drug or other substance has a 
potential for abuse, and (B) mak[ing] with respect to such drug or 
other substance the findings prescribed by subsection (b) of section 
812 of [Title 21] for the schedule in which such drug is to be placed. 
. . .'' Requests for a hearing, notices of appearance at a hearing, and 
waivers of an opportunity for a hearing or to participate in a hearing 
must be submitted to the DEA using the address information provided 
above.

Legal Authority

    The DEA implements and enforces titles II and III of the 
Comprehensive Drug Abuse Prevention and Control Act of 1970, as 
amended. Titles II and III are referred to as the ``Controlled 
Substances Act'' and the ``Controlled Substances Import and Export 
Act,'' respectively, and are collectively referred to as the 
``Controlled Substances Act'' or the ``CSA'' for the purpose of this 
action. 21 U.S.C. 801-971. The DEA publishes the implementing 
regulations for these statutes in title 21 of the Code of Federal 
Regulations (CFR), parts 1300 to 1321. The CSA and its implementing 
regulations are designed to prevent, detect, and eliminate the 
diversion of controlled substances and listed chemicals into the 
illicit market while providing for the legitimate medical, scientific, 
research, and industrial needs of the United States. Controlled 
substances have the potential for abuse and dependence and are 
controlled to protect the public health and safety.
    Under the CSA, controlled substances are classified into one of 
five schedules based upon their potential for abuse, their currently 
accepted medical use, and the degree of dependence the substance may 
cause. 21 U.S.C. 812. The initial schedules of controlled substances 
established by Congress are found at 21 U.S.C. 812(c), and the current 
list of all scheduled substances is published at 21 CFR part 1308.
    Pursuant to 21 U.S.C. 811(a)(1), the Attorney General may, by rule, 
``add to such a schedule or transfer between such schedules any drug or 
other substance if he (A) finds that such drug or other substance has a 
potential for abuse, and (B) makes with respect to such drug or other 
substance the findings prescribed by [21 U.S.C. 812(b)] for the 
schedule in which such drug is to be placed. . . .'' Pursuant to 28 CFR 
0.100(b), the Attorney General has delegated this scheduling authority 
to the Administrator of the DEA who has further delegated this 
authority to the Deputy Administrator of the DEA under 28 CFR 0.104.
    The CSA provides that 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 Health and Human Services (HHS); or (3) on 
the petition of any interested party. 21 U.S.C. 811(a). If finalized, 
this action would impose the regulatory controls and administrative, 
civil, and criminal sanctions of schedule IV controlled substances for 
any person who handles suvorexant.

Background

    Suvorexant ([(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-
diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone), 
also known as MK-4305, is a new chemical entity developed for the 
treatment of insomnia. Suvorexant is a novel, first in class, orexin 
receptor antagonist with a mechanism of action distinct from any 
marketed drug. It acts via inhibition of the orexin 1 (OX1) and orexin 
2 (OX2) receptors. In pharmacological activity studies, suvorexant 
functioned as an antagonist as demonstrated by its ability to block 
agonist-induced calcium (Ca\2+\) release.

Proposed Determination to Schedule Suvorexant

    Pursuant to 21 U.S.C. 811(a), proceedings to add a drug or 
substance to those controlled under the CSA may be initiated by request 
of the Secretary of the HHS.\1\ On June 27, 2013, the HHS provided the 
DEA with a scientific and medical evaluation document prepared by the 
FDA entitled ``Basis for the Recommendation to Place Suvorexant in 
Schedule IV of the Controlled Substances Act.'' Pursuant to 21 U.S.C. 
811(b), this document contained an eight-factor analysis of the abuse 
potential of suvorexant as a new drug, along with the HHS' 
recommendation to control suvorexant under schedule IV of the CSA.
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    \1\ As set forth in a memorandum of understanding entered into 
by the HHS, the Food and Drug Administration, (FDA), and the 
National Institute on Drug Abuse (NIDA), the FDA acts as the lead 
agency within the HHS in carrying out the Secretary's scheduling 
responsibilities under the CSA, with the concurrence of the NIDA. 50 
FR 9518, Mar. 8, 1985. In addition, because the Secretary of the HHS 
has delegated to the Assistant Secretary for Health of the HHS the 
authority to make domestic drug scheduling recommendations, for 
purposes of this document, all subsequent references to 
``Secretary'' have been replaced with ``Assistant Secretary.''
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    In response, the DEA reviewed the scientific and medical evaluation 
and scheduling recommendation provided by the HHS, and all other 
relevant data, and completed its own eight-factor review document 
pursuant to 21 U.S.C. 811(c). Included below is a brief summary of each 
factor as analyzed by the HHS and the DEA, and as

[[Page 8641]]

considered by the DEA in its proposed scheduling action. Please note 
that both the DEA and HHS analyses are available in their entirety 
under ``Supporting and Related Material'' in the public docket for this 
proposed rule at www.regulations.gov, under Docket Number ``DEA-381.'' 
Full analysis of, and citations to, the information referenced in the 
summary may also be found in the supporting and related material.
    1. The Drug's Actual or Relative Potential for Abuse: Suvorexant is 
a new chemical entity that has not been marketed in the United States 
or any other country. As such, there is no information available 
detailing actual abuse of suvorexant. However, the legislative history 
of the CSA offers the following criterion for assessing a new drug or 
substance's potential for abuse:

    The drug or drugs containing such a substance are new drugs so 
related in their action to a drug or drugs already listed as having 
a potential for abuse to make it likely that the drug will have the 
same potentiality for abuse as such drugs, thus making it reasonable 
to assume that there may be significant diversions from legitimate 
channels, significant use contrary to or without medical advice, or 
that it has a substantial capability of creating hazards to the 
health of the user or to the safety of the community.\2\
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    \2\ Comprehensive Drug Abuse Prevention and Control Act of 1970, 
H.R. Rep. No. 91-1444, 91st Cong., Sess. 1 (1970); as reprinted in 
1970 U.S.C.C.A.N. 4566, 4601.

    As described further below, there is strong evidence that 
suvorexant produces behavioral effects in humans and in animals that 
are similar to those produced by zolpidem (schedule IV).
    With a mechanism of action that is distinct from any other marketed 
drug, including those marketed for insomnia (i.e., schedule IV 
benzodiazepines, and non-benzodiazepine hypnotics such as zolpidem 
(schedule IV), eszopiclone \3\ (schedule IV), and zaleplon (schedule 
IV)), suvorexant acts as an antagonist at the OX1 and OX2 receptors and 
produces sedative and sleep promoting effects in humans.
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    \3\ Eszopiclone is the dextrarotory stereoisomer, i.e., an 
isomer, of zopiclone (schedule IV).
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    In a human abuse potential study in subjects with histories of 
recreational sedative use, suvorexant produced reinforcing subjective 
effects similar to zolpidem (schedule IV). Doses of 40, 80, and 150 mg 
of suvorexant were compared to 15 and 30 mg doses of zolpidem (schedule 
IV). On the visual analog scale (VAS), suvorexant produced `` `at the 
moment' Drug Liking'' and ``High and Good,'' effects statistically 
indistinguishable from zolpidem (schedule IV). Suvorexant also produced 
effects similar to zolpidem (schedule IV) in ``Overall Drug Liking,'' 
``Take Drug Again,'' ``Any Drug Effect,'' assessments of subjective 
drug value, and overall familiarity measures. Additionally, on the 
Bowdle VAS (a measure of perceptual and hallucinogenic effects) 
suvorexant produced effects statistically similar to zolpidem (schedule 
IV). Suvorexant produced less dysphoria and adverse effects than 
zolpidem (schedule IV), suggesting that suvorexant may have an 
increased abuse potential relative to zolpidem (schedule IV). Measures 
to evaluate cognitive and psychomotor impairment (e.g., reaction time, 
attention, and vigilance) showed that suvorexant produced levels of 
impairment that were similar to the low dose (15 mg) of zolpidem 
(schedule IV). These data suggest that zolpidem (schedule IV) and 
suvorexant present a similar risk to the public health, and that 
suvorexant impairs cognition at both therapeutic (e.g., 40 mg) and 
supratherapeutic doses. As the dose of suvorexant increased, there was 
no increase in drug effects. This fact is especially important because 
the lowest dose of suvorexant examined in the human abuse potential 
study (40 mg) is the maximum planned therapeutic dose--suggesting that 
therapeutic doses of suvorexant (e.g., 40 mg) will have significant 
abuse liability and produce cognitive and psychomotor impairment.
    These data suggest that suvorexant and zolpidem (schedule IV) have 
a similar abuse potential. The similarities between suvorexant and 
zolpidem (schedule IV) indicate that there will be significant 
diversion of these substances from legitimate channels, and significant 
use contrary to or without medical advice. In addition, as discussed in 
Factor 3, the long half-life of suvorexant may be a critical factor in 
the drug's safety profile as suvorexant's duration of action may create 
significant hazards to the health of the user or to the safety of the 
community, and result in ``next day'' effects in patients.
    2. Scientific Evidence of the Drug's Pharmacological Effects, if 
Known: The orexin signaling system was discovered in 1998 and has been 
implicated in numerous physiological functions involving the central 
nervous system (CNS) such as sleep and wakefulness, appetite/
metabolism, stress response, reward/addiction, and analgesia. Orexin A 
and orexin B are peptide neurotransmitters produced through cleavage of 
a preprohormone. These neurotransmitters bind with a high degree of 
selectivity to two different G-protein coupled receptors (GPCR's), 
namely OX1 and OX2. These orexin receptors are broadly expressed in 
cortical, thalamic, and hypothalamic neuronal circuits. Suvorexant 
blocks the wakefulness promoting effects of the orexins, facilitating 
the sleep process. In pharmacological studies, suvorexant functioned as 
an antagonist as demonstrated by its ability to block agonist-induced 
calcium (Ca\2+\) release.
    In receptor binding studies to determine the binding affinity as 
assessed by the ability of suvorexant to displace a reference compound 
(expressed as Ki value), suvorexant produced Ki 
values of 0.55 nM and 0.35 nM for the OX1 and OX2 receptors, indicating 
a high affinity for these receptor subtypes. In in vitro functional 
studies, suvorexant blocked the effects of orexin receptor agonist in 
cells expressing OX1 and OX2 receptors. The concentrations of 
suvorexant inhibiting 50 percent of response (known as IC50) 
were 49.9 nM at the OX1 receptors and 54.8 nM at OX2 receptors.
    Like zolpidem, suvorexant (10, 20, 30 and 60 mg/kg) dose 
dependently reduced locomotor activity in rats, an expected 
characteristic of a sedative drug. Although rhesus monkeys trained to 
self-administer methohexital (schedule IV) did not self-administer 
suvorexant, the predictive validity of self-administration studies in 
evaluating the abuse potential of drugs acting via orexin receptors is 
unknown.
    A human abuse potential study was performed to assess the abuse 
potential of suvorexant in human participants. The study demonstrated 
that suvorexant and zolpidem (schedule IV) produce similar reinforcing 
effects and have a similar potential for abuse in recreational drug 
users. Results showed that suvorexant produced effects statistically 
indistinguishable from zolpidem (schedule IV) in primary and secondary 
outcome measures. There was no increase in drug effects as the dose of 
suvorexant increased. This is an important observation, as the low dose 
of suvorexant (40 mg) in the human abuse potential study is the maximum 
proposed therapeutic dose. These data suggest that the maximum 
therapeutic dose of suvorexant (40 mg) was shown to produce cognitive 
and psychomotor impairment and will have a significant liability for 
abuse.
    Results from another study measuring the effects of suvorexant (10, 
50, and 100 mg) on sleep parameters and next-day residual effects 
demonstrated that the mid and high doses of suvorexant (50 and 100 mg) 
produced effects on next-day assessments of psychomotor performance and 
subjective effects. These results may be clinically relevant

[[Page 8642]]

as the residual effects may be present in the morning following an 
evening administration (10 hours post-dose).
    3. The State of Current Scientific Knowledge Regarding the Drug or 
Other Substance: The chemical name for suvorexant is [(7R)-4-(5-chloro-
1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-
triazol-2-yl)phenyl]methanone. It is a white to off-white powder. Other 
chemical names include: 1) Methanone, [(7R)-4-(5-chloro-2-
benzoxazolyl)hexahydro-7-methyl-1H-1,4-diazepin-1-yl][5-methyl-2-(2H-
1,2,3-triazol-2-yl)phenyl]-; 2) [(7R)-4-(5-chlorobenzoxazol-2-yl)-7-
methylhexahydro-1H-1,4-diazepin-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-
yl)phenyl]methanone; 3) MK-4305; and 4) DORA-22. The Chemical Abstract 
Services number (CAS ) of suvorexant is: 1030377-33-3. At 25 
[deg]C, suvorexant is insoluble in water, soluble in methanol, very 
slightly soluble in heptane, and soluble in isopropyl acetate. The pH 
of a saturated aqueous solution of suvorexant was 8.6. Suvorexant has a 
molecular formula of 
C23H23ClN6O2 and a 
molecular weight of 450.921 g. Suvorexant has a distinct chemical 
structure that is different from that of other sedative hypnotics such 
as the benzodiazepines (schedule IV).
    There are several metabolites of suvorexant, although none appear 
to contribute significantly to its pharmacodynamic effects or abuse 
potential. Eight metabolites were detected in the plasma of healthy 
males administered radiolabeled suvorexant, with two of the metabolites 
present at concentrations great than 10 percent (M9 and M12). After 
oral administration of 15-40-mg, peak plasma concentrations (i.e., 
Tmax) of suvorexant occurred at approximately 1-2 hours 
(range 0.5-6.0 hours), although the study authors noted slight 
variability based on the time of day. The terminal half-life of 
suvorexant is approximately 8-11 hours after a 40-mg dose. The 
pharmacokinetics of suvorexant following multiple dose administrations 
were similar to those following single dose administrations, with 
slightly less than dose proportional pharmacokinetics over 10-80 mg as 
assessed by AUC0-[infin] and Cmax. Steady state 
exposure was reached after 2-3 days of consecutive dosing.
    4. Its History and Current Pattern of Abuse: Suvorexant is not 
currently marketed or available for sale in any country, therefore 
there is no known history or pattern of abuse. However, results from 
the human abuse potential study suggest that suvorexant produces 
effects that are similar to zolpidem (schedule IV) and would have a 
similar pattern of abuse.
    5. The Scope, Duration, and Significance of Abuse: While the 
current scope, duration, and significance of abuse of suvorexant are 
unknown due to its non-marketed status, the results of the human abuse 
potential study previously described suggest that, upon marketing, the 
scope, duration, and significance of suvorexant abuse may be similar to 
zolpidem (schedule IV). Data from the Drug Abuse Warning Network (DAWN) 
and the Adverse Event Reporting System (AERS) demonstrate the scope, 
duration, and significance of abuse of zolpidem (schedule IV) and 
related sedative-like drugs. In general, emergency department (ED) 
visits reported for zolpidem (schedule IV) along with those 
specifically categorized as ``misuse/abuse'' have increased every year 
from 2004 to 2010, with a modest decrease reported for 2011. ED visits 
related to benzodiazepine sedatives including diazepam (schedule IV) 
and lorazepam (schedule IV) demonstrated a similar trend. Suvorexant 
would be expected to have a similar scope, duration, and significance 
of abuse.
    6. What, If Any, Risk There Is to the Public Health: Suvorexant has 
a long terminal half-life of approximately 8-11 hours, which may 
increase the duration of its sedative effects and psychomotor 
impairment. Suvorexant's extended duration of action increases its risk 
to the public health relative to zolpidem (schedule IV) and other short 
acting sedatives. Results of the human abuse potential study showed 
that suvorexant produces behavioral impairment, as evidenced by its 
effects on psychomotor performance and cognitive function. On these 
assessments, suvorexant generally produced deficits that were 
statistically indistinguishable from 15 mg of zolpidem (schedule IV), 
demonstrating the behavioral impairing effects of suvorexant, and 
suggesting that even at therapeutic doses, suvorexant will present a 
risk to the public health that is at least equivalent to that of 
zolpidem (schedule IV).
    7. Its Psychic or Physiological Dependence Liability: Results of 
the human abuse potential study demonstrate that suvorexant has a 
psychic dependence liability similar to zolpidem (schedule IV). Self-
administration in laboratory animals, epidemiological data documenting 
its use and abuse, and the ability to produce ``Drug Liking'' in human 
drug users demonstrate the psychic dependence liability of zolpidem 
(schedule IV). Similar data was collected for suvorexant and compared 
to zolpidem.
    Discontinuation studies suggest that suvorexant does not produce 
physical dependence or withdrawal syndrome. Observed effects following 
suvorexant discontinuation include the return of insomnia symptoms. 
Furthermore, a lack of tolerance in humans from suvorexant was 
demonstrated by the sustained efficacy of suvorexant in Phase 3 trials 
where subjects reported improvement in sleep-related assessments that 
were still present one month after the start of treatment.
    8. Whether the Substance is an Immediate Precursor of a Substance 
Already Controlled under the CSA: Suvorexant is not an immediate 
precursor of a substance already controlled under the CSA.
    Conclusion: After considering the scientific and medical evaluation 
conducted by the HHS, the HHS' recommendation, and its own eight-factor 
analysis, the DEA has determined that these facts and all relevant data 
constitute substantial evidence of a potential for abuse of suvorexant. 
As such, the DEA hereby proposes to schedule suvorexant as a controlled 
substance under the CSA.

Proposed Determination of Appropriate Schedule

    The CSA outlines 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 the HHS and review of all available 
data, the Deputy Administrator of the DEA, pursuant to 21 U.S.C. 
812(b)(4), finds that:
    1. Suvorexant has a low potential for abuse relative to the drugs 
or other substances in schedule III. The overall abuse potential of 
suvorexant is comparable to schedule IV controlled substances such as 
zolpidem;
    2. Upon approval of the pending new drug application, suvorexant 
will have a currently accepted medical use in the treatment of insomnia 
in the United States; and
    3. The available evidence indicates that abuse of suvorexant may 
lead to limited psychological dependence relative to the drugs or other 
substances in schedule III. The potential for psychological dependence 
is similar to that of zolpidem (schedule IV).
    Based on these findings, the Deputy Administrator of the DEA 
concludes that suvorexant ([(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-
methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-
yl)phenyl]methanone), including its salts, isomers, and salts of 
isomers

[[Page 8643]]

warrants control in schedule IV of the CSA. 21 U.S.C. 812(b)(4).

Requirements for Handling Suvorexant

    If this rule is finalized as proposed, suvorexant would be subject 
to the CSA's schedule IV regulatory controls and administrative, civil, 
and criminal sanctions applicable to the manufacture, distribution, 
dispensing, importing, exporting, research, and conduct of 
instructional activities, including the following:
    Registration. Any person who handles (manufactures, distributes, 
dispenses, imports, exports, engages in research, or conducts 
instructional activities with) suvorexant, or who desires to handle 
suvorexant, would be required to be registered with the 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 suvorexant, and is not registered with the DEA, would need to 
be registered with the DEA by the effective date of the final rule 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.
    Security. Suvorexant would be subject to schedule III-V security 
requirements and would need to be handled and stored pursuant to 21 
U.S.C. 821, 823, 871(b) and in accordance with 21 CFR 1301.71-1301.93.
    Labeling and Packaging. All labels and labeling for commercial 
containers of suvorexant on or after finalization of this rule would 
need to comply with 21 U.S.C. 825, 958(e), and be in accordance with 21 
CFR part 1302.
    Inventory. Every DEA registrant who possesses any quantity of 
suvorexant on the effective date of the final rule would be required to 
take an inventory of all stocks of suvorexant on hand as of the 
effective date of the rule, pursuant to 21 U.S.C. 827, 958, and in 
accordance with 21 CFR 1304.03, 1304.04, and 1304.11(a) and (d).
    Any person who becomes registered with the DEA after the effective 
date of the final rule would be required to take an initial inventory 
of all stocks of controlled substances (including suvorexant) on hand 
at the time of registration pursuant to 21 U.S.C. 827, 958, and in 
accordance with 21 CFR 1304.03, 1304.04, and 1304.11(a) and (b). After 
the initial inventory, every DEA registrant would be required to take a 
biennial inventory of all controlled substances (including suvorexant) 
on hand, on a biennial basis, pursuant to 21 U.S.C. 827, 958, and in 
accordance with 21 CFR 1304.03, 1304.04, and 1304.11.
    Records. All DEA registrants would be required to maintain records 
with respect to suvorexant pursuant to 21 U.S.C. 827, 958, and in 
accordance with 21 CFR parts 1304, 1307, and 1312.
    Prescriptions. All prescriptions for suvorexant or products 
containing suvorexant would need to comply with 21 U.S.C. 829, and be 
issued in accordance with 21 CFR part 1306, and part 1311 subpart C.
    Importation and Exportation. All importation and exportation of 
suvorexant would need to be in compliance with 21 U.S.C. 952, 953, 957, 
and 958, and in accordance with 21 CFR part 1312.
    Criminal Liability. Any activity involving suvorexant not 
authorized by, or in violation of, the CSA, occurring on or after 
finalization of this proposed rule, would be unlawful, and may subject 
the person to administrative, civil, and/or criminal sanctions.

Regulatory Analyses

Executive Orders 12866 and 13563

    In accordance with 21 U.S.C. 811(a), this proposed 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 12866 and the 
principles reaffirmed in Executive Order 13563.

Executive Order 12988

    This proposed regulation meets the applicable standards set forth 
in Sections 3(a) and 3(b)(2) of Executive Order 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

    This proposed rulemaking does not have federalism implications 
warranting the application of Executive Order 13132. The proposed rule 
does not have substantial direct effects on the States, on the 
relationship between the national government and the States, or the 
distribution of power and responsibilities among the various levels of 
government.

Executive Order 13175

    This proposed rule will not have tribal implications warranting the 
application of Executive Order 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 Deputy Administrator, in accordance with the Regulatory 
Flexibility Act (RFA), 5 U.S.C. 601-612, has reviewed this proposed 
rule and by approving it certifies that it will not have a significant 
economic impact on a substantial number of small entities. The purpose 
of this proposed rule is to place suvorexant, including its salts, 
isomers, and salts of isomers, into schedule IV of the CSA. No less 
restrictive measures (i.e., non-control, or control in schedule V) 
enable the DEA to meet its statutory obligations under the CSA. In 
preparing this certification, the DEA has assessed economic impact by 
size category and has considered costs with respect to the various DEA 
registrant business activity classes.
    Suvorexant is a new molecular entity which has not yet been 
marketed in the United States or any other country. Accordingly, the 
number of currently identifiable manufacturers, importers, and 
distributors for suvorexant is extremely small. The publicly available 
materials also specify the readily identifiable persons subject to 
direct regulation by this proposed rule. Based on guidelines utilized 
by the Small Business Administration (SBA), the suvorexant 
manufacturer/distributor/importer was determined not to be a small 
entity. Once generic equivalents are developed and approved for 
manufacturing and marketing, there may be additional manufacturers, 
importers, and distributors of suvorexant, but whether they may qualify 
as small entities cannot be determined at this time.
    There are approximately 1.5 million controlled substance 
registrants, who represent approximately 381,000 entities (which 
include businesses, organizations, and governmental jurisdictions). The 
DEA estimates that 371,000 (97 percent) of these entities are 
considered ``small entities'' in accordance with the RFA and SBA 
standards. 5 U.S.C. 601(6); 15 U.S.C. 632. Due to the wide variety of 
unidentifiable and unquantifiable variables that potentially could 
influence the dispensing rates of new molecular entities, the DEA is 
unable to determine what number of these 371,000 small entities might 
handle suvorexant.

[[Page 8644]]

    Despite the fact that the number of small entities possibly 
impacted by this proposed rule could not be determined, the DEA 
concludes that they would not experience a significant economic impact 
as a result of this proposed rule. The DEA estimates all anticipated 
suvorexant handlers to be DEA registrants and currently 98 percent of 
DEA registrants (most of which are small entities) are authorized to 
handle schedule IV controlled substances. Even assuming that all of 
these registrants were to handle suvorexant the costs that they would 
incur as a result of suvorexant scheduling would be nominal as they 
have already established and implemented the required security, 
inventory, recordkeeping, and labeling systems and processes to handle 
schedule IV controlled substances.
    Because of these facts, this proposed rule will not result in a 
significant economic impact on a substantial number of small entities.

Unfunded Mandates Reform Act of 1995

    In accordance with the Unfunded Mandates Reform Act (UMRA) of 1995, 
2 U.S.C. 1501 et seq., the DEA has determined and certifies that this 
action would not result in any Federal mandate that may result ``in the 
expenditure by State, local, and tribal governments, in the aggregate, 
or by the private sector, of $100,000,000 or more (adjusted for 
inflation) in any one 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.

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, the DEA proposes to amend 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), unless otherwise noted.

0
2. Amend Sec.  1308.14 by redesignating paragraphs (c)(50) through 
(c)(55) as paragraphs (c)(51) through (c)(56) and adding new paragraph 
(c)(50) to read as follows:


Sec.  1308.14  Schedule IV.

* * * * *
    (c) * * *

(50) Suvorexant............................................         2223
 

* * * * *

    Dated: February 7, 2014.
Thomas M. Harrigan,
Deputy Administrator.
[FR Doc. 2014-03124 Filed 2-12-14; 8:45 am]
BILLING CODE 4410-09-P