[Federal Register Volume 82, Number 188 (Friday, September 29, 2017)]
[Rules and Regulations]
[Pages 45436-45438]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2017-20919]


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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Part 1308

[Docket No. DEA-468]


Schedules of Controlled Substances: Removal of Naldemedine From 
Control

AGENCY: Drug Enforcement Administration, Department of Justice.

ACTION: Final rule.

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SUMMARY: With the issuance of this final rule, the Drug Enforcement 
Administration removes the substance naldemedine (4R,4aS,7aR,12bS)-3-
(cyclopropylmethyl)-4a,7,9-trihydroxy-N-(2-(3-phenyl-1,2,4-oxadiazol-5-
yl)propan-2-yl)-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-
e]isoquinoline-6-carboxamide) including its salts from the schedules of 
the Controlled Substances Act. Prior to the effective date of this 
rule, naldemedine was a schedule II controlled substance because it can 
be derived from opium alkaloids. This action removes the regulatory 
controls and administrative, civil, and criminal sanctions applicable 
to controlled substances, including those specific to schedule II 
controlled substances, on persons who handle (manufacture, distribute, 
reverse distribute, dispense, conduct research, import, export, or 
conduct chemical analysis) or propose to handle naldemedine.

DATES: The effective date of this rule is September 29, 2017.

FOR FURTHER INFORMATION CONTACT: Michael J. Lewis, Diversion Control 
Division, Drug Enforcement Administration; Mailing Address: 8701 
Morrissette Drive, Springfield, Virginia 22152; Telephone: (202) 598-
6812.

SUPPLEMENTARY INFORMATION:

Legal Authority

    Pursuant to 21 U.S.C. 811(a)(2), the Attorney General may, by rule, 
``remove any drug or other substance from the schedules if he finds 
that the drug or other substance does not meet the requirements for 
inclusion in any schedule.'' The Attorney General has delegated 
scheduling authority under 21 U.S.C. 811 to the Administrator of the 
Drug Enforcement Administration (DEA). 28 CFR 0.100.
    The Controlled Substances Act (CSA) provides that proceedings for 
the issuance, amendment, or repeal 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). This action was initiated at the request of 
the Acting Assistant Secretary for Health of the HHS and by a petition 
by the drug sponsor to DEA to remove naldemedine from the list of 
scheduled controlled substances of the CSA, and is supported by, inter 
alia, a recommendation from the Assistant Secretary of the HHS and an 
evaluation of all relevant data by the DEA. This action removes the 
regulatory controls and administrative, civil, and criminal sanctions 
applicable to controlled substances, including those specific to 
schedule II controlled substances, on persons who handle or propose to 
handle naldemedine.
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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. The Secretary of the HHS has delegated to the 
Assistant Secretary for Health of the HHS the authority to make 
domestic drug scheduling recommendations. 58 FR 35460, July 1, 1993.
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Background

    Naldemedine, known chemically as (4R,4aS,7aR,12bS)-3-
(cyclopropylmethyl)-4a,7,9-trihydroxy-N-(2-(3-phenyl-1,2,4-oxadiazol-5-
yl)propan-2-yl)-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-
e]isoquinoline-6-carboxamide, is an opium alkaloid derivative. 
Naldemedine is a high-affinity antagonist at the mu, kappa, and delta 
opioid receptors. On March 23, 2016, a new drug application (NDA) was 
submitted by Shionogi Inc. (Sponsor) to the Food and Drug 
Administration (FDA) for approval of naldemedine for the treatment of 
opioid induced constipation in patients with chronic non-cancer pain. 
The FDA approved naldemedine for marketing on March 23, 2017, under the 
trade name Symproic[supreg] (0.2 mg tablets).\2\ Naldemedine is 
indicated for the treatment of opioid-induced constipation (OIC) in 
adults with chronic non-cancer pain. Opioid-induced constipation is 
caused by an activation of mu-opioid receptors in the gastrointestinal 
tract. Naldemedine, a peripheral acting mu-opioid antagonist, can 
prevent OIC.
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    \2\ http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/208854Orig1s000ltr.pdf (last accessed 04/13/2017).
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DEA and HHS Eight Factor Analyses

    On June 8, 2016, the DEA received a petition from the drug sponsor 
requesting that the DEA amend 21 CFR 1308.12(b)(1) to exclude 
naldemedine as a schedule II substance from the Controlled Substances 
Act (CSA). The petitioner stated that naldemedine is a potent 
peripherally acting mu-opioid receptor antagonist. In accordance with 
21 CFR 1308.43(c), the DEA accepted the petition for filing on August 
5, 2016.
    On March 22, 2017, the HHS provided the DEA with a scientific and 
medical evaluation document prepared by the FDA entitled ``Basis for 
the Recommendation to Decontrol Naldemedine and its Salts from the 
Controlled Substances Act.'' After considering the eight factors in 21 
U.S.C. 811(c), including consideration of the substance's abuse 
potential, legitimate medical use, and dependence liability, the 
Assistant Secretary of the HHS recommended that naldemedine

[[Page 45437]]

and its salts be removed from schedule II of the CSA. In response, the 
DEA conducted its own eight factor analysis of naldemedine pursuant to 
21 U.S.C. 811(c). Both the DEA and HHS analyses are available in their 
entirety in the public docket of this rule (Docket Number DEA-468) at 
http://www.regulations.gov under ``Supporting and Related Material.''

Determination To Decontrol Naldemedine

    After a review of the available data, including the scientific and 
medical evaluation and the recommendation to decontrol naldemedine from 
HHS, the DEA published in the Federal Register a notice of proposed 
rulemaking (NPRM) entitled ``Schedules of Controlled Substances: 
Removal of Naldemedine from Control'' which proposed removal of 
naldemedine including its salts from the schedules of the CSA. 82 FR 
32153, July 12, 2017. The proposed rule provided an opportunity for 
interested persons to file a request for a hearing in accordance with 
DEA regulations by August 11, 2017. No requests for such a hearing were 
received by the DEA. The NPRM also provided an opportunity for 
interested persons to submit written comments on the proposal on or 
before August 11, 2017.

Comments Received

    The DEA received six comments on the proposed rule to remove 
naldemedine from control. Five commenters supported the decontrol of 
naldemedine. One commenter submitted a comment not related to the 
proposed decontrol action.

Support

    One commenter stated that naldemedine does not induce euphoria 
therefore limiting its potential for abuse. Another commenter stated 
that naldemedine can help alleviate constipation which will reduce the 
amount of time a patient is absent from work or the need for placement 
on disability. Further, another commenter stated that since naldemedine 
is a naltrexone derivative, it should be unscheduled.
    One commenter stated that senators and representatives should 
support the removal of naldemedine to allow for safe and efficacious 
use of the drug due to its lack of abuse potential in clinical use. 
This commenter further suggested that naldemedine be made available to 
the public without the need for a prescription to treat individuals 
overdosed on opioids.
    DEA Response: The DEA appreciates the comments in support of this 
rulemaking. The comment about making naldemedine available without 
prescription does not relate to the factors determinative of control of 
a substance (21 U.S.C. 811(c)) or the criteria for placement of a 
substance in a particular schedule (21 U.S.C. 812(b)).

Unrelated Comment

    A commenter expressed concerns about reports on ``opioid epidemic'' 
without consideration of the need for opioids by chronic pain patients. 
This commenter felt ``patients are being denied, dismissed and 
overlooked by our drs (sic) due to all the scrutiny associated with 
treating chronic pain disease.''
    DEA Response: Because naldemedine is not an opioid analgesic, this 
comment about the use of opioid analgesic in the management of pain is 
unrelated to the current decontrol action. Further it does not relate 
to the factors determinative of control of a substance (21 U.S.C. 
811(c)) or the criteria for placement of a substance in a particular 
schedule (21 U.S.C. 812(b)).

Request for Immediate Effective Date

    The drug sponsor (Shionogi Inc.) requested that the effective date 
of this decontrol action correspond to the date of publication of the 
Final Rule.
    DEA Response: Generally, DEA scheduling actions are effective 30 
days from the date of publication of the final rule in the Federal 
Register. 21 CFR 1308.45; see also 5 U.S.C. 553(d). In accordance with 
21 CFR 1308.45, the DEA finds that the limited availability of 
effective therapeutic treatments for opioid induced constipation (OIC), 
coupled with the fact that this is an action for decontrol, supports 
the finding that conditions of public health require this action to be 
effective immediately upon publication in the Federal Register. Due to 
adverse side effects, the majority of treatment alternatives currently 
available for OIC have restricted clinical application. By comparison, 
in clinical studies, naldemedine was well tolerated and exhibited a 
good safety profile in patients with opioid-induced bowel dysfunction.
    In making the determination to make this rule effective 
immediately, the DEA took into consideration the effects of immediate 
implementation. The DEA agrees that making this rule immediately 
effective is in the best interest of the public health and will not 
burden registrants, the healthcare system or law enforcement. The DEA 
notes that its decision to make this rule effective immediately aligns 
with the exceptions to the 30-day effective date requirement of the 
Administrative Procedure Act (APA). One of the APA's exceptions to the 
30-day effective date is for a substantive rule granting or recognizing 
an exemption or which relieves a restriction. 5 U.S.C. 553(d)(1).

Scheduling Conclusion

    Based on the consideration of all comments, the scientific and 
medical evaluation and accompanying recommendation of the HHS, and 
based on the DEA's consideration of its own eight-factor analysis, the 
Administrator finds that these facts and all relevant data demonstrate 
that naldemedine does not meet the requirements for inclusion in any 
schedule, and will be removed from control under the CSA.

Regulatory Analyses

Executive Orders 12866 and 15363

    In accordance with 21 U.S.C. 811(a), 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 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 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 rulemaking does not have federalism implications warranting 
the application of Executive Order 13132. The 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 rule does 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

[[Page 45438]]

power and responsibilities between the Federal Government and Indian 
tribes.

Regulatory Flexibility Act

    The Administrator, in accordance with the Regulatory Flexibility 
Act (5 U.S.C. 601-612) (RFA), has reviewed this 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 rule is to 
remove naldemedine from the list of schedules of the CSA. This action 
removes regulatory controls and administrative, civil, and criminal 
sanctions applicable to controlled substances for handlers and proposed 
handlers of naldemedine. Accordingly, it has the potential for some 
economic impact in the form of cost savings.
    This rule will affect all persons who handle, or propose to handle, 
naldemedine. Due to the wide variety of unidentifiable and 
unquantifiable variables that potentially could influence handling of 
naldemedine, the DEA is unable to determine the number of entities and 
small entities which might handle naldemedine. However, the DEA 
estimates that all persons who handle, or propose to handle 
naldemedine, are currently registered with the DEA to handle controlled 
substances. Therefore, the 1.7 million (1,683,023 as of April 2017) 
controlled substance registrations, representing approximately 436,761 
entities, would be the maximum number of entities affected by this 
rule. The DEA estimates that 425,856 (97.5%) of 436,761 affected 
entities are ``small entities'' in accordance with the RFA and Small 
Business Administration size standards.
    The DEA estimates all controlled substance registrants handle both 
controlled and non-controlled substances and these registrants are 
expected to continue to handle naldemedine. Additionally, since 
prospective naldemedine handlers are likely to handle other controlled 
substances, the cost benefits they would receive as a result of the de-
control of naldemedine is minimal. As naldemedine handlers continue to 
handle other controlled substances, they will need to maintain their 
DEA registration and keep the same security and recordkeeping 
processes, equipment, and facilities in place and would experience only 
minimal reduction in security, inventory, recordkeeping, and labeling 
costs. Physical security control requirements are the same for 
controlled substances listed in schedules II, III, IV, and V for the 
vast majority of registrants (practitioners).
    While the DEA does not have a basis to estimate the number of 
affected entities, the DEA estimates that the maximum number of 
affected entities is 436,761 of which 425,856 are estimated to be small 
entities. Since the affected entities are expected to handle other 
controlled substances and maintain security and recordkeeping 
facilities and processes consistent with controlled substances, the DEA 
estimates any economic impact will be minimal. Because of these facts, 
this rule will not have 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

    This action does not impose a new collection of information 
requirement under the Paperwork Reduction Act, 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 section 804 of the 
Small Business Regulatory Enforcement Fairness Act of 1996 
(Congressional Review Act (CRA)). 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 
enterprises to compete with foreign based enterprises in domestic and 
export markets. However, pursuant to the CRA, the DEA has submitted a 
copy of this final rule to both Houses of Congress and to the 
Comptroller General.

List of Subjects in 21 CFR Part 1308

    Administrative practice and procedure, Drug traffic control, 
Reporting and recordkeeping requirements.

    For the reasons set out above, 21 CFR part 1308 is amended 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.  1308.12, revise the introductory text of paragraph (b)(1) 
to read as follows:


Sec.  1308.12  Schedule II.

* * * * *
    (b) * * *
    (1) Opium and opiate, and any salt, compound, derivative, or 
preparation of opium or opiate excluding apomorphine, thebaine-derived 
butorphanol, dextrorphan, nalbuphine, naldemedine, nalmefene, 
naloxegol, naloxone, and naltrexone, and their respective salts, but 
including the following:
* * * * *

    Dated: September 22, 2017.
Chuck Rosenberg,
Acting Administrator.
[FR Doc. 2017-20919 Filed 9-28-17; 8:45 am]
 BILLING CODE 4410-09-P