45436 Federal Register / Vol. 82, No. 188 / Friday, September 29, 2017 / Rules and Regulations 

1As 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. 

2http://www.accessdata.fda.gov/drugsatfda_

docs/appletter/2017/208854Orig1s000ltr.pdf (last 

accessed 04/13/2017). 

EDGAR Filer Manual, Volume II: 

‘‘EDGAR Filing,’’ Version 43 (September 

2017). Additional provisions applicable 

to Form N–SAR filers are set forth in the 

EDGAR Filer Manual, Volume III: ‘‘N– 

SAR Supplement,’’ Version 6 (January 

2017). All of these provisions have been 

incorporated by reference into the Code 

of Federal Regulations, which action 

was approved by the Director of the 

Federal Register in accordance with 5 

U.S.C. 552(a) and 1 CFR part 51. You 

must comply with these requirements in 

order for documents to be timely 

received and accepted. The EDGAR 

Filer Manual is available for Web site 

viewing and printing; the address for 

the Filer Manual is https://www.sec.gov/ 

info/edgar/edmanuals.htm. You can 

obtain paper copies of the EDGAR Filer 

Manual from the following address: 

Public Reference Room, U.S. Securities 

and Exchange Commission, 100 F Street 

NE., Washington, DC 20549, on official 

business days between the hours of 

10:00 a.m. and 3:00 p.m. You can also 

inspect the document at the National 

Archives and Records Administration 

(NARA). For information on the 

availability of this material at NARA, 

call 202–741–6030, or go to: https://

www.archives.gov/federal-register/cfr/ 

ibr-locations.html. 

§ 232.301 [Amended] 

■ 4. Effective June 1, 2018, amend 

§ 232.301 by removing the fourth 

sentence. 

By the Commission. 

Dated: September 13, 2017. 

Brent J. Fields, 

Secretary. 

[FR Doc. 2017–20654 Filed 9–28–17; 8:45 am] 

BILLING CODE 8011–01–P 

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. 

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-trihydroxyN-(2-(3-phenyl-1,2,4-oxadiazol-5- 

yl)propan-2-yl)-2,3,4,4a,5,7a-hexahydro1H-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. 

Background 

Naldemedine, known chemically as 

(4R,4aS,7aR,12bS)-3- 

(cyclopropylmethyl)-4a,7,9-trihydroxyN-(2-(3-phenyl-1,2,4-oxadiazol-5- 

yl)propan-2-yl)-2,3,4,4a,5,7a-hexahydro1H-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® (0.2 mg tablets).2

Naldemedine is indicated for the 

treatment of opioid-induced 

constipation (OIC) in adults with 

chronic non-cancer pain. Opioidinduced constipation is caused by an 

activation of mu-opioid receptors in the 

gastrointestinal tract. Naldemedine, a 

peripheral acting mu-opioid antagonist, 

can prevent OIC. 

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 


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Federal Register / Vol. 82, No. 188 / Friday, September 29, 2017 / Rules and Regulations 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 


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45438 Federal Register / Vol. 82, No. 188 / Friday, September 29, 2017 / Rules and Regulations 

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 

■ 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. 

■ 2. In § 1308.12, revise the introductory 

text of paragraph (b)(1) to read as 

follows: 

§ 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 

DEPARTMENT OF DEFENSE 

Office of the Secretary 

32 CFR Part 199 

[Docket ID: DOD–2017–HA–0039] 

RIN 0720–AB70 

Establishment of TRICARE Select and 

Other TRICARE Reforms 

AGENCY: Office of the Secretary, 

Department of Defense (DoD). 

ACTION: Interim final rule. 

SUMMARY: This interim final rule 

implements the primary features of 

section 701 and partially implements 

several other sections of the National 

Defense Authorization Act for Fiscal 

Year 2017 (NDAA–17). The law makes 

significant changes to the TRICARE 

program, especially to the health 

maintenance organization (HMO)-like 

health plan, known as TRICARE Prime; 

to the preferred provider organization 

(PPO) health plan, previously called 

TRICARE Extra which is to be replaced 


asabaliauskas on DSKBBXCHB2PROD with RULES