82 FR 32153 - Schedules of Controlled Substances: Removal of Naldemedine From Control

DEPARTMENT OF JUSTICE
Drug Enforcement Administration

Federal Register Volume 82, Issue 132 (July 12, 2017)

Page Range		32153-32157
FR Document		2017-14482

The Drug Enforcement Administration (DEA) proposes to remove 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 (CSA). This action is pursuant to the CSA which requires that such actions be made on the record after opportunity for a hearing through formal rulemaking. Naldemedine is currently a schedule II controlled substance because it can be derived from opium alkaloids. This action would remove 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.

Federal Register, Volume 82 Issue 132 (Wednesday, July 12, 2017)

[Federal Register Volume 82, Number 132 (Wednesday, July 12, 2017)]
[Proposed Rules]
[Pages 32153-32157]
From the Federal Register Online [www.thefederalregister.org]
[FR Doc No: 2017-14482]

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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: Notice of proposed rulemaking.

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SUMMARY: The Drug Enforcement Administration (DEA) proposes to remove
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
(CSA). This action is pursuant to the CSA which requires that such
actions be made on the record after opportunity for a hearing through
formal rulemaking. Naldemedine is currently a schedule II controlled
substance because it can be derived from opium alkaloids. This action
would remove 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: 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 August 11, 2017. Commenters
should be aware that the electronic Federal Docket Management System
will not accept comments after 11:59 p.m. Eastern Time on the last day
of the comment period.
Interested persons, may file a request for hearing or waiver of
hearing pursuant to 21 CFR 1308.44 and in accordance with 21 CFR
1316.45, 1316.47, 1316.48, and/or 1316.49, as applicable. Requests for
hearing and waivers of an opportunity for a hearing or to participate
in a hearing must be received on or before August 11, 2017.

ADDRESSES: To ensure proper handling of comments, please reference
``Docket No. DEA-468'' on all electronic and written correspondence,
including any attachments.
Electronic comments: The Drug Enforcement Administration
encourages that all comments be submitted electronically through the
Federal eRulemaking Portal which provides the ability to type short
comments directly into the comment field on the Web page or attach a
file for lengthier comments. Please go to http://www.regulations.gov
and follow the online instructions at that site for submitting
comments. Upon completion of your submission you will receive a Comment
Tracking Number for your comment. Please be aware that submitted
comments are not instantaneously available for public view on
Regulations.gov. If you have received a Comment Tracking Number, your
comment has been successfully submitted and there is no need to
resubmit the same comment.
Paper comments: Paper comments that duplicate the
electronic submission are not necessary. 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/DRW, 8701 Morrissette Drive,
Springfield, Virginia 22152.
Hearing requests: All requests for a hearing and waivers
of participation must be sent to: Drug Enforcement Administration,
Attn: Administrator, 8701 Morrissette Drive, Springfield, Virginia
22152. All requests for hearing and waivers of participation should be
sent to: (1) Drug Enforcement Administration, Attn: Hearing Clerk/LJ,
8701 Morrissette Drive, Springfield, Virginia 22152; and (2) Drug
Enforcement Administration, Attn: DEA Federal Register Representative/
DRW, 8701 Morrissette Drive, Springfield, Virginia 22152.

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:

Posting of Public Comments

Please note that all comments received in response to this docket
are considered part of the public record. They will, unless reasonable
cause is given, be made available by the Drug Enforcement
Administration (DEA) for public inspection online at http://www.regulations.gov. Such information includes personal identifying
information (such as your name, address, etc.) voluntarily submitted by
the commenter. The Freedom of Information Act (FOIA) applies to all
comments received. If you want to submit personal identifying
information (such as your name, address, etc.) as part of your comment,
but do not want it to be made publicly available, you must include the
phrase ``PERSONAL IDENTIFYING INFORMATION'' in the first paragraph of
your comment. You must also place all of the personal identifying
information you do not want made publicly available in the first
paragraph of your comment and identify what information you want
redacted.
If you want to submit confidential business information as part of
your comment, but do not want it to be made publicly available, you
must include the phrase ``CONFIDENTIAL BUSINESS INFORMATION'' in the
first paragraph of your comment. You must also prominently identify the
confidential business information to be redacted within the comment.
Comments containing personal identifying information or
confidential business information identified as directed above will be
made publicly available in redacted form. 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 posted to http://www.regulations.gov may include
any personal identifying information (such as name, address, and phone
number) included in the text of your electronic submission that is not
identified as directed above as confidential.
An electronic copy of this document and supplemental information to
this proposed rule are available at http://www.regulations.gov for easy
reference.

Request for Hearing, or Waiver of Participation in Hearing

Pursuant to 21 U.S.C. 811(a), this action is a formal rulemaking
``on the record after opportunity for a hearing.'' Such proceedings are
conducted pursuant to the provisions of the

[[Page 32154]]

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 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.
Such requests or notices must conform to the requirements of 21 CFR
1308.44(a) or (b), and in accordance with 21 CFR 1316.45, 1316.47,
1316.48, and/or 1316. 49 as applicable, and include a statement of
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 may include 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 this title for the schedule in which such drug is to be placed *
* *.'' All requests for hearing and waivers of participation must be
sent to the DEA using the address information provided above.

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
DEA. 28 CFR 0.100.
The 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
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 would remove
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 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 (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.
On June 8, 2016, the DEA received a petition from the drug sponsor
(Shionogi, Inc.), 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 23, 2017, the FDA approved naldemedine for marketing 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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Naldemedine is a schedule II controlled substance under 21 U.S.C.
812(a)(1) and 21 CFR 1308.12(b)(I), as a derivative of opium alkaloids
and opiates.

Proposed Determination To Decontrol Naldemedine

According to the HHS, the sponsor submitted a New Drug Application
(NDA) for naldemedine on March 23, 2016. In the NDA submission, the
sponsor requested that naldemedine and its salts be removed from all
schedules for control under the CSA. Based on the NDA, the HHS
mentioned that naldemedine is an antagonist of peripheral opioid
receptors.
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.'' Pursuant to 21 U.S.C. 811(b), this
document contained an eight-factor analysis of the abuse potential of
naldemedine as a new drug, along with the HHS' recommendation to
decontrol naldemedine from the schedules of the CSA.
In response, the DEA reviewed the scientific and medical
evaluations and scheduling recommendation provided by the HHS, and all
other relevant data, and completed its own eight-factor review document
on naldemedine pursuant to 21 U.S.C. 811(c). Included below is a brief
summary of each factor as analyzed by the HHS and DEA, and as
considered by the DEA in this proposal to remove naldemedine from the
schedules of the CSA. Please note that both the DEA and HHS analyses
are available in their entirety under ``Supporting and Related
Material'' of the public docket for this rule at http://www.regulations.gov under docket number DEA-468.

1. The Drug's Actual or Relative Potential for Abuse

Naldemedine is a high affinity peripherally acting mu-opioid
receptor antagonist. According to HHS, naldemedine is not available or
marketed in any country, so there is a lack of evidence of diversion,
illicit manufacturing, or deliberate ingestion (HHS review, 2017). Data
obtained from scientific behavioral studies (drug discrimination and
self-administration) show that naldemedine does not demonstrate a
potential for abuse (HHS review, 2017). In clinical studies,
naldemedine did not produce euphoria

[[Page 32155]]

or abuse potential related adverse events (AEs) (HHS review, 2017).
These data demonstrate that naldemedine lacks a potential for abuse.

2. Scientific Evidence of the Drug's Pharmacological Effects, if Known

Data submitted by HHS demonstrate that naldemedine binds strongly
to all three opioid receptor sites: Mu, kappa and delta, and acts as an
antagonist at all three opioid receptor sites. Under both acute and
chronic administration of naldemedine, penetration into the blood-brain
barrier was non-significant, thereby suggesting that naldemedine is
unlikely to have abuse potential (HHS review, 2017). Data obtained from
in vivo studies conducted by Kanemasa (2015) \3\ demonstrate that
naldemedine potently inhibits constipating effects produced by opioids
and that pretreatment with naldemedine (up to 30 mg/kg) had no
influence on morphine's analgesic effect in rats.
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\3\ Kanemasa T, Koike K, Arai T, Horita N, Chiba H, Tsuyoshi K,
Hasegawa M. 2015. Effects of Naldemedine: A Peripherally Acting Mu-
Opioid Receptor Antagonist in Rat Models of Opioid-Induced
Constipation. American Journal of Gastroentrology. S110: 1322.
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According to the HHS, results obtained from Phase 1 study conducted
in a single-dose pooled population (n = 224) showed that naldemedine
was well tolerated in healthy subjects not taking opioid medications
(HHS review, 2017). HHS also presented adverse events (AEs) from three
pooled phase 3 repeated dose studies with naldemedine (n = 1,163 vs
placebo, n = 1,165). It was noted by HHS that naldemedine was well
tolerated in individuals taking opioid drugs. AEs reported at a rate
>=2% for naldemedine included nasopharyngitis, upper respiratory tract
infection, urinary tract infection, diarrhea, abdominal distention,
abdominal pain, flatulence, nausea, vomiting, hyperhidrosis,
arthralgia, and back pain. Headache was the only centrally-mediated AE
reported (2%) for individuals taking naldemedine, but it should be
noted that individuals in the placebo group also reported headaches at
the same percentage (2%). There were no reports of euphoria,
hallucination or other abuse-related adverse events in either the
naldemedine or placebo-treated groups.

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

Naldemedine tosylate (active ingredient in naldemedine drug
product) is 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 4-methylbenzenesulfonate. According to
HHS, naldemedine tosylate is slightly soluble in water and ethanol,
soluble in methanol, and freely soluble in dimethylsulfoxide.
Naldemedine tosylate is synthesized in a two-step/four-reaction
derivation process from naltrexone hydrochloride, an opioid antagonist.
The HHS further notes that the side chain addition makes naldemedine's
lipid solubility low and thereby reduces its ability to cross the
blood-brain barrier.
HHS reported that the Sponsor studied the pharmacokinetic profile
of naldemedine in humans. Study participants were administered a single
oral dose of naldemedine (0.1--100 mg). Data endpoints that were
studied included time to peak plasma concentrations (Tmax), peak plasma
concentrations (Cmax), area under the curve (AUC), and drug half-life
(t \1/2\). Over the tested doses (0.1--100 mg naldemedine),
the pharmacokinetic parameter ranges were as follows: Tmax--0.5 to 1.0
hours; Cmax--2 ng/ml to 2,560 ng/ml; AUC--11 ng.h/ml to 3,980 ng.h/ml;
t \1/2\ - ~9 hours for all doses.

4. Its History and Current Pattern of Abuse

Naldemedine is not marketed in the United States or in other
countries. Based on its pharmacological similarities to other opioid
receptor antagonists, naltrexone, naloxone and naloxegol, it is
unlikely that naldemedine possesses abuse related indications.
According to the HHS, there has been no evidence of abuse-related
symptoms associated with naldemedine from the preclinical and clinical
studies.

5. The Scope, Duration, and Significance of Abuse

The DEA searched the National Forensic Laboratory Information
System (NFLIS) \4\ and STARLiMS (a web-based, commercial laboratory
information management system) \5\ databases; there have been no
reports of naldemedine seizures in the United States. As mentioned in
Factors 1 and 2, there were no abuse or euphoria-related adverse events
reported from naldemedine use in clinical trials submitted by the
Sponsor in the NDA submission.
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\4\ NFLIS is a national drug forensic laboratory reporting
system that systematically collects results from drug chemistry
analyses conducted by participating Federal, State and local
forensic laboratories across the country.
\5\ STRIDE was a database of drug exhibits sent to DEA
laboratories for analysis. STRIDE collected the results of drug
evidence analyzed at DEA laboratories and reflects evidence
submitted by the DEA, other Federal law enforcement agencies, and
some local law enforcement agencies. On October 1, 2014, STARLiMS
replaced STRIDE as the DEA laboratory drug evidence data system of
record. DEA laboratory data submitted after September 30, 2014 are
reposited in STARLiMS.
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6. What, if any, Risk There Is to the Public Health

According to the HHS, there are no signs or symptoms that show that
naldemedine has abuse potential; hence, the possibility of abuse and
public health risk is very unlikely. Naldemedine at a dose up to 5-
times the recommended dose did result in cardiotoxicity (Migoya et al
2017).\6\ Naldemedine's mechanism of action as a mu-opioid receptor
antagonist and lack of cardiotoxicity underscores its minimal potential
to be associated with public health risk and public health risk as
related to abuse.
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\6\ Migoya E, Fukumura K, Yamada T, Arjona Ferreira J. 2017.
Effect of naldemedine, a peripherally acting mu-opioidreceptor
antagonist, on QT interval. The Journal of Pain S81:426.
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7. Its Psychic or Physiological Dependence Liability

In in vivo physical dependence studies, both during the drug
administration period and 7 days following drug discontinuation, no
symptoms of physical dependence were observed for naldemedine (HHS
review, 2017). The HHS also mentioned that the lack of naldemedine
self-administration by animals is consistent with a lack of psychic
dependence liability. Hence, naldemedine does not have psychological or
physical dependence liability.

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

Naldemedine is not considered an immediate precursor of any
controlled substance.

Conclusion

Based on the recommendation of the Assistant Secretary for Health,
received in accordance with section 201(b) of the Act (21 U.S.C.
811(b)), and the independent review of the available data by DEA, the
Acting Administrator of DEA, pursuant to sections 201(a) and 201(b) of
the Act (21 U.S.C. 811(a) and 811(c)), finds that:
(1) Naldemedine has no potential for abuse and does not meet the
finding for control under any CSA schedule. Naldemedine is a high-
affinity

[[Page 32156]]

antagonist at the three opioid receptors, mu, delta, and kappa. It is
not related in action to a drug or other substance already listed as
having potential for abuse and has no abuse potential.
(2) Naldemedine has a currently accepted medical use in the United
States; Naldemedine was approved for marketing on March 23, 2017 under
the brand name Symproic[supreg] for the treatment of opioid-induced
constipation in adults with chronic non-cancer pain.
(3) Naldemedine does not have physical or psychological dependence
potential; Naldemedine does not produce physical dependence in animals.
In animal self-administration studies, naldemedine did not produce
significant self-administration infusions. Hence, naldemedine does not
have psychological dependence liability.
Based on these findings, the Acting Administrator of DEA concludes
that naldemedine does not meet the requirements for inclusion in any
schedule, and should be removed from control under the CSA.

Regulatory Analyses

Executive Orders 12866 and 15363

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
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 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 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 proposed rule and by
approving it certifies that it will not, if promulgated, 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 will remove 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.
If finalized, the proposed rule will affect all persons who would
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 would handle naldemedine.
However, the DEA estimates that all persons who would 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 2016) 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 substances registrants handle both
controlled and non-controlled substances and these registrants are
expected to continue to handle naldemedine if the proposed rule were
finalized. 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, if promulgated, 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.

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:

[[Page 32157]]

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. In Sec. 1308.12, amend 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: July 5, 2017.
Chuck Rosenburg,
Acting Administrator.
[FR Doc. 2017-14482 Filed 7-11-17; 8:45 am]
BILLING CODE 4410-09-P

Federal Register / Vol. 82, No. 132 / Wednesday, July 12, 2017 / Proposed Rules 32153

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Interested persons, may file a request Posting of Public Comments
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Stevens Point Municipal Airport, WI
pursuant to 21 CFR 1308.44 and in received in response to this docket are
(Lat. 44°32′43″ N., long. 89°31′49″ W.)
accordance with 21 CFR 1316.45, considered part of the public record.
That airspace extending upward from 700
1316.47, 1316.48, and/or 1316.49, as They will, unless reasonable cause is
feet above the surface within a 6.6-mile
radius of Stevens Point Municipal Airport. applicable. Requests for hearing and given, be made available by the Drug
waivers of an opportunity for a hearing Enforcement Administration (DEA) for
Issued in Fort Worth, Texas, on June 30, public inspection online at http://
2017.
or to participate in a hearing must be
received on or before August 11, 2017. www.regulations.gov. Such information
Walter Tweedy, includes personal identifying
ADDRESSES: To ensure proper handling
Acting Manager, Operations Support Group, information (such as your name,
ATO Central Service Center. of comments, please reference ‘‘Docket
No. DEA–468’’ on all electronic and address, etc.) voluntarily submitted by
[FR Doc. 2017–14527 Filed 7–11–17; 8:45 am] the commenter. The Freedom of
written correspondence, including any
BILLING CODE 4910–13–P
attachments. Information Act (FOIA) applies to all
• Electronic comments: The Drug comments received. If you want to
Enforcement Administration encourages submit personal identifying information
DEPARTMENT OF JUSTICE that all comments be submitted (such as your name, address, etc.) as
electronically through the Federal part of your comment, but do not want
Drug Enforcement Administration it to be made publicly available, you
eRulemaking Portal which provides the
ability to type short comments directly must include the phrase ‘‘PERSONAL
21 CFR Part 1308 IDENTIFYING INFORMATION’’ in the
into the comment field on the Web page
[Docket No. DEA–468] or attach a file for lengthier comments. first paragraph of your comment. You
Please go to http://www.regulations.gov must also place all of the personal
Schedules of Controlled Substances: and follow the online instructions at identifying information you do not want
Removal of Naldemedine From Control that site for submitting comments. Upon made publicly available in the first
completion of your submission you will paragraph of your comment and identify
AGENCY: Drug Enforcement what information you want redacted.
Administration, Department of Justice. receive a Comment Tracking Number for
If you want to submit confidential
ACTION: Notice of proposed rulemaking. your comment. Please be aware that
business information as part of your
submitted comments are not
comment, but do not want it to be made
SUMMARY: The Drug Enforcement instantaneously available for public
publicly available, you must include the
Administration (DEA) proposes to view on Regulations.gov. If you have
phrase ‘‘CONFIDENTIAL BUSINESS
remove naldemedine (4R,4aS,7aR,12bS)- received a Comment Tracking Number,
INFORMATION’’ in the first paragraph
3-(cyclopropylmethyl)-4a,7,9- your comment has been successfully
of your comment. You must also
trihydroxy-N-(2-(3-phenyl-1,2,4- submitted and there is no need to
prominently identify the confidential
oxadiazol-5-yl)propan-2-yl)- resubmit the same comment.
business information to be redacted
2,3,4,4a,5,7a-hexahydro-1H-4,12- • Paper comments: Paper comments
within the comment.
methanobenzofuro[3,2-e]isoquinoline-6- that duplicate the electronic submission Comments containing personal
carboxamide) including its salts from are not necessary. Should you wish to identifying information or confidential
the schedules of the Controlled mail a paper comment, in lieu of an business information identified as
Substances Act (CSA). This action is electronic comment, it should be sent directed above will be made publicly
pursuant to the CSA which requires that via regular or express mail to: Drug available in redacted form. If a comment
such actions be made on the record after Enforcement Administration, Attn: DEA has so much confidential business
opportunity for a hearing through Federal Register Representative/DRW, information that it cannot be effectively
formal rulemaking. Naldemedine is 8701 Morrissette Drive, Springfield, redacted, all or part of that comment
currently a schedule II controlled Virginia 22152. may not be made publicly available.
substance because it can be derived • Hearing requests: All requests for a
Comments posted to http://
from opium alkaloids. This action hearing and waivers of participation
www.regulations.gov may include any
would remove the regulatory controls must be sent to: Drug Enforcement
personal identifying information (such
and administrative, civil, and criminal Administration, Attn: Administrator,
as name, address, and phone number)
sanctions applicable to controlled 8701 Morrissette Drive, Springfield,
included in the text of your electronic
substances, including those specific to Virginia 22152. All requests for hearing
submission that is not identified as
schedule II controlled substances, on and waivers of participation should be
directed above as confidential.
persons who handle (manufacture, sent to: (1) Drug Enforcement An electronic copy of this document
distribute, reverse distribute, dispense, Administration, Attn: Hearing Clerk/LJ, and supplemental information to this
conduct research, import, export, or 8701 Morrissette Drive, Springfield, proposed rule are available at http://
conduct chemical analysis) or propose Virginia 22152; and (2) Drug www.regulations.gov for easy reference.
nlaroche on DSK30NT082PROD with PROPOSALS

to handle naldemedine. Enforcement Administration, Attn: DEA
DATES: Interested persons may file Federal Register Representative/DRW, Request for Hearing, or Waiver of
written comments on this proposal in 8701 Morrissette Drive, Springfield, Participation in Hearing
accordance with 21 CFR 1308.43(g). Virginia 22152. Pursuant to 21 U.S.C. 811(a), this
Comments must be submitted FOR FURTHER INFORMATION CONTACT: action is a formal rulemaking ‘‘on the
electronically or postmarked on or Michael J. Lewis, Diversion Control record after opportunity for a hearing.’’
before August 11, 2017. Commenters Division, Drug Enforcement Such proceedings are conducted
should be aware that the electronic Administration; Mailing Address: 8701 pursuant to the provisions of the

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32154 Federal Register / Vol. 82, No. 132 / Wednesday, July 12, 2017 / Proposed Rules

Administrative Procedure Act (APA), 5 of any interested party. 21 U.S.C. 811(a). peripheral acting mu-opioid antagonist,
U.S.C. 551–559. 21 CFR 1308.41– This action was initiated at the request can prevent OIC.
1308.45; 21 CFR part 1316, subpart D. of the Acting Assistant Secretary for Naldemedine is a schedule II
In accordance with 21 CFR 1308.44(a)– Health of the HHS and by a petition by controlled substance under 21 U.S.C.
(c), requests for hearing, notices of the sponsor to DEA to remove 812(a)(1) and 21 CFR 1308.12(b)(I), as a
appearance, and waivers of an naldemedine from the list of scheduled derivative of opium alkaloids and
opportunity for a hearing or to controlled substances of the CSA, and is opiates.
participate in a hearing may be supported by, inter alia, a Proposed Determination To Decontrol
submitted only by interested persons, recommendation from the Assistant Naldemedine
defined as those ‘‘adversely affected or Secretary of the HHS and an evaluation
aggrieved by any rule or proposed rule of all relevant data by the DEA. This According to the HHS, the sponsor
issuable pursuant to section 201 of the submitted a New Drug Application
action would remove the regulatory
Act (21 U.S.C. 811).’’ 21 CFR 1300.01. (NDA) for naldemedine on March 23,
controls and administrative, civil, and
Such requests or notices must conform 2016. In the NDA submission, the
criminal sanctions applicable to
to the requirements of 21 CFR sponsor requested that naldemedine and
controlled substances, including those
1308.44(a) or (b), and in accordance its salts be removed from all schedules
specific to schedule II controlled
with 21 CFR 1316.45, 1316.47, 1316.48, for control under the CSA. Based on the
substances, on persons who handle or NDA, the HHS mentioned that
and/or 1316. 49 as applicable, and propose to handle naldemedine.
include a statement of interest of the naldemedine is an antagonist of
person in the proceeding and the Background peripheral opioid receptors.
objections or issues, if any, concerning On March 22, 2017, the HHS provided
which the person desires to be heard. Naldemedine, known chemically as the DEA with a scientific and medical
Any waiver must conform to the (4R,4aS,7aR,12bS)-3- evaluation document prepared by the
requirements of 21 CFR 1308.44(c) and (cyclopropylmethyl)-4a,7,9-trihydroxy- FDA entitled ‘‘Basis for the
may include a written statement N-(2-(3-phenyl-1,2,4-oxadiazol-5- Recommendation to Decontrol
regarding the interested person’s yl)propan-2-yl)-2,3,4,4a,5,7a-hexahydro- Naldemedine and its Salts from the
position on the matters of fact and law 1H-4,12-methanobenzofuro[3,2- Controlled Substances Act.’’ Pursuant to
involved in any hearing. e]isoquinoline-6-carboxamide, is an 21 U.S.C. 811(b), this document
Please note that pursuant to 21 U.S.C. opium alkaloid derivative. Naldemedine contained an eight-factor analysis of the
811(a), the purpose and subject matter is a high-affinity antagonist at the mu, abuse potential of naldemedine as a new
of a hearing held in relation to this kappa, and delta opioid receptors. On drug, along with the HHS’
rulemaking is restricted to: ‘‘(A) March 23, 2016, a new drug application recommendation to decontrol
find[ing] that such drug or other (NDA) was submitted by Shionogi naldemedine from the schedules of the
substance has a potential for abuse, and (Sponsor) to the Food and Drug CSA.
(B) mak[ing] with respect to such drug Administration (FDA) for approval of In response, the DEA reviewed the
or other substance the findings naldemedine for the treatment of opioid scientific and medical evaluations and
prescribed by subsection (b) of section induced constipation in patients with scheduling recommendation provided
812 of this title for the schedule in chronic non-cancer pain. by the HHS, and all other relevant data,
which such drug is to be placed * * *.’’ and completed its own eight-factor
On June 8, 2016, the DEA received a
All requests for hearing and waivers of review document on naldemedine
petition from the drug sponsor pursuant to 21 U.S.C. 811(c). Included
participation must be sent to the DEA (Shionogi, Inc.), requesting that the DEA
using the address information provided below is a brief summary of each factor
amend 21 CFR 1308.12(b)(1) to exclude as analyzed by the HHS and DEA, and
above. naldemedine as a schedule II substance as considered by the DEA in this
Legal Authority from the Controlled Substances Act proposal to remove naldemedine from
Pursuant to 21 U.S.C. 811(a)(2), the (CSA). The petitioner stated that the schedules of the CSA. Please note
Attorney General may, by rule, ‘‘remove naldemedine is a potent peripherally that both the DEA and HHS analyses are
any drug or other substance from the acting mu-opioid receptor antagonist. In available in their entirety under
schedules if he finds that the drug or accordance with 21 CFR 1308.43(c), the ‘‘Supporting and Related Material’’ of
other substance does not meet the DEA accepted the petition for filing on the public docket for this rule at http://
requirements for inclusion in any August 5, 2016. www.regulations.gov under docket
schedule.’’ The Attorney General has On March 23, 2017, the FDA number DEA–468.
delegated scheduling authority under 21 approved naldemedine for marketing
1. The Drug’s Actual or Relative
U.S.C. 811 to the Administrator of the under the trade name Symproic® (0.2
Potential for Abuse
DEA. 28 CFR 0.100. mg tablets).2 Naldemedine is indicated
The CSA provides that proceedings for the treatment of opioid-induced Naldemedine is a high affinity
for the issuance, amendment, or repeal constipation (OIC) in adults with peripherally acting mu-opioid receptor
of the scheduling of any drug or other chronic non-cancer pain. Opioid- antagonist. According to HHS,
substance may be initiated by the induced constipation is caused by an naldemedine is not available or
Attorney General (1) on his own motion, activation of mu-opioid receptors in the marketed in any country, so there is a
(2) at the request of the Secretary of the gastrointestinal tract. Naldemedine, a lack of evidence of diversion, illicit
nlaroche on DSK30NT082PROD with PROPOSALS

Department of Health and Human manufacturing, or deliberate ingestion
Services (HHS),1 or (3) on the petition 9518, Mar. 8, 1985. The Secretary of the HHS has (HHS review, 2017). Data obtained from
delegated to the Assistant Secretary for Health of scientific behavioral studies (drug
1 As set forth in a memorandum of understanding the HHS the authority to make domestic drug discrimination and self-administration)
entered into by the HHS, the FDA, and the National scheduling recommendations. 58 FR 35460, July 1, show that naldemedine does not
Institute on Drug Abuse (NIDA), the FDA acts as the 1993.
lead agency within the HHS in carrying out the 2 http://www.accessdata.fda.gov/drugsatfda_ demonstrate a potential for abuse (HHS
Secretary’s scheduling responsibilities under the docs/appletter/2017/208854Orig1s000ltr.pdf (last review, 2017). In clinical studies,
CSA, with the concurrence of the NIDA. 50 FR accessed 04/13/2017). naldemedine did not produce euphoria

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Federal Register / Vol. 82, No. 132 / Wednesday, July 12, 2017 / Proposed Rules 32157

PART 1308—SCHEDULES OF See the ‘‘Public Participation and passage of trains or for maintenance.
CONTROLLED SUBSTANCES Request for Comments’’ portion of the There will be no modifications to the
SUPPLEMENTARY INFORMATION section operation of the bridge as it relates to
■ 1. The authority citation for 21 CFR below for instruction on submitting the passage of vessels. Instead, this
part 1308 continues to read as follows: comments. change will allow the bridge owner to
Authority: 21 U.S.C. 811, 812, 871(b), FOR FURTHER INFORMATION CONTACT: If increase efficiency by coordinating
unless otherwise noted. you have questions on this proposed bridge operations and vessel transits
rule, call or email Ms. Donna Gagliano; with train dispatch operations in
■ 2. In § 1308.12, amend the
Bridge Administration Branch, Eighth Decatur, AL.
introductory text of paragraph (b)(1) to
read as follows: Coast Guard District; telephone 504– IV. Regulatory Analyses
671–2128, email Donna.Gagliano@
§ 1308.12 Schedule II. We developed this proposed rule after
uscg.mil.
considering numerous statutes and
* * * * * SUPPLEMENTARY INFORMATION: Executive Orders related to rulemaking.
(b) * * *
I. Table of Abbreviations Below we summarize our analyses
(1) Opium and opiate, and any salt,
based on these statues and Executive
compound, derivative, or preparation of CFR Code of Federal Regulations Orders and we discuss First
opium or opiate excluding DHS Department of Homeland Security Amendment rights of protesters.
apomorphine, thebaine-derived E.O. Executive Order
butorphanol, dextrorphan, nalbuphine, FR Federal Register A. Regulatory Planning and Review
naldemedine, nalmefene, naloxegol, NPRM Notice of proposed rulemaking
U.S.C. United States Code
E.O.s 12866 and 13563 direct agencies
naloxone, and naltrexone, and their to assess the costs and benefits of
respective salts, but including the NSRR Norfolk Southern Railroad
Pub. L. Public Law available regulatory alternatives and, if
following: regulation is necessary, to select
§ Section
* * * * * U.S.C. United States Code regulatory approaches that maximize
Dated: July 5, 2017. net benefits. E.O. 13563 emphasizes the
II. Background, Purpose and Legal
Chuck Rosenburg, importance of quantifying both costs
Basis
Acting Administrator. and benefits, of reducing costs, of
In accordance with 33 CFR 117.42, harmonizing rules, and of promoting
[FR Doc. 2017–14482 Filed 7–11–17; 8:45 am]
the District Commander may authorize flexibility. This NPRM has not been
BILLING CODE 4410–09–P a drawbridge to operate under an designated a ‘‘significant regulatory
automated system or from a remote action,’’ under E.O. 12866. Accordingly,
location. The purpose of this rule is to NPRM it has not been reviewed by the
DEPARTMENT OF HOMELAND allow the draw of this bridge to operate Office of Management and Budget.
SECURITY from a remote location. The draw will This interim rule is not a significant
continue to be maintained in the open regulatory action because the draw will
Coast Guard to navigation position except during the be maintained in the open-to-navigation
passage of trains. Mariners should not position. Therefore, mariners will
33 CFR Part 117 experience any changes in the level of experience no changes in transiting
[Docket No. USCG–2017–0108] service. through the bridge site. No new
III. Discussion of the Proposed Rule restrictions on or actions from the
RIN 1625–AA09 mariner are required by this rule.
The Coast Guard, at the request of The intent of the proposed rule is to
Drawbridge Operation Regulation; NSRR, is changing the method of improve safety and efficiency of bridge
Tombigbee River, Near Jackson, operation for the NSRR Vertical Lift operations as it relates to vessel and
Alabama Bridge across Tombigbee River, mile railroad traffic.
AGENCY: Coast Guard, DHS. 44.90, near Jackson, Alabama. Due to Centralizing the bridge tender would
the need for increased efficiency in have no impact on the existing
ACTION: Notice of proposed rulemaking. railroad operations, NSRR requested a regulations regarding hours or methods
SUMMARY: The Coast Guard proposes to change to the method of operating the of bridge operations.
change the operating schedule that draw from on-site to a draw tender
operating the bridge remotely. B. Impact on Small Entities
governs the Norfolk Southern Railroad
(NSRR) Vertical Lift Span Bridge across Presently, the draw is maintained in The Regulatory Flexibility Act of 1980
Tombigbee River, mile 44.90, near the open-to-navigation position and (RFA), 5 U.S.C. 601–612, as amended,
Jackson, between Washington and closed only for the passage of trains or requires federal agencies to consider the
Clarke Counties, Alabama. This rule maintenance. The bridge owner would potential impact of regulations on small
proposes to move the current on-site like to operate the draw remotely using entities during rulemaking. The term
bridge tender control station to a a drawtender at a centralized railroad ‘‘small entities’’ comprises small
geographically remote centralized operation in Decatur, Alabama, rather businesses, not-for-profit organizations
control point located in Decatur, than maintaining the current on-site that are independently owned and
Alabama. operation and drawtender. The operated and are not dominant in their
nlaroche on DSK30NT082PROD with PROPOSALS

implementation of this rule, in effect, fields, and governmental jurisdictions
DATES: Comments and related material removes the requirement that a with populations of less than 50,000.
must reach the Coast Guard on or before drawtender be present on site at all The Coast Guard certifies under 5 U.S.C.
September 11, 2017. times. 605(b) that this proposed rule will not
ADDRESSES: You may submit comments Under the new remote operation have a significant economic impact on
identified by docket number USCG– procedure, the draw will continue to be a substantial number of small entities.
2017–0108 using Federal eRulemaking maintained in the open-to-navigation ‘‘While some owners or operators of
Portal at http://www.regulations.gov. position and lowered only for the vessels intending to transit the bridge

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Document Created: 2017-07-12 03:00:34
Document Modified: 2017-07-12 03:00:34

Category		Regulatory Information
Collection		Federal Register
sudoc Class		AE 2.7: GS 4.107: AE 2.106:
Publisher		Office of the Federal Register, National Archives and Records Administration
Section		Proposed Rules
Action		Notice of proposed rulemaking.
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 August 11, 2017. 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.
Contact		Michael J. Lewis, Diversion Control
FR Citation		82 FR 32153
CFR Associated		Administrative Practice and Procedure; Drug Traffic Control and Reporting and Recordkeeping Requirements

82 FR 32153 - Schedules of Controlled Substances: Removal of Naldemedine From Control

DEPARTMENT OF JUSTICEDrug Enforcement Administration

Federal Register Volume 82, Issue 132 (July 12, 2017)

DEPARTMENT OF JUSTICE
Drug Enforcement Administration