Schedules of Controlled Substances: Removal of Naldemedine From Control, 32153-32157 [2017-14482]
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AGL WI E5 Stevens Point, WI [Amended]
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[FR Doc. 2017–14527 Filed 7–11–17; 8:45 am]
BILLING CODE 4910–13–P
DEPARTMENT OF JUSTICE
Drug Enforcement Administration
21 CFR Part 1308
[Docket No. DEA–468]
Schedules of Controlled Substances:
Removal of Naldemedine From Control
Drug Enforcement
Administration, Department of Justice.
ACTION: Notice of proposed rulemaking.
AGENCY:
The Drug Enforcement
Administration (DEA) proposes to
remove naldemedine (4R,4aS,7aR,12bS)3-(cyclopropylmethyl)-4a,7,9trihydroxy-N-(2-(3-phenyl-1,2,4oxadiazol-5-yl)propan-2-yl)2,3,4,4a,5,7a-hexahydro-1H-4,12methanobenzofuro[3,2-e]isoquinoline-6carboxamide) 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
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SUMMARY:
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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 https://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
PO 00000
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32153
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 https://
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 https://
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 https://
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
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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
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
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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.
Background
Naldemedine, known chemically as
(4R,4aS,7aR,12bS)-3(cyclopropylmethyl)-4a,7,9-trihydroxyN-(2-(3-phenyl-1,2,4-oxadiazol-5yl)propan-2-yl)-2,3,4,4a,5,7a-hexahydro1H-4,12-methanobenzofuro[3,2e]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® (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
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.
2 https://www.accessdata.fda.gov/drugsatfda_
docs/appletter/2017/208854Orig1s000ltr.pdf (last
accessed 04/13/2017).
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peripheral acting mu-opioid antagonist,
can prevent OIC.
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 https://
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
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or abuse potential related adverse events
(AEs) (HHS review, 2017). These data
demonstrate that naldemedine lacks a
potential for abuse.
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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.
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 placebotreated 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-trihydroxy3 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 OpioidInduced Constipation. American Journal of
Gastroentrology. S110: 1322.
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N-(2-(3-phenyl-1,2,4-oxadiazol-5yl)propan-2-yl)-2,3,4,4a,5,7a-hexahydro1H-4,12-methanobenzofuro[3,2e]isoquinoline-6-carboxamide 4methylbenzenesulfonate. 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 abuserelated 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
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.
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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.
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.
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
DEA laboratory data submitted after September 30,
2014 are reposited in STARLiMS.
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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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® for the
treatment of opioid-induced
constipation in adults with chronic noncancer 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.
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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.
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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
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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:
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Federal Register / Vol. 82, No. 132 / Wednesday, July 12, 2017 / Proposed Rules
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),
unless otherwise noted.
2. In § 1308.12, amend 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: July 5, 2017.
Chuck Rosenburg,
Acting Administrator.
BILLING CODE 4410–09–P
DEPARTMENT OF HOMELAND
SECURITY
Coast Guard
33 CFR Part 117
[Docket No. USCG–2017–0108]
RIN 1625–AA09
Drawbridge Operation Regulation;
Tombigbee River, Near Jackson,
Alabama
Coast Guard, DHS.
Notice of proposed rulemaking.
AGENCY:
The Coast Guard proposes to
change the operating schedule that
governs the Norfolk Southern Railroad
(NSRR) Vertical Lift Span Bridge across
Tombigbee River, mile 44.90, near
Jackson, between Washington and
Clarke Counties, Alabama. This rule
proposes to move the current on-site
bridge tender control station to a
geographically remote centralized
control point located in Decatur,
Alabama.
nlaroche on DSK30NT082PROD with PROPOSALS
SUMMARY:
Comments and related material
must reach the Coast Guard on or before
September 11, 2017.
ADDRESSES: You may submit comments
identified by docket number USCG–
2017–0108 using Federal eRulemaking
Portal at https://www.regulations.gov.
DATES:
VerDate Sep<11>2014
14:04 Jul 11, 2017
Jkt 241001
I. Table of Abbreviations
CFR Code of Federal Regulations
DHS Department of Homeland Security
E.O. Executive Order
FR Federal Register
NPRM Notice of proposed rulemaking
U.S.C. United States Code
NSRR Norfolk Southern Railroad
Pub. L. Public Law
§ Section
U.S.C. United States Code
II. Background, Purpose and Legal
Basis
In accordance with 33 CFR 117.42,
the District Commander may authorize
a drawbridge to operate under an
automated system or from a remote
location. The purpose of this rule is to
allow the draw of this bridge to operate
from a remote location. The draw will
continue to be maintained in the open
to navigation position except during the
passage of trains. Mariners should not
experience any changes in the level of
service.
[FR Doc. 2017–14482 Filed 7–11–17; 8:45 am]
ACTION:
See the ‘‘Public Participation and
Request for Comments’’ portion of the
SUPPLEMENTARY INFORMATION section
below for instruction on submitting
comments.
FOR FURTHER INFORMATION CONTACT: If
you have questions on this proposed
rule, call or email Ms. Donna Gagliano;
Bridge Administration Branch, Eighth
Coast Guard District; telephone 504–
671–2128, email Donna.Gagliano@
uscg.mil.
SUPPLEMENTARY INFORMATION:
III. Discussion of the Proposed Rule
The Coast Guard, at the request of
NSRR, is changing the method of
operation for the NSRR Vertical Lift
Bridge across Tombigbee River, mile
44.90, near Jackson, Alabama. Due to
the need for increased efficiency in
railroad operations, NSRR requested a
change to the method of operating the
draw from on-site to a draw tender
operating the bridge remotely.
Presently, the draw is maintained in
the open-to-navigation position and
closed only for the passage of trains or
maintenance. The bridge owner would
like to operate the draw remotely using
a drawtender at a centralized railroad
operation in Decatur, Alabama, rather
than maintaining the current on-site
operation and drawtender. The
implementation of this rule, in effect,
removes the requirement that a
drawtender be present on site at all
times.
Under the new remote operation
procedure, the draw will continue to be
maintained in the open-to-navigation
position and lowered only for the
PO 00000
Frm 00009
Fmt 4702
Sfmt 4702
32157
passage of trains or for maintenance.
There will be no modifications to the
operation of the bridge as it relates to
the passage of vessels. Instead, this
change will allow the bridge owner to
increase efficiency by coordinating
bridge operations and vessel transits
with train dispatch operations in
Decatur, AL.
IV. Regulatory Analyses
We developed this proposed rule after
considering numerous statutes and
Executive Orders related to rulemaking.
Below we summarize our analyses
based on these statues and Executive
Orders and we discuss First
Amendment rights of protesters.
A. Regulatory Planning and Review
E.O.s 12866 and 13563 direct agencies
to assess the costs and benefits of
available regulatory alternatives and, if
regulation is necessary, to select
regulatory approaches that maximize
net benefits. E.O. 13563 emphasizes the
importance of quantifying both costs
and benefits, of reducing costs, of
harmonizing rules, and of promoting
flexibility. This NPRM has not been
designated a ‘‘significant regulatory
action,’’ under E.O. 12866. Accordingly,
NPRM it has not been reviewed by the
Office of Management and Budget.
This interim rule is not a significant
regulatory action because the draw will
be maintained in the open-to-navigation
position. Therefore, mariners will
experience no changes in transiting
through the bridge site. No new
restrictions on or actions from the
mariner are required by this rule.
The intent of the proposed rule is to
improve safety and efficiency of bridge
operations as it relates to vessel and
railroad traffic.
Centralizing the bridge tender would
have no impact on the existing
regulations regarding hours or methods
of bridge operations.
B. Impact on Small Entities
The Regulatory Flexibility Act of 1980
(RFA), 5 U.S.C. 601–612, as amended,
requires federal agencies to consider the
potential impact of regulations on small
entities during rulemaking. The term
‘‘small entities’’ comprises small
businesses, not-for-profit organizations
that are independently owned and
operated and are not dominant in their
fields, and governmental jurisdictions
with populations of less than 50,000.
The Coast Guard certifies under 5 U.S.C.
605(b) that this proposed rule will not
have a significant economic impact on
a substantial number of small entities.
‘‘While some owners or operators of
vessels intending to transit the bridge
E:\FR\FM\12JYP1.SGM
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Agencies
[Federal Register Volume 82, Number 132 (Wednesday, July 12, 2017)]
[Proposed Rules]
[Pages 32153-32157]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[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.
-----------------------------------------------------------------------
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 https://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 https://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 https://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 https://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.
---------------------------------------------------------------------------
\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.
---------------------------------------------------------------------------
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.
---------------------------------------------------------------------------
\2\ https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/208854Orig1s000ltr.pdf (last accessed 04/13/2017).
---------------------------------------------------------------------------
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 https://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.
---------------------------------------------------------------------------
\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.
---------------------------------------------------------------------------
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.
---------------------------------------------------------------------------
\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.
---------------------------------------------------------------------------
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.
---------------------------------------------------------------------------
\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.
---------------------------------------------------------------------------
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