[Federal Register Volume 83, Number 196 (Wednesday, October 10, 2018)]
[Notices]
[Pages 50938-50942]
[FR Doc No: 2018-21954]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2018-N-3685]

International Drug Scheduling; Convention on Psychotropic
Substances; Single Convention on Narcotic Drugs; ADB-FUBINACA; ADB-
CHMINACA; Cyclopropyl Fentanyl; Methoxyacetyl Fentanyl; para-Fluoro
Butyrfentanyl; Tramadol; Pregabalin; Cannabis Plant and Resin; and
Eight Additional Substances; Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice; request for comments.

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SUMMARY: The Food and Drug Administration (FDA) is requesting
interested persons to submit comments concerning abuse potential,
actual abuse, medical usefulness, trafficking, and impact of scheduling
changes on availability for medical use of 16 drug substances. These
comments will be considered in preparing a response from the United
States to the World Health Organization (WHO) regarding the abuse
liability and diversion of these drugs. WHO will use this information
to consider whether to recommend that certain international
restrictions be placed on these drugs. This notice requesting comments
is required by the Controlled Substances Act (the CSA).

DATES: Submit either electronic or written comments by October 31,
2018.

ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. Electronic comments
must be submitted on or before (enter date), 2018. The https://www.regulations.gov electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of October 31, 2018. Comments
received by mail/hand delivery/courier (for written/paper submissions)
will be considered timely if they are postmarked or the delivery
service acceptance receipt is on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any

confidential information that you or a third party may not wish to be
posted, such as medical information, your or anyone else's Social
Security number, or confidential business information, such as a
manufacturing process. Please note that if you include your name,
contact information, or other information that identifies you in the
body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No.
FDA-2018-N-3685 for ``International Drug Scheduling; Convention on
Psychotropic Substances; Single Convention on Narcotic Drugs; ADB-
FUBINACA; FUB-AMB(MMB-FUBINACA_AMB-FUBINACA); ADB-CHMINACA; CUMYL-4CN-
BINACA; Cyclopropyl Fentanyl; Methoxyacetyl Fentanyl; Ortho-
Fluorofentanyl; Para-Fluoro Butyrfentanyl; Para-Methoxybutyrfentanyl;
N-Ethylnorpentylone; Tramadol; Pregabalin; Cannabis Plant and Resin;
Extracts and Tinctures of Cannabis; Delta-9-Tetrahydrocannabinol;
Stereoisomers of Tetrahydrocannabinol; Request for Comments.'' Received
comments, those filed in a timely manner (see ADDRESSES), will be
placed in the docket and, except for those submitted as ``Confidential
Submissions,'' publicly viewable at https://www.regulations.gov or at
the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through
Friday.
     Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: James R. Hunter, Center for Drug
Evaluation and Research, Controlled Substance Staff, Food and Drug
Administration, 10903 New Hampshire Ave., Bldg. 51, Rm. 5150, Silver
Spring, MD 20993-0002,<PHONE_NUMBER>, email: [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    The United States is a party to the 1971 Convention on Psychotropic
Substances (Psychotropic Convention). Article 2 of the Psychotropic
Convention provides that if a party to the convention or WHO has
information about a substance, which in its opinion may require
international control or change in such control, it shall so notify the
Secretary-General of the United Nations (the U.N. Secretary-General)
and provide the U.N. Secretary-General with information in support of
its opinion.
    Paragraph (d)(2)(A) of the CSA (21 U.S.C. 811) (Title II of the
Comprehensive Drug Abuse Prevention and Control Act of 1970) provides
that when WHO notifies the United States under Article 2 of the
Psychotropic Convention that it has information that may justify adding
a drug or other substances to one of the schedules of the Psychotropic
Convention, transferring a drug or substance from one schedule to
another, or deleting it from the schedules, the Secretary of State must
transmit the notice to the Secretary of Health and Human Services
(Secretary of HHS). The Secretary of HHS must then publish the notice
in the Federal Register and provide opportunity for interested persons
to submit comments that will be considered by HHS in its preparation of
the scientific and medical evaluations of the drug or substance.

II. WHO Notification

    The Secretary of HHS received the following notice from WHO (non-
relevant text removed):

Ref.: C.L.26.2018

    The World Health Organization (WHO) presents its compliments to
Member States and Associate Members and has the pleasure of
informing that the 41th Expert Committee on Drug Dependence (ECDD)
will meet in Geneva from 12 to 16 November 2018. The 41th ECDD will
convene to review psychoactive substances on their potential to
cause dependence, abuse and harm to health, and their potential
therapeutic applications. WHO will make recommendations to the UN
Secretary-General on the need for and level of international control
of these substances.
    Member States are invited to collaborate, as in the past, in
this process by providing pertinent information as requested in the
questionnaire and concerning substances under review. At its 126th
session in January 2010, the Executive Board approved the
publication ``Guidance on the WHO review of psychoactive substances
for international control'' (EB126/2010/REC1, Annex 6) which
requires the Secretariat to request relevant information from
Ministers of Health in Member States to prepare a report for
submission to the ECDD.
    For this purpose, a questionnaire was designed to gather
information on the legitimate use, harmful use, status of national
control and potential impact of international control for each
substance under evaluation. A list of substances for which Member
States will receive questionnaires is attached.
    Kindly note that Member States who submitted questionnaire
responses that were reviewed at the 40th ECDD on cannabis and
cannabis-related substances will not be requested to re-submit
questionnaires for those substances for the 41st ECDD. However, if
Member States would like to amend their responses or submit
additional information on cannabis and cannabis-related substances,
it is requested that they inform the Secretariat.
    It would be appreciated if a person from the Ministry of Health
could be designated as the focal point responsible for coordinating
answers to the questionnaires. A list of focal

points designated by Member States for the 40th ECDD in June 2018 is
attached. It is requested that if a focal point's contact details
including email address are to be added or amended, that Member
States inform the Secretariat by 17 September 2018. Any additions or
amendments to focal point designations should be emailed to
[email protected].
    If no additions or amendments to focal point details are made by
this date, the focal point from 2018 will be approached by the
Secretariat for questionnaire completion. Where there is a competent
National Authority under the International Drug Control Treaties, it
is kindly requested that the questionnaires be completed in
collaboration with such body.
    Once the Secretariat has received the contact details, focal
points will be given further instructions and direct access to an
online questionnaire. The questionnaires will be analysed by the
Secretariat and prepared as a report that will be shared with the
Committee for review.
    Member States are also encouraged to provide any additional
relevant information (unpublished or published) that is available on
these substances to: [email protected]. This information will
be an invaluable contribution to the ECDD and all submissions will
be treated as confidential.
    The WHO takes this opportunity to renew to Member States and
Associate Members the assurance of its highest consideration.
GENEVA, 21 August 2018

Attachment:

41st WHO Expert Committee on Drug Dependence

Member State Questionnaire Substances

SYNTHETIC CANNABINOIDS

ADB-FUBINACA
FUB-AMB (MMB-FUBINACA, AMB-FUBINACA)
ADB-CHMINACA
CUMYL-4CN-BINACA

FENTANYLS

Cyclopropyl Fentanyl
Methoxyacetyl Fentanyl
Ortho-Fluorofentanyl
Para-Fluoro Butyrfentanyl
Para-Methoxybutyrfentanyl

(METH)CATHINONE

N-Ethylnorpentylone

MEDICINES

Tramadol
Pregabalin

    FDA has verified the website addresses contained in the WHO notice,
as of the date this document publishes in the Federal Register, but
websites are subject to change over time. Access to view the WHO
questionnaire can be found at http://www.who.int/medicines/access/controlled-substances/ecdd_41_meeting/en/.

III. Substances Under WHO Review

    ADB-FUBINACA (chemical name: N-[1-(aminocarbonyl)-2,2-
dimethylpropyl]-1-[(4-fluorophenyl)methyl]-1H-indazole-3-carboxamide)
is an indazole-based synthetic cannabinoid that is a potent, full
agonist at CB1 receptors. This substance functionally (biologically)
mimics the effects of the structurally unrelated delta-9-
tetrahydrocannabinol (THC), a Schedule I substance, and the main
psychoactive chemical constituent in the cannabis (marijuana) plant.
Synthetic cannabinoids have been marketed under the guise of ``herbal
incense,'' and promoted by drug traffickers as legal alternatives to
marijuana. ADB-FUBINACA use has been associated with serious adverse
events including death in the United States. There are no commercial or
approved medical uses for ADB-FUBINACA. On April 10, 2017, ADB-FUBINACA
was temporarily controlled as a Schedule I substance under the CSA.
    FUB-AMB (other names: MMB-FUBINACA; AMB-FUBINACA; chemical name:
methyl 2-(1-(4-fluorobenzyl)-1H-indazole-3-carboxamido)-3-
methylbutanoate) is an indazole-based synthetic cannabinoid that is a
potent full agonist at CB1 receptors. This substance functionally
(biologically) mimics the effects of the structurally unrelated THC, a
Schedule I substance, and the main psychoactive chemical constituent in
marijuana. Synthetic cannabinoids have been marketed under the guise of
``herbal incense,'' and promoted by drug traffickers as legal
alternatives to marijuana. FUB-AMB use has been associated with serious
adverse events including death in the United States. There are no
commercial or approved medical uses for FUB-AMB. On November 3, 2017,
FUB-AMB was temporarily controlled as a Schedule I substance under the
CSA.
    ADB-CHMINACA (other name: MAB-CHMINACA; chemical name: N-(1-amino-
3,3-dimethyl-1-oxobutan-2-yl)-1-(cyclohexylmethyl)-1H-indole-3-
carboxamide) is an indazole-based synthetic cannabinoid that is a
potent full agonist at CB1 receptors. This substance functionally
(biologically) mimics the effects of the structurally THC, a Schedule I
substance, and the main psychoactive chemical constituent in marijuana.
Synthetic cannabinoids have been marketed under the guise of ``herbal
incense,'' and promoted by drug traffickers as legal alternatives to
marijuana. ADB-CHMINACA use has been associated with serious adverse
events including death in the United States. There are no commercial or
approved medical uses for ADB-CHMINACA. On February 5, 2016, ADB-
CHMINACA was temporarily controlled as a Schedule I substance under the
CSA.
    CUMYL-4CN-BINACA (chemical name: 1-(4-cyanobutyl)-N-(2-
phenylpropan-2-yl)-1 H-indazole-3-carboxamide) is a clandestinely
produced indazole-3-carboxamide based synthetic cannabinoid that has
been sold online and used to mimic the biological effects of THC, the
main psychoactive chemical constituent in marijuana. Synthetic
cannabinoids have been marketed under the guise of ``herbal incense,''
and promoted by drug traffickers as legal alternatives to marijuana.
Hospital, scientific publications and law enforcement reports show that
CUMYL-4CN-BINACA is abused for its psychoactive properties. CUMYL-4CN-
BINACA has been associated with serious adverse events in the United
States, in addition to multiple deaths in Europe. CUMYL-4CN-BINACA has
no commercial or medical uses. On July 10, 2018, CUMYL-4CN-BINACA was
temporarily controlled as a Schedule I substance under the CSA.
    Cyclopropyl fentanyl is a synthetic opioid that has a
pharmacological profile similar to other Schedule I and II controlled
opioid substances such as acetyl fentanyl, fentanyl, and other related
mu-opioid receptor agonist substances. This clandestinely produced
analog of fentanyl is associated with adverse events typically
associated with opioid use such as respiratory depression, anxiety,
constipation, tiredness, hallucinations, and withdrawal. Cyclopropyl
fentanyl has been associated with numerous fatalities. At least 115
confirmed overdose deaths involving cyclopropyl fentanyl abuse have
been reported in the United States. Cyclopropyl fentanyl has no
commercial or currently accepted medical uses in the United States. On
January 4, 2018, cyclopropyl fentanyl was temporarily placed into
Schedule I of the CSA.
    Methoxyacetyl fentanyl has a pharmacological profile similar to
other Schedule I and II opioid substances such as acetyl fentanyl,
fentanyl, and other related mu-opioid receptor agonist substances.
Evidence suggests that the pattern of abuse of fentanyl analogues,
including methoxyacetyl fentanyl is similar to heroin and prescription
opioid analgesics. Law enforcement and public health reports
demonstrate that methoxyacetyl fentanyl is being illicitly distributed
and abused. The Drug Enforcement Administration (DEA) is aware of at
least two overdose deaths associated with the abuse of methoxyacetyl
fentanyl in the United

States. Methoxyacetyl fentanyl has no currently accepted medical use in
treatment in the United States. On October 26, 2017, methoxyacetyl
fentanyl was temporarily placed into Schedule I of the CSA.
    Ortho-fluorofentanyl has a pharmacological profile similar to
fentanyl and other related mu-opioid receptor agonist. Ortho-
fluorofentanyl has no currently accepted medical use in treatment in
the United States. Ortho-fluorofentanyl has been encountered by law
enforcement and public health officials. The DEA has received reports
for at least 13 confirmed overdose deaths involving ortho-
fluorofentanyl abuse in the United States. On October 26, 2017, ortho-
fluorofentanyl was temporarily placed into Schedule I of the CSA.
    Para-fluorobutyrfentanyl shares pharmacological profile with other
Schedule I (e.g., butyryl fentanyl) and II (e.g., fentanyl) opioid
substances. Para-fluorobutyrfentanyl has no currently accepted medical
use in treatment in the United States. The abuse of para-
fluorobutyrfentanyl carries public health risks similar to that of
heroin, fentanyl, and prescription opioid analgesics. On February 1,
2018, para-fluorobutyrfentanyl was temporarily placed into Schedule I
of the CSA.
    Para-methoxybutyrfentanyl shares pharmacological profile with other
Schedule I (e.g., butyryl fentanyl) and II (e.g., fentanyl) opioid
substances. Para-methoxybutyrfentanyl has no currently accepted medical
use in treatment in the United States. The abuse of para-
methoxybutyrfentanyl carries public health risks similar to that of
heroin, fentanyl, and prescription opioid analgesics. On February 1,
2018, para-methoxybutyrfentanyl was temporarily placed into Schedule I
of the CSA.
    N-ethylnorpentylone (other name: N-ethylpentylone) is a synthetic
cathinone with stimulant and psychoactive properties similar to
cathinone, a Schedule I substance. N-ethylpentylone abuse has been
associated with adverse health effects leading to emergency department
admissions, and deaths. N-ethylpentylone has no currently accepted
medical use in treatment in the United States. On August 31, 2018, N-
ethylnorpentylone was temporarily controlled as a Schedule I substance
under the CSA.
    Tramadol, an opioid analgesic, was first approved by the FDA for
medical use in March of 1995 for the treatment of moderate to
moderately severe pain. It is available as immediate-release, extended-
release, and combination products containing acetaminophen. Tramadol
has been abused alone or in combination with other psychoactive
substances. On July 2, 2014, the DEA issued a Final Rule controlling
tramadol as a Schedule IV substance under the CSA with effective date
of August 18, 2014.
    The ECDD pre-reviewed tramadol at its 39th meeting in November 2017
noting growing evidence of abuse of tramadol in many countries, in some
cases serious, accompanied by adverse reactions and tramadol-associated
deaths and recommending that tramadol be subject to a critical review
at a subsequent meeting.
    Pregabalin is an FDA-approved medication in the United States and
is available as an oral capsule and oral solution and approved for the
management of neuropathic pain associated with diabetic peripheral
neuropathy, postherpetic neuralgia, and adjunctive therapy for partial
onset seizures, fibromyalgia, and neuropathic pain associated with
spinal cord injury. Although the mechanism of action of pregabalin is
unknown, pregabalin is thought to produce its therapeutic effects on
neuropathic pain via binding with high affinity to the alpha 2-delta
receptor site (a subunit of voltage gated calcium channels) within the
central nervous system. Reports indicate that patients are self-
administering higher than recommended doses to achieve euphoria,
especially patients who have a history of substance abuse, particularly
opioids. While effects of excessively high doses are generally non-
lethal, gabapentinoids such as pregabalin are increasingly being
identified in postmortem toxicology analyses. Pregabalin is a Schedule
V controlled substance in the United States under the CSA. At its 39th
meeting in November 2017, the WHO Expert Committee on Drug Dependence
(ECDD) pre-reviewed pregabalin and, noting increasing evidence of
misuse and abuse in many countries, the ECDD recommended that
pregabalin be subject to a future critical review.
    Cannabis, also known as marijuana, is a plant known by biological
names Cannabis sativa or Cannabis indica. It is a complex plant
substance containing multiple cannabinoids and other compounds,
including the psychoactive chemical THC and other structurally similar
compounds. Cannabinoids are defined as having activity at cannabinoid 1
and 2 (CB1 and CB2 respectively) receptors. Agonists of CB1 receptors
are widely abused and are known to modulate motor coordination, memory
processing, pain, and inflammation, and have anxiolytic effects.
    The principal cannabinoids in the cannabis plant include THC,
cannabidiol (CBD), and cannabinol. These substances are controlled in
Schedule I under the CSA. The synthetically derived single pure
stereoisomer, (-)-trans-delta-9-THC (also known as dronabinol) is the
active ingredient in two approved drug products in the United States,
MARINOL (dronabinol) capsules (and generics) and SYNDROS (dronabinol)
oral solution. MARINOL is controlled in Schedule III, while SYNDROS is
controlled in Schedule II under the CSA. Both MARINOL and SYNDROS are
approved to treat anorexia associated with weight loss in patients with
acquired immunodeficiency syndrome (AIDS), and nausea and vomiting
associated with cancer chemotherapy in patients who have failed to
respond adequately to conventional treatment.
    CBD is another cannabinoid constituent of the cannabis plant. In
the United States, one CBD-containing product, Epidiolex oral solution,
has received marketing approval by FDA for the treatment of seizures
associated with two rare and severe forms of epilepsy, Lennox-Gastaut
syndrome and Dravet syndrome, in patients 2 years of age and older. The
CBD in Epidiolex is extracted and purified from the cannabis plant.
Currently, CBD is controlled generally as a Schedule I substance under
the CSA. However, the recent scheduling action on September 28, 2018,
by the DEA for Epidiolex, and any future, similar formulations of CBD
that become FDA-approved medications, places these FDA-approved CBD
formulations in Schedule V under the CSA.\1\ CBD is not specifically
listed in the schedules of the 1961, 1971, or 1988 International Drug
Control conventions.
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    \1\ https://www.ecfr.gov/cgi-bin/text-idx?SID=f43ff6b6883b0b81774fab03dcea8fa5&mc=true&node=pt21.9.1308&rgn=div5#se21.9.1308_115.
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    At the 40th (2018) meeting of the ECDD, the committee critically-
reviewed CBD and pre-reviews of cannabis plant and resin; extracts and
tinctures of cannabis; THC; and isomers of THC. The 40th ECDD
recommended that preparations considered to be pure CBD should not be
scheduled within the International Drug Control Conventions, and that
cannabis plant and resin; extracts and tinctures of cannabis; THC; and
isomers of THC proceed to a Critical Review.

IV. Opportunity To Submit Domestic Information

    As required by paragraph (d)(2)(A) of the CSA, FDA, on behalf of
HHS, invites

interested persons to submit comments regarding the 16 drug substances.
Any comments received will be considered by HHS when it prepares a
scientific and medical evaluation for drug substances that is
responsive to the WHO Questionnaire for these drug substances. HHS will
forward such evaluation of these drug substances to WHO, for WHO's
consideration in deciding whether to recommend international control/
decontrol of any of these drug substances. Such control could limit,
among other things, the manufacture and distribution (import/export) of
these drug substances and could impose certain recordkeeping
requirements on them.
    Although FDA is, through this notice, requesting comments from
interested persons, which will be considered by HHS when it prepares an
evaluation of these drug substances, HHS will not now make any
recommendations to WHO regarding whether any of these drugs should be
subjected to international controls. Instead, HHS will defer such
consideration until WHO has made official recommendations to the
Commission on Narcotic Drugs, which are expected to be made in mid-
2018. Any HHS position regarding international control of these drug
substances will be preceded by another Federal Register notice
soliciting public comments, as required by paragraph (d)(2)(B) of the
CSA.

    Dated: October 3, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-21954 Filed 10-9-18; 8:45 am]
 BILLING CODE 4164-01-P