[Federal Register Volume 83, Number 196 (Wednesday, October 10, 2018)]
[Notices]
[Pages 50938-50942]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[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

[[Page 50939]]

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, 301-796-3156, 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

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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

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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

[[Page 50942]]

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


