[Federal Register Volume 84, Number 175 (Tuesday, September 10, 2019)]
[Notices]
[Pages 47521-47525]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-19492]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2019-N-3968]


International Drug Scheduling; Convention on Psychotropic 
Substances; Single Convention on Narcotic Drugs; APINACA; AB-FUBINACA; 
5F-AMB; 5F-MDMB-PICA; 4-F-MDMB-BINACA; 4-CMC; N-ethylhexedrone; alpha-
PHP; DOC; Crotonyl Fentanyl; Valeryl Fentanyl; Flualprazolam; Etizolam; 
and 8 Additional Preparations Listed in Schedule III of the 1961 Single 
Convention on Narcotic Drugs; 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

[[Page 47522]]

abuse, medical usefulness, trafficking, and impact of scheduling 
changes on availability for medical use of 21 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 4, 2019.

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 (October 4, 2019. The https://www.regulations.gov electronic filing system will accept comments until 
11:59 p.m. Eastern Time at the end of October 4, 2019. 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-2019-N-3968 for ``International Drug Scheduling; Convention on 
Psychotropic Substances; Single Convention on Narcotic Drugs; APINACA 
(AKB-48); AB-FUBINACA; 5F-AMB (5F-AMB-PINACA, 5F-MMB-PINACA); 5F-MDMB-
PICA (5F-MDMB-2201); 4-F-MDMB-BINACA (4F-ADB); 4-CMC (4-
chloromethcathinone; clefedrone); N-ethylhexedrone (NEH, hexen, ethyl-
hex); alpha-PHP (PV-7, [alpha]-pyrrolidinohexanophenone); DOC (2,5-
dimethoxy-4-chloroamfetamine); Crotonyl Fentanyl; Valeryl Fentanyl; 
Flualprazolam; Etizolam; Preparations listed in Schedule III of the 
1961 Single Convention on Narcotic Drugs as follows: 
Acetyldihydrocodeine, Codeine; Dihydrocodeine; Ethylmorphine; 
Nicocodine; Nicodicodine; Norcodeine; Pholcodine: 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: james.hunter@fda.hhs.gov.

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

[[Page 47523]]

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.30.2019

    The World Health Organization (WHO) presents its compliments to 
Member States and Associate Members and in reference to C.L.14.2019 
has the pleasure of informing that the 42nd Expert Committee on Drug 
Dependence (ECDD) will meet in Geneva from 21 to 25 October 2019. 
The Expert Committee on Drug Dependence meetings are of a closed 
nature, however a public information session on 21 October will be 
open to Member States.
    Further information, including a full agenda of the meeting, 
will be available on the ECDD website: https://www.who.int/medicines/access/controlled-substances/ecdd/ecdd/en/.
    The 42nd ECDD will convene to review psychoactive substances 
(attached) regarding 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 in this process through 
designated national focal points, as in the past and in line with 
the publication ``Guidance on the WHO review of psychoactive 
substances for international control'' (EB126/2010/REC1, Annex 6, 
Para 21).\1\
    For this purpose, a questionnaire was designed to gather country 
information on the legitimate use, harmful use, status of national 
control and potential impact of international control for each 
substance under evaluation.
    National focal points designated by Member States following 
C.L.14.2019 will be approached to complete the questionnaire on 
substances under review at the 42nd ECDD meeting. Focal points will 
be given further instructions and direct access to online 
questionnaires. The questionnaires will be analysed by the 
Secretariat and prepared as a report that will be shared with the 
Committee for review.
    Focal points are also encouraged to provide any additional 
relevant information (unpublished or published) on substances to be 
reviewed at the 42nd ECDD to: ecddsecretariat@who.int by 20 
September 2019.
    The World Health Organization takes this opportunity to renew to 
Member States and Associate Members the assurance of its highest 
consideration.
    GENEVA, 29 July 2019

\1\http://apps.who.int/gb/ebwha/pdf_files/EB126-REC1/B126_REC1-en.pdf#page=95.

42nd Expert Committee on Drug Dependence (ECDD) 21 to 25 October 2019, 
WHO headquarters, Geneva, Switzerland Substances Under Review

                             Critical Review
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Synthetic cannabinoids.................  1. APINACA (AKB-48).
                                         2. AB-FUBINACA.
                                         3. 5F-AMB (5F-AMB-PINACA, 5F-
                                          MMB-PINACA).
                                         4. 5F-MDMB-PICA (5F-MDMB-2201).
                                         5. 4-F-MDMB-BINACA (4F-ADB).
Synthetic stimulants...................  6. 4-CMC (4-
                                          chloromethcathinone;
                                          clefedrone).
                                         7. N-ethylhexedrone (NEH,
                                          Hexen, Ethyl-Hex).
                                         8. Alpha-PHP (PV-7, [alpha]-
                                          pyrrolidinohexanophenone).
                                         9. DOC (2,5-Dimethoxy-4-
                                          chloroamfetamine).
Fentanyl Analogues.....................  10. Crotonyl fentanyl.
                                         11. Valeryl fentanyl.
Benzodiazepines........................  12. Flualprazolam.
                                         13. Etizolam.
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                               Pre-Review
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Preparations listed in Schedule III of   Preparations of:
 the 1961 Single Convention on Narcotic  [cir] Acetyldihydrocodeine.
 Drugs.                                  [cir] Codeine.
                                         [cir] Dihydrocodeine.
                                         [cir] Ethylmorphine.
                                         [cir] Nicocodine.
                                         [cir] Nicodicodine.
                                         [cir] Norcodeine.
                                         [cir] Pholcodine.
                                         when compounded with one or
                                          more other ingredients and
                                          containing not more than 100
                                          milligrams of the drug per
                                          dosage unit and with a
                                          concentration of not more than
                                          2.5 percent in undivided
                                          preparation.
------------------------------------------------------------------------


    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 https://www.who.int/medicines/access/controlled-substances/ecdd_41_meeting/en/.

III. Substances Under WHO Review

    APINACA (AKB-48) (chemical name: N-(1-adamantyl)-1-pentyl-1H-
indazole-3-carboxamide) is a synthetic cannabinoid with a high affinity 
for the CB1 receptor. This substance functionally (biologically) mimics 
the effects of delta-9-tetrahydrocannabinol (THC), a Schedule I 
substance, and the main psychoactive 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. Chronic abuse of synthetic cannabinoids has 
been linked to adverse health effects including signs of addiction and 
withdrawal, as well as numerous reports of emergency room admissions 
resulting from their abuse. There are no commercial or approved medical 
uses for APINACA. On May 16, 2013, APINACA was temporarily controlled 
as a Schedule I substance under the CSA. On May 11, 2016, APINACA was 
permanently placed in Schedule I under the CSA.
    AB-FUBINACA (chemical name: N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-
(4-fluorobenzyl)-1H-indazole-3-carboxamide) is a synthetic cannabinoid

[[Page 47524]]

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. AB-FUBINACA use has 
been associated with serious adverse events including death in the 
United States. There are no commercial or approved medical uses for AB-
FUBINACA. On February 10, 2014, AB-FUBINACA was temporarily controlled 
as a Schedule I substance under the CSA. On September 6, 2016, AB-
FUBINACA was permanently placed as a Schedule I controlled substance 
under the CSA.
    5F-AMB (5F-AMB-PINACA, 5F-MMB-PINACA) (chemical name: Methyl 2-(1-
(5-fluoropentyl)-1H-indazole-3-carboxamido)-3-methylbutanoate) is a 
synthetic cannabinoid that is a potent full agonist at CB1 receptors. 
This substance functionally (biologically) mimics the effects of THC, a 
Schedule I substance, and the main psychoactive constituent in 
marijuana. Synthetic cannabinoids have been marketed under the guise of 
``herbal incense,'' and promoted by drug traffickers as legal 
alternatives to marijuana. The use of synthetic cannabinoids, 
including, 5F-AMB has been associated with nausea and vomiting, 
shortness of breath or depressed breathing, hypertension, tachycardia, 
chest pain, muscle twitching, acute renal failure, anxiety, agitation, 
psychosis, suicidal ideation, and/or cognitive impairment. There are no 
commercial or approved medical uses for 5F-AMB. On April 10, 2017, 5F-
AMB was temporarily controlled as a Schedule I substance under the CSA. 
This temporary rule was extended effective April 10, 2019. On April 8, 
2019, a Drug Enforcement Administration Notice of Proposed Rulemaking 
proposed permanently placing 5F-AMB into Schedule I of the CSA.
    5F-MDMB-PICA (5F-MDMB-2201) (chemical name: Methyl 2-(1-(5-
fluoropentyl)-1H-indazole-3-carboxamido)-3,3-dimethylbutanoate) is a 
synthetic cannabinoid that has been sold online and used to mimic the 
biological effects of THC, the main psychoactive constituent in 
marijuana. Research and clinical reports have demonstrated that 
synthetic cannabinoids are applied onto plant material so that the 
material may be smoked as users attempt to obtain a euphoric and 
psychoactive ``high.'' Synthetic cannabinoids have been marketed under 
the guise of ``herbal incense,'' and promoted by drug traffickers as 
legal alternatives to marijuana. 5F-MDMB-PICA has been associated with 
law enforcement seizures and overdoses requiring emergency medical 
intervention. On April 16, 2019, 5F-MDMB-PICA was temporarily 
controlled as a Schedule I substance under the CSA.
    4F-MDMB-BINACA (4F-ADB) (chemical name: Methyl 2-(1-(4-
fluorobutyl)-1H-indazole-3-carboxamido)-3,3-dimethylbutanoate) is a 
synthetic cannabinoid that is a potent full agonist at CB1 receptors. 
This substance functionally (biologically) mimics the effects of THC, a 
Schedule I substance, and the main psychoactive constituent in 
marijuana. 4F-MDMB-BINACA has been encountered in numerous synthetic 
cannabinoid products that are smoked for their psychoactive effects. 
Multiple law enforcement encounters of 4F-MDMB-BINACA have been 
reported involving overdose deaths, illicit use, and seizures of drug 
evidence between December 2018 and February 2019. There are no 
commercial or approved medical uses for 4F-MDMB-BINACA. 4F-MDMB-BINACA 
is a positional isomer of 5F-AMB (chemical name: Methyl 2-(1-(5-
fluoropentyl)-1H-indazole-3-carboxamido)-3-methylbutanoate), as defined 
by 21 CFR 1300.01, and has been a Schedule I controlled substance under 
the CSA since April 10, 2017.
    4-CMC (4-chloromethcathinone; clefedrone, clephedrone) (chemical 
name: 1-(4-chlorophenyl)-2-(methylamino)propan-1-one) is a synthetic 
cathinone. 4-CMC produces central nervous system stimulant effects and 
is abused for its psychoactive properties. 4-CMC abuse has been 
associated with adverse health effects. 4-CMC has no currently accepted 
medical use in treatment in the United States. 4-CMC is not controlled 
under the CSA, but it is considered a Schedule I controlled substance 
by a number of states in the United States.
    N-Ethylhexedrone (chemical name: 2-(ethylamino)-1-phenylhexan-1-
one; NEH, hexen, Ethyl-Hex) and alpha-PHP (chemical name: 1-phenyl-2-
(pyrrolidin-1-yl)hexan-1-one; PV-7, [alpha]-pyrrolidinohexanophenone) 
are synthetic cathinones. N-Ethylhexedrone and alpha-PHP produce 
central nervous system stimulant effects and are abused for their 
psychoactive properties. N-Ethylhexedrone and alpha-PHP have been 
associated with adverse health effects leading to emergency department 
admissions, and deaths. N-Ethylhexedrone and alpha-PHP have no 
currently accepted medical use in treatment in the United States. On 
July 18, 2019, N-Ethylhexedrone and alpha-PHP were temporarily 
controlled as a Schedule I substance under the CSA.
    DOC (chemical names: 2,5-Dimethoxy-4-chloroamfetamine; 2,5-
dimethoxy-4-chloroamphetamine; 1-(4-chloro-2,5-dimethoxyphenyl)propan-
2-amine) is a hallucinogenic substance with psychedelic effects. Law 
enforcement has encountered DOC in tablet, capsule, powder, liquid, and 
blotter paper forms. Its use has been associated with at least one 
death. DOC has no currently accepted medical use in treatment in the 
United States. DOC is not controlled under the CSA but is a Schedule I 
controlled substance in the state of Florida.
    Crotonyl fentanyl (chemical name: N-(1-phenethylpiperidin-4-yl)-N-
phenylbut-2-enamide) and valeryl fentanyl (chemical name: N-(1-
phenethylpiperidin-4-yl)-N-phenylpentanamide) are synthetic opioids 
that have a pharmacological profile similar to other Schedule I and II 
controlled opioid substances such as cyclopropyl fentanyl, fentanyl, 
and other related mu-opioid receptor agonist substances. They are 
clandestinely produced and associated with adverse events typically 
associated with opioid use such as respiratory depression, anxiety, 
constipation, tiredness, hallucinations, and withdrawal. Crotonyl 
fentanyl and valeryl fentanyl have been encountered by law enforcement 
and/or reported in the scientific literature by public health officials 
as being illicitly distributed and abused. Crotonyl fentanyl and 
valeryl fentanyl have no commercial or currently accepted medical uses 
in the United States. On February 1, 2018, valeryl fentanyl was 
temporarily placed into Schedule I of the CSA. The chemical structure 
of crotonyl fentanyl defines it as a fentanyl-related substance, as 
defined in 21 CFR 1308.11(h)(30); therefore, crotonyl fentanyl was 
temporarily controlled as a Schedule I controlled substance under the 
CSA as of February 6, 2018.
    Flualprazolam and etizolam belong to a class of substances known as 
benzodiazepines. Benzodiazepines produce central nervous system 
depression and are commonly used to treat insomnia, anxiety, and 
seizure disorders. Etizolam is currently prescribed in some countries; 
however, neither drug substance is approved for medical use in the 
United States. Currently, flualprazolam and etizolam are not controlled 
under the CSA, but are controlled in a number of States.

[[Page 47525]]

    Acetyldihydrocodeine is an opiate derivative of low to moderate 
potency used as a cough suppressant and analgesic in various other 
countries. Acetyldihydrocodeine is not approved for medical use in the 
United States and is controlled under Schedule I of the CSA.
    Codeine is an opioid drug closely related to morphine. Codeine can 
cause opioid tolerance, dependence, addiction, poisoning, and 
respiratory depression in high doses. It is an active ingredient in 
several approved narcotic analgesic and antitussive medicines in the 
United States. Codeine is approved for marketing in the United States 
and available as a single-ingredient product, or in combination with 
one or more nonnarcotic ingredients in recognized therapeutic amounts. 
Codeine is controlled in Schedule II of the CSA. Some codeine 
combination products are controlled in Schedule III and some in 
Schedule V, depending on the concentration or amount of codeine present 
in the approved product.
    Dihydrocodeine is a semisynthetic narcotic related to codeine. 
Dihydrocodeine is an active ingredient in prescription-only oral tablet 
combination products approved for marketing in the United States for 
the treatment of moderate to moderately severe pain. Dihydrocodeine is 
controlled in Schedule II of the CSA. Some dihydrocodeine-containing 
combination products are controlled in Schedule III and some in 
Schedule V, depending on the concentration or amount of dihydrocodeine 
present in the approved product.
    Ethylmorphine is a derivative of morphine with analgesic and 
antitussive effects. It is not approved for medical use in the United 
States but is approved for use in various other countries around the 
world. Ethylmorphine is controlled in Schedule II of the CSA. Some 
ethylmorphine containing combination products are controlled in 
Schedule III and some in Schedule V, depending on the concentration or 
amount of ethylmorphine present in the approved product.
    Nicocodine (nicocodeine) and nicodicodine (nicodicodeine) are 
esters of codeine and dihydrocodeine, respectively. They are opioids 
with analgesic and cough suppressant effects. They are not approved for 
medical use in the United States. Nicocodeine is controlled in Schedule 
I of the CSA. As an ester of dihydrocodeine, nicodicodeine is 
controlled in Schedule II of the CSA.
    Pholcodine is an opiate with cough suppressant effects but little 
to no analgesic effects. It is an active ingredient in cough lozenges 
in some countries but is not an ingredient in any products approved for 
medical use in the United States. Pholcodine is controlled in Schedule 
I of the CSA.

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 21 
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 late 
2019. 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: September 4, 2019.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2019-19492 Filed 9-9-19; 8:45 am]
BILLING CODE 4164-01-P


