[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]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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: [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
[[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: [email protected] 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
------------------------------------------------------------------------
------------------------------------------------------------------------
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.
------------------------------------------------------------------------
Pre-Review
------------------------------------------------------------------------
------------------------------------------------------------------------
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