[Federal Register Volume 89, Number 157 (Wednesday, August 14, 2024)]
[Notices]
[Pages 66117-66119]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2024-18045]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2024-N-3677]
International Drug Scheduling; Single Convention on Narcotic
Drugs; Convention on Psychotropic Substances; Hexahydrocannabinol; N-
Pyrrolidino Protonitazene (Protonitazepyne); N-Pyrrolidino Metonitazene
(Metonitazepyne); N-Piperidinyl Etonitazene (Etonitazepipne); N-
Desethyl-isotonitazene; 3-Hydroxy-phencyclidine; N-Ethylheptedrone;
Carisoprodol; 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 or Agency) is inviting
interested persons to submit comments concerning abuse potential,
actual abuse, medical usefulness, trafficking, and impact of scheduling
changes on availability for medical use of eight 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 drug substances. This notice requesting
comments is required by the Controlled Substances Act (CSA).
DATES: Either electronic or written comments must be submitted by
August 23, 2024.
ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. The https://www.regulations.gov electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of August 21, 2024. Comments
received by mail/hand delivery/courier (for written/paper submissions)
will be considered timely if they are received 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-2024-N-3677 for ``International Drug Scheduling; Single Convention
on Narcotic Drugs; Convention on Psychotropic Substances;
Hexahydrocannabinol (HHC); N-Pyrrolidino Protonitazene
(Protonitazepyne); N-Pyrrolidino Metonitazene (Metonitazepyne); N-
Piperidinyl Etonitazene (Etonitazepipne); N-Desethyl-isotonitazene; 3-
Hydroxy-phencyclidine (3-OH-PCP); N-Ethylheptedrone; Carisoprodol;
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, 240-402-7500.
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.govinfo.gov/content/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, 240-402-7500.
FOR FURTHER INFORMATION CONTACT: Edward (Greg) Hawkins, Center for Drug
Evaluation and Research, Controlled Substance Staff, Food and Drug
Administration, 10903 New Hampshire Ave., Bldg. 51, Rm. 5110, Silver
Spring, MD 20993-0002, 301-796-0727, [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
[[Page 66118]]
may require international control or change in such control, it shall
so notify the Secretary-General of the United Nations (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(d)(2)(A)) (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
(nonrelevant text removed):
Ref.: C.L.29.2024
The World Health Organization (WHO) presents its compliments to
Member States and Associate Members and would like to inform that
all recommendations made by the 46th WHO Expert Committee on Drug
Dependence (ECDD), held in October 2023, were accepted by the 67th
UN Commission on Narcotic Drugs.
WHO further has the pleasure of announcing that the 47th Expert
Committee on Drug Dependence (ECDD) will meet from 14 to 18 October
2024 in Geneva, Switzerland. Given that WHO Expert Committee
meetings are of a closed nature, this circular letter serves to
notify Member States of the agenda of the 47th ECDD, which are in
the Annex I file, attached for reference.
WHO is mandated by the 1961 and 1971 International Drug Control
Conventions to make recommendations to the UN Secretary-General on
the need for and level of international control of psychoactive
substances. To fulfil this mandate, WHO convenes the ECDD to advise
on appropriate international drug control measures in view of a
substance's ability to lead to public health harms as a result of
their psychoactive properties, as well as its therapeutic
applications.
Although the meetings are of a closed nature, Member States,
Associate Members, individuals, and representatives of public and
private institutions and civil society who wish to present
information to the Expert Committee on issues related to the meeting
agenda are invited to attend a virtual information meeting (public
consultation) on 14 October 2024. The purpose of the information
meeting is to afford the Expert Committee the opportunity to receive
presentations and to question representatives of interested parties
concerning data that have been provided about substances on the ECDD
agenda. Registration information will be made available on the ECDD
website in due course: Forty-seventh Expert Committee on Drug
Dependence (who.int).
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), Member States and Associate
Members can also contribute to the ECDD review process by providing
up to date and accurate information concerning the substances under
review in advance of the meeting. For this purpose, and as per
previous practice, a questionnaire will be sent to Member States and
Associate Members 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.
The World Health Organization takes this opportunity to renew to
Member States and Associate Members the assurance of its highest
consideration.
GENEVA, 3 July 2024
Annex I
47th Expert Committee on Drug Dependence (ECDD) Substances for
Review 14-18 October 2024
Critical reviews: The substances listed below have been proposed
by WHO for critical review and are not currently under international
control. Information was brought to WHO's attention that these
substances are clandestinely manufactured, of especially serious
risk to public health and society, and of no recognized therapeutic
use by any Party. The Expert Committee will consider whether
information presented during a critical review may justify the
scheduling or a change in the scheduling of the substance in the
1961 or 1971 Conventions.
Synthetic Cannabinoids
1. Hexahydrocannabinol (HHC)
Novel Synthetic Opioids
1. N-Pyrrolidino protonitazene (protonitazepyne)
2. N-Pyrrolidino metonitazene (metonitazepyne)
3. N-Piperidinyl etonitazene (etonitazepipne)
4. N-Desethyl-isotonitazene
Dissociative-Type Substances
1. 3-Hydroxy-phencyclidine (3-OH-PCP)
Cathinone/Stimulant
1. N-Ethylheptedrone
Medicine
1. Carisoprodol
FDA has verified the website addresses contained in the WHO notice
as of the date this document publishes in the Federal Register;
however, websites are subject to change over time. Access to view the
WHO questionnaire can be found at https://www.who.int/groups/ecdd/forty-seventh-ecdd-documents.
III. Substances Under WHO Review
Hexahydrocannabinol (HHC) is a semi-synthetic cannabinoid. Several
synthetic mechanisms for HHC have been published, which involve
hydrogenating tetrahydrocannabinol (THC). In vitro receptor binding and
activity studies indicate that HHC has higher affinity and agonist
activity at the cannabinoid type 1 (CB1) receptor compared to that of
the CB2 receptor. These data suggest that HHC produces effects similar
to CB1 agonists, such as sedation, analgesia, mood changes, altered
memory, psychosis, and panic. According to the National Forensic
Laboratory Information System (NFLIS) database, HHC was first detected
in the United States in 2022 with a total of 54 law enforcement
seizures. There are no commercial uses or approved medical uses for HHC
in the United States, and it is not controlled under the CSA.
N-Pyrrolidino protonitazene (protonitazepyne) is a synthetic opioid
of the nitazene family that is similar in structure to protonitazene.
In vitro binding and activity data indicate that protonitazepyne is
approximately 25-fold more potent at the mu opioid receptor than
fentanyl. Common adverse events of opioid agonists include nausea,
vomiting, constipation, pruritus, dizziness, sedation, and respiratory
depression, which can lead to death. Protonitazepyne has been detected
in 20 forensic toxicology cases in the United States and the United
Kingdom. However, other new psychoactive substances (NPS) or other
drugs of abuse were detected in all of these individuals and could have
been a contributing factor to the fatality. According to the NFLIS
database, protonitazepyne was first detected in 2023 and has been
confirmed in 16 law enforcement seizures to date. There are no
commercial uses or approved medical uses for protonitazepyne in the
United States, and it is not controlled under the CSA.
N-Pyrrolidino metonitazene (metonitazepyne) is a synthetic opioid
of the nitazene family that is similar in structure to metonitazene. In
vitro binding and activity data indicate that protonitazepyne is
approximately 2-fold more potent at the mu opioid receptor than
fentanyl. In animal behavior studies it produced subjective effects
that were indistinguishable from morphine. As a result, it is assumed
that metonitazepyne will have an abuse potential similar to that of
other opioid agonists and produce adverse events that include nausea,
vomiting,
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constipation, pruritus, dizziness, sedation, and respiratory
depression, which can lead to death. In the United States,
metonitazepyne was detected in six toxicology cases; however, other NPS
or other drugs of abuse were detected in all of these individuals and
could have been a contributing factor to the fatality. According to the
NFLIS database, metonitazepyne was first detected in 2023 and there
have been seven confirmed law enforcement seizures to date. There are
no commercial uses or approved medical uses for metonitazepyne in the
United States, and it is not controlled under the CSA.
N-Piperidynyl etonitazene (etonitazepipne) is a synthetic opioid of
the nitazene family and is similar in structure to etonitazene. In
vitro binding and activity data indicate that protonitazepyne is
approximately 100-fold more potent at the mu opioid receptor than
morphine. In animal behavior studies it produced subjective effects
that were indistinguishable from morphine. As a result, it is assumed
that etonitazepipne will have an abuse potential similar to that of
other opioid agonists and produce adverse events that include nausea,
vomiting, constipation, pruritus, dizziness, sedation, and respiratory
depression, which can lead to death. According to the NFLIS database,
etonitazepipne was first detected in 2022 and there have been 10
confirmed law enforcement seizures to date. There are no commercial
uses or approved medical uses for etonitazepipne in the United States.
As of July 29, 2024, etonitazepipne is temporarily controlled in
schedule I under the CSA.
N-Desethyl-isotonitazene is a synthetic opioid of the nitazene
family and is similar in structure to isotonitazene and is a known
active metabolite of isotonitazene. In vitro binding and activity data
indicate that N-desethyl-isotonitazene is approximately 20-fold more
potent at the mu opioid receptor than fentanyl. In animal behavior
studies it produced subjective effects that were indistinguishable from
morphine. As a result, it is assumed that N-desethyl-isotonitazene will
have an abuse potential similar to that of other opioid agonists and
produce adverse events that include nausea, vomiting, constipation,
pruritus, dizziness, sedation, and respiratory depression, which can
lead to death. According to the NFLIS database, N-desethyl-
isotonitazene was first detected in 2022 and there have been 10
confirmed law enforcement seizures to date. There are no commercial
uses or approved medical uses for N-desethyl-isotonitazene in the
United States. As of July 29, 2024, N-desethyl-isotonitazene is
temporarily controlled in schedule I under the CSA.
3-Hydroxy-phencyclidine (3-OH-PCP) is a dissociative hallucinogen
of the arylcyclohexylamine class that has a structure similar to that
of phencyclidine (PCP). In vitro binding and activity data indicate
that 3-OH-PCP functions as a high affinity antagonist of the N-methyl-
D-aspartate receptor. Unlike PCP, 3-OH-PCP was also found to have high
agonist activity at opioid receptors. In animal behavior studies it
produced subjective effects that were indistinguishable from PCP. As a
result, it is assumed that it will have a potential of abuse similar to
that of PCP and produce effects such as hallucinations, audio and
visual distortions, analgesia, and convulsions at high doses. According
to the NFLIS database, 3-OH-PCP was first detected in the United States
in 2020 with 45 law enforcement seizures. The following years saw a
dramatic increase in law enforcement detections with 598 in 2021, 335
in 2022, and 42 in 2023.\1\ Since 2020 there have been 34 fatalities in
which 3-OH-PCP was determined to be a contributing factor by the
medical examiner. There are no commercial uses or approved medical uses
for 3-OH-PCP in the United States, and it is not controlled under the
CSA.
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\1\ The data from 2023 are still being accumulated as of the
time of these data were collected (May 2024). As a result, the 2023
data will likely increase.
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N-Ethylheptedrone is a stimulant from the substituted cathinone
class of drugs that has been used for recreational use. As a stimulant,
N-ethylheptedrone, would be expected to produce adverse effects
consistent with other stimulants such as decreased appetite, anxiety,
headaches, weight loss, insomnia, and psychosis. It was first detected
in 2019 in Hungry and has since been detected in New Zealand. There are
no commercial uses or approved medical uses for N-ethylheptedrone in
the United States, and it is not controlled under the CSA.
Carisoprodol is a sedative-hypnotic that is used as a centrally
acting muscle relaxant and hypnotic. Carisoprodol is a prodrug that is
metabolized in the liver to form meprobamate, which functions similarly
to benzodiazepines and barbiturates. It was approved for medical use in
the United States in 1959 as a muscle relaxant and is typically
prescribed in combination with analgesics to treat muscle pain. FDA's
Adverse Event Reporting System reported a total of 6,426 adverse events
involving carisoprodol since 1969, and 18 of those being reported as
drug abuse (data retrieved July 2024). Only 5 of the 18 were reported
as abuse of carisoprodol alone. According to the NFLIS database, there
were 405 law enforcement seizures of carisoprodol in 2022 alone.
Scientific studies indicated that carisoprodol demonstrated abuse
potential similar to that of benzodiazepines, resulting in it being
controlled in schedule IV under the CSA on January 11, 2012 (76 FR
77330).
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 eight
drug substances identified in this document. Any comments received by
the deadline 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
2024. 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 (21 U.S.C. 811).
Dated: August 8, 2024.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2024-18045 Filed 8-13-24; 8:45 am]
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