Document ID: FDA-2013-N-1676-0001
Agency: fda
Document Type: Notice
Title: International Drug Scheduling; Convention on Psychotropic
Substances; Single Convention on Narcotic Drugs; Tapentadol; Tramadol;
Ketamine; gamma-Butyrolactone; 22 Additional Substances; Request for
Comments
Posted Date: 2013-12-30T05:00Z

[Federal Register Volume 78, Number 250 (Monday, December 30, 2013)]
[Notices]
[Pages 79465-79469]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2013-31212]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2013-N-1676]

International Drug Scheduling; Convention on Psychotropic 
Substances; Single Convention on Narcotic Drugs; Tapentadol; Tramadol; 
Ketamine; gamma-Butyrolactone; 22 Additional Substances; Request for 
Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is requesting

[[Page 79466]]

interested persons to submit comments concerning abuse potential, 
actual abuse, medical usefulness, trafficking, and impact of scheduling 
changes on availability for medical use of 26 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 (CSA).

DATES: Submit written or electronic comments by January 29, 2014.

ADDRESSES: Submit written comments to the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852. Submit electronic comments to http://www.regulations.gov.

FOR FURTHER INFORMATION CONTACT: James R. Hunter, Center for Drug 
Evaluation and Research, Controlled Substance Staff, Food and Drug 
Administration, Bldg. 51, Rm. 5150, 10903 New Hampshire Ave., Silver 
Spring, MD 20993-0002, 301-796-3156, email: james.hunter@fda.hhs.gov.

SUPPLEMENTARY INFORMATION: The United States is a party to the 1971 
Convention on Psychotropic Substances. Article 2 of the Convention on 
Psychotropic Substances 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 and provide the Secretary 
General of the United Nations with information in support of its 
opinion.
    Section 201 of the CSA (21 U.S.C. 801 et seq.) (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 
Convention on Psychotropic Substances that it has information that may 
justify adding a drug or other substances to one of the schedules of 
the 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 (the 
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.

I. WHO Notification

    The Secretary of HHS received the following notices from WHO:

Ref.: C.L.29.2013

    The World Health Organization (WHO) presents its compliments to 
Member States and Associate Members and has the pleasure of 
informing that the Thirty-sixth Expert Committee on Drug Dependence 
(ECDD) will meet in June 2014 to review a number of substances with 
potential for misuse in order to make recommendations to the 
Director-General, on the need for and level of international control 
of these substances.
    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. Member 
States are invited to collaborate, as in the past, in this process 
by providing pertinent information mentioned in the questionnaire 
concerning substances under review.
    It would be appreciated if a person from the Ministry of Health 
could be designated as the focal point responsible for coordinating 
and answering the questionnaire. It is requested that the email 
address of the focal point be shared with the Secretariat * * *. 
Upon receipt of the email of the designated person, the focal point 
will receive a unique user name, password and link for accessing the 
questionnaire and responding to questions. Further instructions on 
answering the questionnaire will be provided, along with the 
questionnaire, online. Further clarification on the above items can 
be obtained from the Secretariat by emailing: ecdd_secretariat@who.int. Replies to the questionnaire must reach the 
Secretariat by 1 February 2014 in order to facilitate analyses and 
preparation of the report before the planned meeting. Where there is 
a Competent National Authority under the International Drug Control 
Treaties, it is kindly requested that the questionnaire be completed 
in collaboration with such body. The summary information from the 
questionnaire will be published online as part of the report at the 
Web site for the Thirty-sixth ECDD linked to the Department of 
Essential Medicines and Health Products (EMP): http://www.who.int/medicines/areas/quality_safety/ECDD/en/index.html.
    The World Health Organization takes this opportunity to renew to 
Member States and Associate Members the assurance of its highest 
consideration.

    GENEVA, 11 November 2013
* * * * *
ENCL.: (1)

Substances Identified for Evaluation During the 36th Expert Committee 
on Drug Dependence

Tapentadol
N-benzylpiperazine (BZP)
Gamma-Butyrolactone (GBL)
1,4-Butanediol (I,4BD)
Synthetic cannabinoids
    JWH-018
    JWH-073
    AM-2201
    UR-144
    APINACA (AKB 48)
    RCS-4
    JWH-250

Synthetic Cathinones
    Mephedrone 4-methylmethcathinone (4-MMC)
    3,4-Methylenedioxypyrovalerone (MDPV)
    Methylone (bk-MDMA)
    4-Methylethcathinone (4-MEC)
    4-Fluoromethcathinone (flephedrone; 4-FMC)
Miscellaneous
    25 B NBOMe
    25 C NBOMe
    25 I NBOMe
    Alpha-methyltryptamine (AMT)
    AH-7921
    Methoxetamine (MXE)
    Methiopropamine (MPA)
Lisdexamphetamine
Tramadol
Ketamine

* * * * *

WHO Questionnaire for the 36th Meeting of Expert Committee on Drug 
Dependence: Substance

Definitions:

    (Def. 1) Legitimate use is use of a substance for legally valid 
purposes such as medical scientific and industrial.
    (Def. 2) Harmful use is defined as a pattern of psychoactive 
substance use that increases the risk of harmful physical, mental, 
and social consequences for the user or to others. Harmful use of 
drugs by an individual has potential for adverse effects on the 
substance user's family, the community and society in general.

Substance* (Insert name of substance)

--Do you have any information on this substance on legitimate use, 
recreational/harmful use or control status in your country? \*\ 
(Yes/No)

A. LEGITIMATE MEDICAL OR OTHER SCIENTIFIC USE OF THE SUBSTANCE (Def. 1)

--Is the substance currently authorized or in the process of being 
authorized/registered as a medical product in your country? (Yes/No)

    If ``yes,'' since when has it been on the market? (input year)

--Please state registered indications for this medicine:
--Please mention other, if any, medical use not included in the 
approved indications (off label use):
--Please indicate dosage form(s) and strength(s) available in your 
country; also

[[Page 79467]]

indicate special properties such as slow release, etc.:

------------------------------------------------------------------------
                      Dosage form         Strength           Remarks
------------------------------------------------------------------------
1.                 .................  ................  ................
2.                 .................  ................  ................
3.                 .................  ................  ................
------------------------------------------------------------------------

--Please list alphabetically the brand names available in your 
country (there is no need for dosage forms, strengths, etc.):
--Are there any other uses for the substance in health care (such as 
for diagnostic tests) in your country? (Yes/No)
    If ``yes,'' what is the use?
--Is the chemical used for medical or scientific research in your 
country? (Yes/No)
    If ``yes,'' please specify:
--Is the substance used for animal care (veterinary use)? (Yes/No)
--Is there any other legitimate (Def. 1) use of the substance (e.g. 
industry uses)? (Yes/No)
    If ``yes,'' please state the purpose:
--If there is any legitimate (Def. 1) use of the substance, how is 
the substance sourced? (Manufactured in country/Imported)
--What is the estimated approximate amount needed for its legitimate 
use in your country per year?
--Is the substance used for cultural or ceremonial purposes? (Yes/
No)
    If ``yes,'' specify why it is used:
    Who uses it (the group using)?
    How is it used? (route of administration):
    What is its source?

B. HARMFUL USE OF THE SUBSTANCE (Def. 2)

--Is there recreational/harmful use of this substance in your 
country? (Def. 2) (Yes/No/Unknown)
    If ``yes,'' please specify how the substance is used and the 
extent of use by answering the following questions:
    Common route(s) of administration (Oral/Injection/Inhaling or 
sniffing)
    How is it obtained? (Diversion/Trafficking/Clandestine 
manufacturing)
    Common formulation(s) available: (Powder/Tablet/Liquid)

--Any other information on recreational/harmful use:
--Quantity of substance used by an average misuse per sitting 
(average dose used):
--Is it used by special population(s)? (Club use/General population)

------------------------------------------------------------------------
                                                            General
                                         Club use          population
                                        (percent)          (percent)
------------------------------------------------------------------------
Estimated proportion of the
 population using the substance...
------------------------------------------------------------------------

--Please provide any information on the extent/magnitude of public 
health or social harm from the use of the substance (Def. 2) in your 
country:

----------------------------------------------------------------------------------------------------------------
                                                             Addiction
                                                             programme        Emergency room
                                       Overdose deaths     enrolment from    visits resulting    Dependence to
                                           reported       the use of this    from the use of     this substance
                                                             substance        this substance
----------------------------------------------------------------------------------------------------------------
Numbers in 2012.....................
----------------------------------------------------------------------------------------------------------------

--Are there reports of withdrawal, tolerance, other adverse effects 
or medical illnesses caused by this substance in your country? (Yes/
No)
    If ``yes,'' please provide details:
--Any other relevant information on harm to individuals or the 
society:
--Please indicate the sources of information on harm:
--If actual data are not available, please provide a short 
description on harm caused by this substance:

C. CONTROL OF THE SUBSTANCE

--Is the substance controlled under legislation that is intended to 
regulate its availability in the country? (Yes/No)

    If ``yes,'' please select which one: (Controlled substances act/
Medicines law/Poisons acts/Consumer protection acts/Generic 
legislation/Analogue legislation/Temporary ban/Other legislation 
(name))

--How is this law enforced? Please provide a short description:
--Are there challenges to implementation? (Yes/No)

    If ``yes,'' please specify (e.g. laboratory capacity, resources 
to implement and/or enforce, expertise):

--Are there illicit activities involving the substance? (Yes/No)
    Clandestine manufacture? (Yes/No)
    The manufacture (synthesis) of the chemical itself (Yes/No)
    The processing into the consumer product, i.e. adding it to 
herbal material, packaging (Yes/No)
    Trafficking (Yes/No)
    Diversion (Yes/No)
    Internet market (Yes/No)
    Other (please specify):
--Please provide any other relevant information on illicit 
activities:
--Data on seizures

--------------------------------------------------------------------------------------------------------------------------------------------------------
                                            Number of                                                Number of      Number of tablets/     Other type
                 Year                        seizures          Kilograms            Litres            ampoules            pills            (quantity)
--------------------------------------------------------------------------------------------------------------------------------------------------------
2011..................................
2012..................................
--------------------------------------------------------------------------------------------------------------------------------------------------------

D. IMPACT OF SCHEDULING

--If this substance is placed under international control, does your 
country have the lab capacity to identify the substance? (Yes/No/
Unknown)
--If this substance is placed under international control, do you 
think its availability for medical use will be affected? (Yes/No)

    If ``yes,'' please explain (consider both human and veterinary 
needs): How could control impact its medical availability? Please 
identify specific population groups that may be affected, and 
describe the implications of increased control.

--Any additional information on impact of scheduling:
* * * * *

II. Background

    Tapentadol is a central nervous system active analgesic agent that 
has mu ([micro]) opioid agonist properties and inhibits the reuptake of 
norepinephrine. Tapentadol is approved for marketing in the United 
States for the treatment of moderate to severe acute pain.

[[Page 79468]]

Tapentadol is controlled in Schedule II under the CSA in the United 
States. Tapentadol was pre-reviewed by the WHO Expert Committee on Drug 
Dependence at its 35th meeting and recommended for critical review at 
its 36th meeting.
    N-benzylpiperazine (BZP) is used as an intermediate in chemical 
synthesis but has been taken orally as either powder or tablets and by 
other routes, including smoking or snorting. It has no medical use in 
the United States. BZP is controlled in Schedule I under the CSA in the 
United States. BZP is not controlled internationally under the 
Convention on Psychotropic Substances or the Single Convention on 
Narcotic Drugs. BZP was pre-reviewed by the WHO Expert Committee on 
Drug Dependence at its 35th meeting and recommended for critical review 
at its 36th meeting.
    Gamma-Butyrolactone (GBL) is used as an industrial solvent. GBL can 
be converted in the body to the central nervous system depressant drug 
gamma-hydroxybutyric acid (GHB). GBL is controlled as a List I chemical 
in the United States under the CSA. It is not controlled 
internationally under the Convention on Psychotropic Substances or the 
Single Convention on Narcotic Drugs. GBL was pre-reviewed by the WHO 
Expert Committee on Drug Dependence at its 35th meeting and recommended 
for critical review at its 36th meeting.
    1,4-Butanediol is used as an industrial solvent for manufacturing 
and also used for the synthesis of GBL. 1,4-Butanediol can also be 
converted to the central nervous depressant drug GHB. It has no medical 
use in the United States. 1,4-Butanediol is not controlled under the 
CSA in the United States, but it is subject to controls in several 
states under state law. 1,4-Butanediol was pre-reviewed by the WHO 
Expert Committee on Drug Dependence at its 35th meeting and recommended 
for critical review at its 36th meeting.
    The following substances are classified as synthetic cannabinoids 
with pharmacological properties like tetrahydrocannabinol: (1-pentyl-
1H-indol-3-yl)-1-naphthalenyl-methanone (JWH-018), (1-butyl-1H-indol-3-
yl)-1-naphthalenyl-methanone (JWH-073), 1-(1-pentyl-1H-indol-3-yl)-2-
(2-methoxyphenyl)-ethanone (JWH-250), [1-(5-fluoropentyl)-1H-indol-3-
yl]-1-naphthalenyl-methanone (AM-2201), (1-pentyl-1H-indol-3-
yl)(2,2,3,3-tetramethylcyclopropyl)-methanone (UR-144), 1-pentyl-N-
tricyclo[3.3.1.13,7]dec-l-yl-1H-indazole-3-carboxamide (APINACA; 
AKB48), and (4-methoxyphenyl)(1-pentyl-1H-indol-3-yl)methanone (RCS-4). 
JWH-018, JWH-073, JWH-250, AM-2201, and RCS-4 are controlled in 
Schedule I under the CSA in the United States. On May 16, 2013, UR-144 
and AKB 48 were temporarily placed in Schedule I under the CSA pursuant 
to the temporary scheduling provisions of section 201(h) of the CSA (21 
U.S.C. 811(h)).
    4-Methylmethcathinone (4-MMC; mephedrone), 3,4-
methylenedioxypyrovalerone (MDPV), 3,4-methylenedioxy-N-methylcathinone 
(bk-MDMA; Methylone), 4-methylethcathinone (4-MEC), and 4-
fluoromethcathinone (flephedrone; 4-FMC) are classified as synthetic 
cathinones in the phenethylamine class and are structurally and 
pharmacologically similar to amphetamine, 3,4-
methylenedioxymethamphetamine (MDMA), cathinone and other related 
substances. 4-MMC, MDPV, and Methylone are controlled in Schedule I 
under the CSA in the United States. 4-MEC and 4-FMC are not controlled 
under the CSA in the United States.
    2-(4-bromo-2,5-dimethoxyphenyl)-N-[(2-
methoxyphenyl)methyl]ethanamine (25B-NBOMe), 2-(4-chloro-2,5-
dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25C-NBOMe), and 2-(4-
iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25I-
NBOMe) are synthetic 2C phenethylamine substances and were developed 
for use in mapping and investigating the serotonin receptors in the 
mammalian brain. On November 15, 2013, 25B-NBOMe, 25C-NBOMe, and 25I-
NBOMe were temporarily placed in Schedule I of the CSA pursuant to the 
temporary scheduling provision of section 201(h) of the CSA.
    Alpha-Methyltryptamine (AMT) is a tryptamine (indoleethylamine) 
derivative and shares several similarities with the Schedule I 
tryptamine hallucinogens, such as alpha-ethyltryptamine (AET) and N,N-
dimethyltryptamine (DMT). AMT is controlled in Schedule I under the CSA 
in the United States.
    AH-7921, or 1-(3,4-dichlorobenzamidomethyl)cyclohexyldimethylamine, 
is an opioid analgesic drug selective for the [micro]-opioid receptor 
and is not controlled under the CSA in the United States.
    Methoxetamine (MXE), or 2-(ethylamino)-2-(3-methoxyphenyl)-
cyclohexanone, is an arylcyclohexamine and is not controlled under the 
CSA in the United States. MXE can be considered as a controlled 
substance analogue of eticyclidine (PCE) under the CSA if intended for 
human consumption.
    Methiopropamine (MPA) is a thiophene analog of methamphetamine and 
is not controlled under the CSA in the United States.
    Lisdexamphetamine is an amide ester conjugate comprised of the 
amino acid L-lysine covalently bound to the amino group of d-
amphetamine. Lisdexamphetamine was approved for marketing in the United 
States in 2007 and is used for the treatment of Attention Deficit 
Hyperactivity Disorder. Lisdexamphetamine was placed in Schedule II of 
the CSA in June 2007.
    Tramadol is an opioid analgesic that produces its primary opioid-
like action through an active metabolite referred to as the M1 
metabolite[middot](O-desmethyltramadol). Tramadol was first approved 
for marketing in the United States in 1995 and is available in 
immediate-release, extended-release, and combination product for the 
treatment of moderate to moderately-severe pain. In November 2013, 
Tramadol was proposed to be placed in Schedule IV of the CSA. The 
Secretariat indicates that additional safety information on this 
substance is available, thus an updated review for Tramadol is 
necessary for presentation at the 36th meeting of the WHO Expert 
Committee on Drug Dependence.
    Ketamine is classified as a rapid-acting general anesthetic agent 
used for short diagnostic and surgical procedures that do not require 
skeletal muscle relaxation. It is marketed in the United States as an 
injectable. Ketamine is controlled in Schedule III of the CSA in the 
United States. It is not controlled internationally under the 
Convention on Psychotropic Substances or the Single Convention on 
Narcotic Drugs. The WHO Expert Committee on Drug Dependence reviewed 
ketamine at its 34th and 35th meetings. The Secretariat indicates that 
additional safety information on this substance is available, thus an 
updated review for ketamine is necessary for presentation at the 36th 
meeting of the WHO Expert Committee on Drug Dependence.

III. Opportunity To Submit Domestic Information

    As required by section 201(d)(2)(A) of the CSA, FDA, on behalf of 
the Department of Health and Human Services (HHS), invites interested 
persons to submit comments regarding the 26 named drugs. Any comments 
received will be considered by HHS when it prepares a scientific and 
medical evaluation of these drugs. HHS will forward a scientific and 
medical

[[Page 79469]]

evaluation of these drugs to WHO, through the Secretary of State, for 
WHO's consideration in deciding whether to recommend international 
control/decontrol of any of these drugs. Such control could limit, 
among other things, the manufacture and distribution (import/export) of 
these drugs and could impose certain recordkeeping requirements on 
them.
    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 early 2015. Any HHS position regarding international 
control of these drugs will be preceded by another Federal Register 
notice soliciting public comments, as required by section 201(d)(2)(B) 
of the CSA.

IV. Comments

    Interested persons may submit either electronic comments regarding 
the drugs to http://www.regulations.gov or written comments to the 
Division of Dockets Management (see ADDRESSES) by January 29, 2014. It 
is only necessary to send one set of comments. Identify comments with 
the docket number found in brackets in the heading of this notice. 
Received comments may be seen in the Division of Dockets Management 
between 9 a.m. and 4 p.m., Monday through Friday, and will be posted to 
the docket at http://www.regulations.gov.

    Dated: December 24, 2013.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2013-31212 Filed 12-27-13; 8:45 am]
BILLING CODE 4160-01-P