
[Federal Register Volume 82, Number 155 (Monday, August 14, 2017)]
[Notices]
[Pages 37866-37869]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2017-17119]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2017-N-4515]


International Drug Scheduling; Convention on Psychotropic 
Substances; Single Convention on Narcotic Drugs; Ocfentanil, 
Carfentanil, Pregabalin, Tramadol, Cannabidiol, Ketamine, and Eleven 
Other 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 
interested persons to submit comments concerning abuse potential, 
actual abuse, medical usefulness, trafficking, and impact of scheduling 
changes on availability for medical use of 17 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 September 13, 
2017.

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 September 13, 2017. The https://www.regulations.gov electronic filing system will accept comments until 
midnight Eastern Time at the end of September 13, 2017. 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-2017-N-4515 for ``International Drug Scheduling; Convention on 
Psychotropic Substances; Single Convention on Narcotic Drugs; 
Ocfentanil; Furanyl fentanyl (Fu-F); Acryloylfentanyl (Acrylfentanyl); 
Carfentanil; 4-fluoroisobutyrfentanyl (4-FIBF); 
Tetrahydrofuranylfentanyl (THF-F); 4-fluoroamphetamine (4-FA); AB-
PINACA; AB-CHMINACA; 5F-PB-22; UR-144; 5F-ADB; Etizolam; Pregabalin; 
Tramadol; Cannabidiol; Ketamine; 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

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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.
    Section 201 of the CSA (21 U.S.C. 811) (Title II of the 
Comprehensive Drug Abuse Prevention and Control Act of 1970) provides 
that when WHO notifies the United States under Article 2 of the 
Psychotropic Convention that it has information that may justify adding 
a drug or other substances to one of the schedules of the Psychotropic 
Convention, transferring a drug or substance from one schedule to 
another, or deleting it from the schedules, the Secretary of State must 
transmit the notice to the Secretary of Health and Human Services 
(Secretary of HHS). The Secretary of HHS must then publish the notice 
in the Federal Register and provide opportunity for interested persons 
to submit comments that will be considered by HHS in its preparation of 
the scientific and medical evaluations of the drug or substance.

II. WHO Notification

    The Secretary of HHS received the following notice from WHO (non-
relevant text removed):

Ref.: C.L.xx.2017

    The World Health Organization (WHO) presents its compliments to 
Member States and Associate Members and has the pleasure of 
informing that the Thirty-ninth Expert Committee on Drug Dependence 
(ECDD) will meet in Geneva from 6 to 10 November 2017 to review a 
number of substances with potential for dependence, abuse and harm 
to health, and will make recommendations to the U.N. Secretary-
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 as requested in the questionnaire 
and 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. (non relevant information from 
letter not shown, see letter for text not shown here) The designated 
focal point, and only this person, should access and complete the 
questionnaires:

1. Ocfentanil
2. Furanyl fentanyl (Fu-F)
3. Acryloylfentanyl (Acrylfentanyl)
4. Carfentanil
5. 4-fluoroisobutyrfentanyl (4-FIBF)
6. Tetrahydrofuranylfentanyl (THF-F)
7. 4-fluoroamphetamine (4-FA)
8. AB-PINACA
9. AB-CHMINACA
10. 5F-PB-22
11. UR-144
12. 5F-ADB
13. Etizolam
14. Pregabalin
15. Tramadol
16. Cannabidiol
17. Ketamine

    PDF versions of the questionnaire in English, French and Spanish 
may be downloaded from the link http://www.who.int/medicines/access/controlled-substances/ecdd/en/. Please note that these versions are 
for reference only and all questionnaires must be answered through 
the online system. Further clarification regarding the questionnaire 
may be obtained from the Secretariat by emailing: 
ecddsecretariat@who.int.
    Replies to the questionnaire must reach the Secretariat by 30 
September 2017 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 on the Web site for the Thirty-ninth 
ECDD linked to the Department of Essential Medicines and Health 
Products (EMP). The provisional agenda of the Thirty-ninth ECDD and 
the list of psychoactive substances under review are also published 
on Thirty-ninth ECDD Web page: http://www.who.int/medicines/access/controlled-substances/ecdd/en/.
    Member States are also encouraged to provide any additional 
relevant information (unpublished or published) that is available on 
these substances to: ecddsecretariat@who.int. This information will 
be an invaluable contribution to the ECDD and all submissions will 
be treated as confidential.
    The World Health Organization takes this opportunity to renew to 
Member States and Associate Members the assurance of its highest 
consideration.

GENEVA, 7 July 2017

    FDA has verified the Web site addresses contained in the WHO 
notice, as of the date this document publishes in the Federal Register, 
but Web sites are subject to change over time.

III. Substances Under WHO Review

    Ocfentanil is a synthetically produced opioid that is structurally 
related to fentanyl and approximately equipotent in effect. Reported 
risks associated with use of ocfentanil include development of opioid 
use disorder, overdose, and fatal overdose. It has no approved medical 
use in the United States and is not a controlled substance in the 
United States under the CSA.
    Furanyl fentanyl (Fu-F) is a potent clandestinely produced 
synthetic opioid that is an analog of fentanyl. Evidence suggests that 
the pattern of abuse of fentanyl analogues, including furanyl fentanyl, 
parallels that of heroin and

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prescription opioid analgesics. Fu-F produces the typical opioid 
effects that include respiratory depression and loss of consciousness. 
Seizures of Fu-F have been encountered in powder form. Fu-F has been 
connected to fatal overdoses, in which intravenous routes of 
administration are documented. It has no approved medical use in the 
United States. On November 29, 2016, the Drug Enforcement 
Administration (DEA) issued a final order to temporarily schedule Fu-F 
and its isomers, esters, ethers, salts and salts of isomers, esters and 
ethers, into Schedule I pursuant to the temporary scheduling provisions 
of the CSA.
    Acryloylfentanyl (Acrylfentanyl) belongs to the 4-anilidopiperidine 
class of synthetic opioids and is similar in structure to fentanyl. 
Acryloylfentanyl is a clandestinely produced analog of fentanyl and 
sold illegally as a research chemical on several Web sites. 
Acryloylfentanyl has also been associated with adverse events typically 
associated with opioid use such as respiratory depression, anxiety, 
constipation, tiredness, hallucinations, and withdrawal. The use of 
acryloylfentanyl has also been linked to the development of opioid use 
disorder, overdose, and fatal overdose. Acryloylfentanyl has no 
commercial or medical uses. On July 14, 2017, the DEA issued a 
temporary order to temporarily schedule acryloylfentanyl, its isomers, 
esters, ethers, salts and salts of isomers, esters, and ethers, into 
Schedule I pursuant to the temporary scheduling provisions of the CSA.
    Carfentanil, also known as 4-carbomethoxyfentanyl, is an extremely 
potent synthetic opioid that is similar in structure to and 
approximately 100 times more potent than fentanyl as an analgesic. At 
one time legitimately produced, carfentanil is no longer manufactured, 
marketed, or used in the United States; it is approved by FDA for use 
under restricted conditions by veterinarians as a immobilizing agent 
for certain large animals. Illicitly produced carfentanil is a 
particularly harmful fentanyl analogue that is also being laced into 
heroin or sold by itself and trafficked in the United States. It is not 
approved for human use. Drug seizure data indicate that carfentanil is 
typically used in small doses to cut heroin and other illicitly abused 
drugs. The significant risk to public health associated with 
carfentanil use stems from its respiratory depressive effects with very 
small amounts. Several fatalities have been reported as the result of 
carfentanil overdoses. On October 28, 1988, the DEA placed carfentanil 
in Schedule II of the CSA.
    4-fluoroisobutyrfentanyl is a clandestinely produced synthetic 
opioid that is an analog of fentanyl. It has [micro]-receptor agonist 
activity similar to that of fentanyl. This would result in effects 
associated with opioid agonists such as analgesia, respiratory 
depression, anxiety, constipation, tiredness, hallucinations, 
withdrawal, the development of opioid use disorder, overdose, and fatal 
overdose. The use of 4-fluoroisobutyrfentanyl has been implicated in 
several cases of overdose and fatal overdoses. 4-fluoroisobutyrfentanyl 
has not been approved for medical use in the U.S. On May 3, 2017, the 
DEA issued a temporary order to temporarily schedule 4-
fluoroisobutyrfentanyl, its isomers, esters, ethers, salts and salts of 
isomers, esters and ethers, into Schedule I pursuant to the temporary 
scheduling provisions of the CSA.
    Tetrahydrofuranylfentanyl (THF-F) is a synthetic opioid that is an 
analog of fentanyl. It has [micro]-receptor agonist activity similar to 
that of fentanyl, resulting in effects associated with opioid agonists 
such as analgesia, respiratory depression, anxiety, constipation, 
tiredness, hallucinations, withdrawal, the development of opioid use 
disorder, overdose, and fatal overdose. THF-F is not approved for 
medical use or controlled in the United States under the CSA.
    4-Fluoroamphetamine (4-FA) is a psychoactive substance of the 
phenethylamine and substituted amphetamine chemical classes and 
produces stimulant effects. WHO reports that 4-FA is clandestinely 
produced, and its use is associated with fatal and non-fatal 
intoxications. 4-FA was reviewed at the 37th ECDD (2015) and, while not 
placed under international control due to insufficient data, was kept 
under surveillance. 4-FA is not approved for medical use in the United 
States and it is not controlled under the CSA.
    AB-PINACA is a clandestinely produced synthetic cannabinoid agonist 
approximately 1.5 times as potent as delta-9-tetrahydrocannabinol. 
Adverse effects produced by cannabinoid agonists include tachycardia, 
agitation, hallucination, chest pain, seizure, anxiety, acute 
psychosis, and death. AB-PINACA has been detected in illicit synthetic 
cannabinoid substances, and reported in cases of overdose and 
hospitalizations. It has not been approved for medical use in the 
United States. On January 27, 2017, the DEA published a Notice of 
Proposed Rulemaking to permanently control AB-PINACA as a Schedule I 
substance under the CSA.
    AB-CHMINACA is a clandestinely produced synthetic cannabinoid 
agonist that is approximately 16 times more potent than delta-9-
tetrahydrocannabinol. Adverse effects produced by cannabinoid agonists 
include tachycardia, agitation, hallucination, chest pain, seizure, 
anxiety, acute psychosis, and death. AB-CHMINACA has been detected in 
illicit synthetic cannabinoid substances and found in cases of overdose 
and hospitalizations. AB-CHMINACA has not been pre-reviewed or 
critically reviewed by the WHO. On January 27, 2017, the DEA published 
a Notice of Proposed Rulemaking to permanently control AB-CHMINACA as a 
Schedule I substance under the CSA.
    5F-PB-22 is a synthetic cannabinoid agonist with similar effects to 
delta-9-tetrahydrocannabinol, one of the main psychoactive components 
of cannabis. Adverse effects produced by cannabinoid agonists include 
tachycardia, agitation, hallucination, chest pain, seizure, anxiety, 
acute psychosis, and death. 5F-PB-22 is clandestinely produced. It has 
been found laced on plant material and marketed as herbal products, and 
is smoked for its psychoactive effects. According to the WHO, 5F-PB-22 
has been associated with fatal intoxications. On September 6, 2016, the 
DEA issued a final rule to permanently place 5F-PB-22 into Schedule I 
of the CSA.
    UR-144 is a clandestinely produced synthetic cannabinoid agonist. 
In general, adverse effects produced by cannabinoid agonists include 
tachycardia, agitation, hallucination, chest pain, seizure, anxiety, 
and acute psychosis. UR-144 has been detected in herbal smoking blends 
that are sold as herbal incense. In June 2014, the 36th (2014) ECDD 
reviewed UR-144 and recommended that it be placed under surveillance. 
On May 11, 2016, the DEA issued a final rule to permanently schedule 
UR-144 into Schedule I of the CSA.
    5F-ADB is a clandestinely produced synthetic cannabinoid agonist. 
In general, adverse effects produced by cannabinoid agonists include 
tachycardia, agitation, hallucination, chest pain, seizure, anxiety, 
and acute psychosis. 5F-ADB has been identified in overdose and/or 
cases involving death attributed to their abuse. Adverse health effects 
reported from incidents involving 5F-ADB and other synthetic 
cannabinoids have included: Nausea, persistent vomiting, agitation, 
altered mental status, seizures, convulsions, loss of consciousness, 
and/or cardio toxicity. On April 10, 2017, the DEA issued a temporary 
scheduling order to

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temporarily schedule 5F-ADB, its isomers, esters, ethers, salts and 
salts of isomers, esters, and ethers into Schedule I pursuant to the 
temporary scheduling provisions of the CSA.
    Etizolam belongs 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 to treat generalized 
anxiety disorder with depressive symptoms, but is not approved for 
medical use or controlled in the United States under the CSA. WHO 
reported that non-fatal intoxications that include cases of driving 
under the influence of drugs have been linked to etizolam. The ECDD at 
its 37th (2015 meeting reviewed etizolam and recommended that a 
critical review of etizolam is warranted.
    Pregabalin is an anticonvulsant-type drug used to treat pain 
generated from the nervous system. It is available as an oral capsule 
and oral solution and approved for medical use in the United States for 
the management of neuropathic pain associated with diabetic peripheral 
neuropathy, post-herpetic neuralgia, and adjunctive therapy for partial 
onset seizures, fibromyalgia, and neuropathic pain associated with 
spinal cord injury. Although the mechanism of action of pregabalin is 
unknown, studies in animals suggest that binding to the nervous system 
tissues may be involved in its pain-relieving and anti-seizure effects. 
Pregabalin binds with high affinity to the alpha 2-delta receptor site 
(a subunit of voltage-gated calcium channels) in the central nervous 
system. The binding of pregabalin at this site is thought to be 
responsible for its therapeutic effect on neuropathic pain. Reports 
indicate that patients are self-administering higher than recommended 
doses to achieve euphoria, especially patients who have a history of 
substance abuse, particularly opioids, and psychiatric illness. While 
effects of excessively high doses are generally non-lethal, 
gabapentinoids such as pregabalin are increasingly being identified in 
post-mortem toxicology analyses. Pregabalin is a Schedule V controlled 
substance in the United States under the CSA.
    Tramadol is an opioid analgesic that produces its primary opioid-
like action through an active metabolite referred to as the M1 
metabolite (O-desmethyltramadol). Tramadol was first approved for 
marketing in the United States in 1995 and is available as immediate-
release, extended-release, and combination products for the treatment 
of moderate to moderately severe pain. On July 2, 2014, the DEA 
published a final rule in the Federal Register controlling tramadol as 
a Schedule IV substance of the CSA effective from August 18, 2014. 
Tramadol was pre-reviewed by the ECDD at its 28th (1992) and 32nd 
(2000) meetings, and critically reviewed at the 33rd (2002) meeting and 
not recommended for international control but placed on surveillance. 
Tramadol was pre-reviewed again by the ECDD at its 34th (2006) meeting; 
however, the ECDD concluded that there was not sufficient evidence to 
justify a critical review. At the 36th (2014) meeting, the ECDD 
considered updated information on tramadol, but again concluded that 
there was insufficient evidence to warrant a critical review.
    Cannabidiol (CBD) is one of the active cannabinoids identified in 
cannabis. CBD has been shown to be beneficial in experimental models of 
several neurological disorders, including those of seizure and 
epilepsy. In the United States, CBD-containing products are in human 
clinical testing in three therapeutic areas, but no such products are 
approved by FDA for marketing for medical purposes in the United 
States. CBD is a Schedule I controlled substance under the CSA. At the 
37th (2015) meeting of the ECDD, the committee requested that the 
Secretariat prepare relevant documentation to conduct pre-reviews for 
several substances, including CBD.
    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 a 
solution for injection. 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 ECDD reviewed ketamine at its 34th (2006), 35th 
(2012), and 36th (2014) meetings. On March 13, 2015, the Commission on 
Narcotic Drugs (CND) decided by consensus to postpone the consideration 
of a proposal concerning the recommendation to place ketamine in 
Schedule IV of the Psychotropic Convention. The CND requested 
additional information from the WHO. The ECDD reviewed updated 
information at its 37th (2015) meeting and found no reason to recommend 
a new pre-review or critical review of ketamine that could potentially 
change its standing 2014 recommendation that ketamine should not be 
placed under international control.

IV. Opportunity To Submit Domestic Information

    As required by section 201(d)(2)(A) of the CSA, FDA, on behalf of 
HHS, invites interested persons to submit comments regarding the 17 
named drug substances. Any comments received will be considered by HHS 
when it prepares a scientific and medical evaluation of these drug 
substances. HHS will forward a scientific and medical evaluation of 
these drug substances to WHO, through the Secretary of State, 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 early 
2018. Any HHS position regarding international control of these drug 
substances will be preceded by another Federal Register notice 
soliciting public comments, as required by section 201(d)(2)(B) of the 
CSA.

V. Electronic Access

    Persons with access to the Internet may obtain the document at 
either https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or 
https://www.regulations.gov.

    Dated: August 9, 2017.
Anna K. Abram,
Deputy Commissioner for Policy, Planning, Legislation, and Analysis.
[FR Doc. 2017-17119 Filed 8-11-17; 8:45 am]
 BILLING CODE 4164-01-P


