81 FR 29487 - Schedules of Controlled Substances: Placement of Brivaracetam Into Schedule V

DEPARTMENT OF JUSTICE
Drug Enforcement Administration

Federal Register Volume 81, Issue 92 (May 12, 2016)

Page Range		29487-29492
FR Document		2016-11245

The Drug Enforcement Administration is placing the substance brivaracetam ((2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl] butanamide) (also referred to as BRV; UCB-34714; Briviact) (including its salts) into schedule V of the Controlled Substances Act. This scheduling action is pursuant to the Controlled Substances Act, as revised by the Improving Regulatory Transparency for New Medical Therapies Act which was signed into law on November 25, 2015.

Federal Register, Volume 81 Issue 92 (Thursday, May 12, 2016)

[Federal Register Volume 81, Number 92 (Thursday, May 12, 2016)]
[Rules and Regulations]
[Pages 29487-29492]
From the Federal Register Online [www.thefederalregister.org]
[FR Doc No: 2016-11245]

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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Part 1308

[Docket No. DEA-435]

Schedules of Controlled Substances: Placement of Brivaracetam
Into Schedule V

AGENCY: Drug Enforcement Administration, Department of Justice.

ACTION: Interim final rule, with request for comments.

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SUMMARY: The Drug Enforcement Administration is placing the substance
brivaracetam ((2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl] butanamide)
(also referred to as BRV; UCB-34714; Briviact) (including its salts)
into schedule V of the Controlled Substances Act. This scheduling
action is pursuant to the Controlled Substances Act, as revised by the
Improving Regulatory Transparency for New Medical Therapies Act which
was signed into law on November 25, 2015.

DATES: The effective date of this rulemaking is May 12, 2016.
Interested persons may file written comments on this rulemaking in
accordance with 21 CFR 1308.43(g). Electronic comments must be
submitted, and written comments must be postmarked, on or before June
13, 2016. Commenters should be aware that the electronic Federal Docket
Management System will not accept comments after 11:59 p.m. Eastern
Time on the last day of the comment period.
Interested persons, defined at 21 CFR 1300.01 as those ``adversely
affected or aggrieved by any rule or proposed rule issuable pursuant to
section 201 of the Act (21 U.S.C. 811),'' may file a request for
hearing or waiver of hearing pursuant to 21 CFR 1308.44. Requests for
hearing and waivers of an opportunity for a hearing or to participate
in a hearing must be received on or before June 13, 2016.

ADDRESSES: To ensure proper handling of comments, please reference
``Docket No. DEA-435'' on all correspondence, including any
attachments.
Electronic comments: The Drug Enforcement Administration
encourages that all comments be submitted electronically through the
Federal eRulemaking Portal, which provides the ability to type short
comments directly into the comment field on the Web page or attach a
file for lengthier comments. Please go to http://www.regulations.gov
and follow the online instructions at that site for submitting
comments. Upon completion of your submission, you will receive a
Comment Tracking Number for your comment. Please be aware that
submitted comments are not instantaneously available for public view on
Regulations.gov. If you have received a Comment Tracking Number, your
comment has been successfully submitted and there is no need to
resubmit the same comment.
Paper comments: Paper comments that duplicate the
electronic submission are not necessary and are discouraged. Should you
wish to mail a paper comment in lieu of an electronic comment, it
should be sent via regular or express mail to: Drug Enforcement
Administration, Attn: DEA Federal Register Representative/ODW, 8701
Morrissette Drive, Springfield, VA 22152.
Hearing requests: All requests for hearing and waivers of
participation must be sent to: Drug Enforcement Administration, Attn:
Administrator, 8701 Morrissette Drive, Springfield, Virginia 22152. All
requests for hearing and waivers of participation should also be sent
to: (1) Drug Enforcement Administration, Attn: Hearing Clerk/LJ, 8701
Morrissette Drive, Springfield, Virginia 22152; and (2) Drug
Enforcement Administration, Attn: DEA Federal Register Representative/
ODW, 8701 Morrissette Drive, Springfield, Virginia 22152.

FOR FURTHER INFORMATION CONTACT: Barbara J. Boockholdt, Office of
Diversion Control, Drug Enforcement Administration; Mailing Address:
8701 Morrissette Drive, Springfield, Virginia 22152; Telephone: (202)
598-6812.

SUPPLEMENTARY INFORMATION:

Posting of Public Comments

Please note that all comments received are considered part of the
public record. They will, unless reasonable cause is given, be made
available by the Drug Enforcement Administration (DEA) for public
inspection online at http://www.regulations.gov. Such information
includes personal identifying information (such as your name, address,
etc.) voluntarily submitted by the commenter. The Freedom of
Information Act (FOIA) applies to all comments received. If you want to
submit personal identifying information (such as your name, address,
etc.) as part of your comment, but do not want it to be made publicly
available, you must include the phrase ``PERSONAL IDENTIFYING
INFORMATION'' in the first paragraph of your comment. You must also
place all of the personal identifying information you do not want made
publicly available in the first paragraph of your comment and identify
what information you want redacted.
If you want to submit confidential business information as part of
your comment, but do not want it to be made publicly available, you
must include the phrase ``CONFIDENTIAL BUSINESS INFORMATION'' in the
first paragraph of your comment. You must also prominently identify the
confidential business information to be redacted within the comment.
Comments containing personal identifying information and
confidential business information identified as directed above will
generally be made publicly available in redacted form. If a comment has
so much confidential business information or personal identifying
information that it cannot be effectively redacted, all or part of that
comment may not be made publicly available. Comments posted to http://www.regulations.gov may include any personal identifying information
(such as name, address, and phone number) included in the text of your
electronic submission that is not identified as directed above as
confidential.
An electronic copy of this document and supplemental information,
including the complete Department of Health and Human Services and Drug
Enforcement Administration eight-factor analyses, to this interim final
rule are available at http://www.regulations.gov for easy reference.

Request for Hearing, Notice of Appearance at Hearing, or Waiver of
Participation in Hearing

Pursuant to 21 U.S.C. 811(a), this action is a formal rulemaking
``on the record after opportunity for a hearing.'' Such proceedings are
conducted pursuant to the provisions of the Administrative Procedure
Act (APA), 5 U.S.C. 551-559. 21 CFR 1308.41-1308.45; 21 CFR part 1316,
subpart D. In accordance with 21 CFR 1308.44(a)-

[[Page 29488]]

(c), requests for a hearing, notices of appearance, and waivers of an
opportunity for a hearing or to participate in a hearing may be
submitted only by interested persons, defined as those ``adversely
affected or aggrieved by any rule or proposed rule issuable pursuant to
section 201 of the Act (21 U.S.C. 811).'' 21 CFR 1300.01. Requests for
a hearing and notices of participation must conform to the requirements
of 21 CFR 1308.44(a) or (b), as applicable, and include a statement of
the interest of the person in the proceeding and the objections or
issues, if any, concerning which the person desires to be heard. Any
waiver of an opportunity for a hearing must conform to the requirements
of 21 CFR 1308.44(c) including a written statement regarding the
interested person's position on the matters of fact and law involved in
any hearing.
Please note that pursuant to 21 U.S.C. 811(a), the purpose and
subject matter of the hearing are restricted to ``(A) find[ing] that
such drug or other substance has a potential for abuse, and (B)
mak[ing] with respect to such drug or other substance the findings
prescribed by subsection (b) of section 812 of this title for the
schedule in which such drug is to be placed. * * *'' Requests for a
hearing and waivers of participation in the hearing should be submitted
to DEA using the address information provided above.

Legal Authority

The DEA implements and enforces titles II and III of the
Comprehensive Drug Abuse Prevention and Control Act of 1970, as
amended. 21 U.S.C. 801-971. Titles II and III are referred to as the
``Controlled Substances Act'' and the ``Controlled Substances Import
and Export Act,'' respectively, and are collectively referred to as the
``Controlled Substances Act'' or the ``CSA'' for the purpose of this
action. The DEA publishes the implementing regulations for these
statutes in title 21 of the Code of Federal Regulations (CFR), chapter
II. The CSA and its implementing regulations are designed to prevent,
detect, and eliminate the diversion of controlled substances and listed
chemicals into the illicit market while providing for the legitimate
medical, scientific, research, and industrial needs of the United
States. Controlled substances have the potential for abuse and
dependence and are controlled to protect the public health and safety.
Under the CSA, controlled substances are classified into one of
five schedules based upon their potential for abuse, their currently
accepted medical use in treatment in the United States, and the degree
of dependence the substance may cause. 21 U.S.C. 812. The initial
schedules of controlled substances established by Congress are found at
21 U.S.C. 812(c), and the current list of all scheduled substances is
published at 21 CFR part 1308.
Pursuant to 21 U.S.C. 811(a)(1), the Attorney General may, by rule,
``add to such a schedule or transfer between such schedules any drug or
other substance if he * * * finds that such drug or other substance has
a potential for abuse, and * * * makes with respect to such drug or
other substance the findings prescribed by subsection (b) of section
812 of this title for the schedule in which such drug is to be placed *
* *'' The Attorney General has delegated this scheduling authority
under 21 U.S.C. 811 to the Administrator of the DEA. 28 CFR 0.100.
The CSA provides that scheduling of any drug or other substance may
be initiated by the Attorney General (1) on her own motion; (2) at the
request of the Secretary of Health and Human Services (HHS); or (3) on
the petition of any interested party. 21 U.S.C. 811(a). This action
imposes the regulatory controls and administrative, civil, and criminal
sanctions of schedule V controlled substances for any person who
handles or proposes to handle BRV.
The Improving Regulatory Transparency for New Medical Therapies Act
(Pub. L. 114-89) was signed into law on November 25, 2015. This law
amended 21 U.S.C. 811 and states that in cases where a new drug is (1)
approved by the Department of Health and Human Services (HHS) and (2)
HHS recommends control in CSA schedule II-V, DEA shall issue an interim
final rule scheduling the drug, within 90 days.
The law further states that the 90-day timeframe starts the later
of (1) the date DEA receives the HHS scientific and medical evaluation/
scheduling recommendation or (2) the date DEA receives notice of drug
approval by HHS. In addition, the law specifies that the rulemaking
shall become immediately effective as an interim final rule without
requiring the DEA to demonstrate good cause therefor.
Specifically, Public Law 114-89 revised section 201 of the CSA (21
U.S.C. 811) by inserting after subsection (i) a new paragraph (j),
which requires that with respect to a drug referred to in subsection
(f), if the Secretary recommends that the Attorney General control the
drug in schedule II, III, IV, or V pursuant to subsections (a) and (b),
the Attorney General is required to, within 90 days, issue an interim
final rule controlling the drug in accordance with such subsections and
21 U.S.C. 812(b) using the specified procedures. For purposes of
calculating the 90 days, Public Law 114-89 states that such date shall
be the later of the date on which the Attorney General receives the
scientific and medical evaluation and the scheduling recommendation
from the Secretary in accordance with subsection (b), or the date on
which the Attorney General receives notification from the Secretary
that the Secretary has approved an application under section 505(c),
512, or 571 of the Federal Food, Drug, and Cosmetic Act or section
351(a) of the Public Health Service Act, or indexed a drug under
section 572 of the Federal Food, Drug, and Cosmetic Act, with respect
to the drug described in paragraph (1). Public Law 114-89 further
stipulates that a rule issued by the Attorney General under paragraph
(1) becomes immediately effective as an interim final rule without
requiring the Attorney General to demonstrate good cause and requires
that the interim final rule give interested persons the opportunity to
comment and to request a hearing. After the conclusion of such
proceedings, the Attorney General must issue a final rule in accordance
with the scheduling criteria of subsections 21 U.S.C. 811(b), (c), and
(d) of this section and 21 U.S.C. 812(b).

Background

Brivaracetam ((2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl]
butanamide) (also referred to as BRV; UCB-34714; Briviact) is a new
molecular entity with central nervous system (CNS) depressant
properties. BRV is known to be a high affinity ligand for the synaptic
vesicle protein, SV2A, which is found on excitatory synapses in the
brain. On November 22, 2014, UCB Inc. (Sponsor) submitted three New
Drug Applications (NDAs) to the U.S. Food and Drug Administration (FDA)
for the tablet, oral, and intravenous formulations of BRV. The FDA
accepted the NDA filings for BRV on January 21, 2015.
On March 28, 2016 the DEA received notification that HHS/FDA
approved BRV as an add-on treatment to other medications to treat
partial onset seizures in patients age 16 years and older with
epilepsy.

Determination to Schedule BRV

Pursuant to 21 U.S.C. 811(a)(1), proceedings to add a drug or
substance to those controlled under the CSA may be initiated by request
of the Secretary

[[Page 29489]]

of the HHS.\1\ On September 8, 2015, the HHS provided the DEA with a
scientific and medical evaluation document prepared by the FDA entitled
``Basis for the Recommendation to Place Brivaracetam in Schedule V of
the Controlled Substances Act.'' Pursuant to 21 U.S.C. 811(b), this
document contained an eight-factor analysis of the abuse potential of
BRV as a new drug, along with the HHS' recommendation to control BRV
under schedule V of the CSA.
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\1\ As set forth in a memorandum of understanding entered into
by the HHS, the FDA, and the National Institute on Drug Abuse
(NIDA), the FDA acts as the lead agency within the HHS in carrying
out the Secretary's scheduling responsibilities under the CSA, with
the concurrence of the NIDA. 50 FR 9518, Mar. 8, 1985. The Secretary
of the HHS has delegated to the Assistant Secretary for Health of
the HHS the authority to make domestic drug scheduling
recommendations. 58 FR 35460, July 1, 1993.
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In response, in December 2015, the DEA reviewed the scientific and
medical evaluation and scheduling recommendation provided by the HHS,
along with all other relevant data, and completed its own eight-factor
review document pursuant to 21 U.S.C. 811(c). The DEA concluded that
BRV met the 21 U.S.C. 812(b)(5) criteria for placement in schedule V of
the CSA. Subsequently, on March 28, 2016, the DEA received notification
that HHS/FDA approved three NDAs for BRV (see Background section).
Pursuant to the provisions of the Improving Regulatory Transparency
for New Medical Therapies Act (Pub. L. 114-89), and based on the HHS
recommendation, NDA approvals by HHS/FDA, and DEA's determination, DEA
is issuing this interim final rule to schedule brivaracetam ((2S)-2-
[(4R)-2-oxo-4-propylpyrrolidin-1-yl] butanamide) (including its salts)
as a controlled substance under the CSA.
Included below is a brief summary of each factor as analyzed by the
HHS and the DEA, and as considered by the DEA in its scheduling action.
Please note that both the DEA and HHS analyses are available in their
entirety under ``Supporting Documents'' in the public docket for this
interim final rule at http://www.regulations.gov, under Docket Number
``DEA-435.'' Full analysis of, and citations to, the information
referenced in the summary may also be found in the supporting and
related material.
1. The Drug's Actual or Relative Potential for Abuse: BRV is a new
chemical entity and has not been marketed in the United States or in
any other country; information on actual abuse of BRV is not available.
The HHS characterized BRV as related in its action to lacasamide and
ezogabine, which are both schedule V CNS depressant anti-epileptics
(AEDs). Based on data submitted by the Sponsor in their NDAs, the HHS
indicated that administration of BRV in mice, rats, and dogs resulted
in CNS depressant effects, including decreased locomotor activity and
reactivity, motor incoordination, and ataxia.
BRV is not self-administered in animals and, unlike schedule IV
benzodiazepines and the schedule III AED perampanel, lacks
pentobarbital-like (schedule II) discriminative stimulus and
reinforcing effects (HHS review, 2015). In humans, BRV is most similar
to the schedule V AEDs lacosamide, ezogabine, and pregabalin in
producing positive subjective effects without producing sedation and
withdrawal following drug discontinuation that is observed with
schedule IV benzodiazepines. Based on this collective evidence, the HHS
concluded that BRV has an abuse potential that is most similar to AEDs
in schedule V.
2. Scientific Evidence of the Drug's Pharmacological Effects, if
Known: BRV selectively binds with high affinity to synaptic vesicle
protein 2A (SV2A). It produces reverse inhibition caused by negative
modulators of gamma aminobutyric acid (GABA) and glycine and inhibits
sodium (Na+) channels. These sites appear to underlie pharmacological
activity of BRV.
In rats, BRV at high doses partially generalizes to the schedule IV
benzodiazepine chlordiazepoxide. BRV, across a wide range of doses,
neither initiates nor maintains self-administration in rats trained to
self-administer cocaine. Human studies have reported that healthy
individuals may experience euphoria, sedation, and a drunken-like
feeling following BRV administration. When treatment-emergent adverse
events (TEAEs) \2\ were pooled across several clinical BRV studies, the
most common TEAEs were dizziness and sedative-related events such as
fatigue, extreme drowsiness, and extreme weakness. In a human abuse
potential study, the oral abuse potential, safety, tolerability, and
pharmacokinetics of BRV (50 mg, 200 mg, and 1000 mg) were compared to
1.5 and 3.0 mg of the schedule IV CNS depressant alprazolam (ALP) and
placebo. When surveyed, for all doses of BRV, there was an increase of
drug likability, feeling of a high, and taking the drug again in
comparison to placebo. The HHS mentioned that individuals who took BRV
had fewer sedative, euphoric, stimulant, dizziness, and overall
negative subjective effects compared to ALP.
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\2\ Treatment-emergent adverse event (TEAE): An event or
unexpected medical occurrence (e.g. adverse event) which first
appears during treatment with a drug or substance. TEAEs are
typically absent prior to the onset of treatment or would have been
exacerbated relative to pre-treatment conditions.
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3. The State of Current Scientific Knowledge Regarding
Brivaracetam: The chemical name for brivaracetam is (2S)-2-[(4R)-2-oxo-
4-propylpyrrolidin-1-yl] butanamide. Other names include BRV and UCB-
34714. The Chemical Abstract Services number (CAS #) of BRV is: 357336-
20-0. BRV is a racetam derivative.\3\ As the HHS noted, BRV does not
have structural similarities to any other scheduled AED or to any major
classes of abused sedative drugs with noted euphoric effects. Chemical
synthesis of BRV is considered highly complex and includes several
steps, reagents and specialized equipment.
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\3\ Racetams are a class of drugs that have a pyrrolidoline
center.
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BRV is readily soluble in water at up to 700 mg/mL. In an in vitro
oral tablet dissolution evaluation, BRV oral tablets were placed in a
buffer (pH 6.4) for 16 hours. Approximately 86-96% of BRV was released
after 16 hours in the buffer; 14-30% of BRV was released following 1
hour and 40-66% BRV was released after 4 hours.
Following oral ingestion, BRV is rapidly and completely absorbed.
In healthy young males, the half-life of BRV was determined to be
approximately 9 hours. According to the HHS, the half-life of BRV is
decreased to 6 hours when a repeated oral dose of 800 mg/day BRV is
administered. The HHS noted that BRV binds weakly to plasma proteins
and is extensively metabolized through several pathways. Clearance
through the kidneys represents 5-10% of the total clearance and only 3-
7% of the parent compound (BRV) was detected in the urine. The three
main metabolites of BRV were detected in urine and according to the
HHS, these metabolites are relatively inactive. One BRV metabolite was
characterized as having a potency that was 20 times less than BRV, and
this metabolite was not detected in human plasma and represented less
than 3% of the dose in urine.
4. Its History and Current Pattern of Abuse: As noted by the HHS,
information on the history and current pattern of abuse of BRV is not
available since this drug is currently not marketed in any country. A
review of the animal and human data indicates that BRV has an abuse
potential similar to other schedule V AEDs. If BRV were to be

[[Page 29490]]

approved for medical use, the HHS indicated that BRV would be abused
for its euphoric properties and other abuse-related TEAEs that were
reported in human clinical studies. Based on the available information,
the HHS concluded that the history and pattern of abuse of BRV will be
similar to other schedule V CNS depressants.
5. The Scope, Duration, and Significance of Abuse: As noted by the
HHS, information on the scope, duration, and significance of abuse of
BRV is not available since this drug is currently not marketed in any
country. Results from animal and human studies suggest that there is
abuse potential associated with BRV and if marketed in the United
States, it is likely that BRV will be abused similar to other AEDs that
are CNS depressants. The HHS stated that it is unlikely that epileptic
individuals (the population expected to take this drug) will abuse BRV.
The HHS concluded that based on abuse potential similarities between
BRV and other schedule V AEDs, it is likely that the scope, duration,
and significance of abuse of BRV will be similar to these compounds.
6. What, if any, Risk There is to the Public Health: The HHS
characterized BRV's drug abuse potential to be similar to schedule V
AEDs. As such, the public health risk with BRV will also be similar to
other schedule V AEDs. The HHS noted that if BRV were approved for
medical use, it would be abused for its rewarding properties. In
healthy volunteers administered 600 mg or higher of BRV, cognitive and
motor impairment and sedation were observed. It is unknown how BRV
would interact in combination with other CNS depressants and if the
sedative effects would be additive or even a lethal combination. In an
interaction study with BRV and intravenous ethanol in healthy
individuals, it was determined that BRV enhanced the effects of
ethanol.
7. Its Psychic or Physiological Dependence Liability: BRV has
limited psychological dependence and does not appear to have physical
dependence. When rats were administered BRV for 30 days, no signs of
physical dependence were noted in comparison to the schedule IV
comparator, chlordiazepoxide. Similarly, in human clinical studies with
healthy volunteers, there were no reports or adverse events that noted
physical dependence or a withdrawal syndrome associated with BRV use.
The low potential for physical dependence observed with BRV is
consistent with other schedule V AEDs. There is limited evidence for
psychological dependence with BRV. Clinical studies have reported
individuals experiencing increasing euphoria with increasing doses of
BRV. Tolerance does not appear to develop with respect to BRV treatment
on epileptic seizure reduction.
8. Whether the Substance is an Immediate Precursor of a Substance
Already Controlled under the CSA: BRV is not an immediate precursor of
any controlled substance.
Conclusion: After considering the scientific and medical evaluation
conducted by the HHS, the HHS' recommendation, and its own eight-factor
analysis, the DEA has determined that these facts and all relevant data
constitute substantial evidence of a potential for abuse of BRV. As
such, the DEA hereby schedules BRV as a controlled substance under the
CSA.

Determination of Appropriate Schedule

The CSA outlines the findings required to place a drug or other
substance in any particular schedule (I, II, III, IV, or V). 21 U.S.C.
812(b). After consideration of the analysis and recommendation of the
Assistant Secretary for Health of the HHS and review of all available
data, the Acting Administrator of the DEA, pursuant to 21 U.S.C.
812(b)(5), finds that:
1. BRV has a low potential for abuse relative to the drugs or other
substances in schedule IV. The overall abuse potential of BRV is
comparable to schedule V controlled substances such as ezogabalin,
pregabalin, and lacosamide;
2. With FDA's approval of the new drug applications, BRV has a
currently accepted medical use in the United States as adjunctive
treatment of partial onset seizures in epileptic individuals ages 16
and older; and
3. Human and animal studies demonstrate that BRV has limited
psychological dependence and does not appear to have physical
dependence. There was no evidence of physical dependence associated
with BRV in human and animal studies since there have been no reports
of withdrawal syndromes or other physical dependence effects. Based on
these data, abuse of BRV may lead to limited psychological dependence
similar to schedule V AEDs but less than that of drugs in schedule IV.
Based on these findings, the Acting Administrator of the DEA
concludes that brivaracetam ((2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-
yl] butanamide) (also referred to as BRV; UCB-34714; Briviact),
including its salts, warrants control in schedule V of the CSA. 21
U.S.C. 812(b)(5).

Requirements for Handling Brivaracetam

BRV is subject to the CSA's schedule V regulatory controls and
administrative, civil, and criminal sanctions applicable to the
manufacture, distribution, reverse distribution, dispensing, importing,
exporting, research, and conduct of instructional activities and
chemical analysis with, and possession involving schedule V substances,
including the following:
1. Registration. Any person who handles (manufactures, distributes,
reverse distributes, dispenses, imports, exports, engages in research,
or conducts instructional activities or chemical analysis with, or
possesses) BRV, or who desires to handle BRV, must be registered with
the DEA to conduct such activities pursuant to 21 U.S.C. 822, 823, 957,
and 958 and in accordance with 21 CFR parts 1301 and 1312. Any person
who currently handles BRV, and is not registered with the DEA, must
submit an application for registration and may not continue to handle
BRV, unless the DEA has approved that application for registration,
pursuant to 21 U.S.C. 822, 823, 957, and 958, and in accordance with 21
CFR parts 1301 and 1312.
2. Disposal of stocks. Any person who does not desire or is not
able to obtain a schedule V registration must surrender all quantities
of currently held BRV, or may transfer all quantities of currently held
BRV to a person registered with the DEA in accordance with 21 CFR part
1317, in additional to all other applicable federal, state, local, and
tribal laws.
3. Security. BRV is subject to schedule III-V security requirements
and must be handled and stored pursuant to 21 U.S.C. 821, 823, and
871(b), and in accordance with 21 CFR 1301.71-1301.93.
4. Labeling and Packaging. All labels, labeling, and packaging for
commercial containers of BRV must comply with 21 U.S.C. 825 and 958(e),
and be in accordance with 21 CFR part 1302.
5. Inventory. Every DEA registrant who possesses any quantity of
BRV must take an inventory of BRV on hand, pursuant to 21 U.S.C. 827
and 958, and in accordance with 21 CFR 1304.03, 1304.04, and 1304.11.
Any person who becomes registered with the DEA must take an initial
inventory of all stocks of controlled substances (including BRV) on
hand on the date the registrant first engages in the handling of
controlled substances, pursuant to 21 U.S.C. 827 and 958, and in
accordance with 21 CFR 1304.03, 1304.04, and 1304.11.

[[Page 29491]]

After the initial inventory, every DEA registrant must take a new
inventory of all stocks of controlled substances (including BRV) on
hand every two years, pursuant to 21 U.S.C. 827 and 958, and in
accordance with 21 CFR 1304.03, 1304.04, and 1304.11.
6. Records and Reports. Every DEA registrant must maintain records
and submit reports for BRV, or products containing BRV, pursuant to 21
U.S.C. 827 and 958(e), and in accordance with 21 CFR parts 1304, 1312,
and 1317.
7. Prescriptions. All prescriptions for BRV or products containing
BRV must comply with 21 U.S.C. 829, and be issued in accordance with 21
CFR parts 1306 and 1311, subpart C.
8. Importation and Exportation. All importation and exportation of
BRV must be in compliance with 21 U.S.C. 952, 953, 957, and 958, and in
accordance with 21 CFR part 1312.
9. Liability. Any activity involving BRV not authorized by, or in
violation of, the CSA or its implementing regulations, is unlawful, and
may subject the person to administrative, civil, and/or criminal
sanctions.

Regulatory Analyses

Administrative Procedure Act

Public Law 114-89 was signed into law, amending 21 U.S.C. 811. This
amendment provides that in cases where a new drug is (1) approved by
the Department of Health and Human Services (HHS) and (2) HHS
recommends control in CSA schedule II-V, the DEA shall issue an interim
final rule scheduling the drug within 90 days. Additionally, the law
specifies that the rulemaking shall become immediately effective as an
interim final rule without requiring the DEA to demonstrate good cause.
Therefore, the DEA has determined that the notice and comment
requirements of section 553 of the APA, 5 U.S.C. 553, do not apply to
this scheduling action.

Executive Orders 12866, Regulatory Planning and Review, and 13563,
Improving Regulation and Regulatory Review

In accordance with Public Law 114-89, this scheduling action is
subject to formal rulemaking procedures performed ``on the record after
opportunity for a hearing,'' which are conducted pursuant to the
provisions of 5 U.S.C. 556 and 557. The CSA sets forth the procedures
and criteria for scheduling a drug or other substance. Such actions are
exempt from review by the Office of Management and Budget (OMB)
pursuant to section 3(d)(1) of Executive Order 12866 and the principles
reaffirmed in Executive Order 13563.

Executive Order 12988, Civil Justice Reform

This regulation meets the applicable standards set forth in
sections 3(a) and 3(b)(2) of Executive Order 12988 to eliminate
drafting errors and ambiguity, minimize litigation, provide a clear
legal standard for affected conduct, and promote simplification and
burden reduction.

Executive Order 13132, Federalism

This rulemaking does not have federalism implications warranting
the application of Executive Order 13132. The rule does not have
substantial direct effects on the States, on the relationship between
the national government and the States, or on the distribution of power
and responsibilities among the various levels of government.

Executive Order 13175, Consultation and Coordination With Indian Tribal
Governments

This rule does not have tribal implications warranting the
application of Executive Order 13175. It does not have substantial
direct effects on one or more Indian tribes, on the relationship
between the Federal government and Indian tribes, or on the
distribution of power and responsibilities between the Federal
government and Indian tribes.

Regulatory Flexibility Act

In accordance with 5 U.S.C. 603(a), ``[w]henever an agency is
required by [5 U.S.C. 553], or any other law, to publish general notice
of proposed rulemaking for any proposed rule, or publishes a notice of
proposed rulemaking for an interpretive rule involving the internal
revenue laws of the United States, the agency shall prepare and make
available for public comment an initial regulatory flexibility
analysis.'' As noted in the above discussion regarding applicability of
the Administrative Procedure Act, the DEA has determined that the
notice and comment requirements of section 553 of the APA, 5 U.S.C.
553, do not apply to this scheduling action. Consequently, the RFA does
not apply to this interim final rule.

Unfunded Mandates Reform Act of 1995

In accordance with the Unfunded Mandates Reform Act (UMRA) of 1995,
2 U.S.C. 1501 et seq., the DEA has determined and certifies that this
action would not result in any Federal mandate that may result ``in the
expenditure by State, local, and tribal governments, in the aggregate,
or by the private sector, of $100,000,000 or more (adjusted for
inflation) in any one year.'' Therefore, neither a Small Government
Agency Plan nor any other action is required under UMRA of 1995.

Paperwork Reduction Act of 1995

This action does not impose a new collection of information
requirement under the Paperwork Reduction Act of 1995. 44 U.S.C. 3501-
3521. This action would not impose recordkeeping or reporting
requirements on State or local governments, individuals, businesses, or
organizations. An agency may not conduct or sponsor, and a person is
not required to respond to, a collection of information unless it
displays a currently valid OMB control number.

Congressional Review Act

This rule is not a major rule as defined by section 804 of the
Small Business Regulatory Enforcement Fairness Act of 1996
(Congressional Review Act (CRA)). This rule will not result in: An
annual effect on the economy of $100,000,000 or more; a major increase
in costs or prices for consumers, individual industries, Federal,
State, or local government agencies, or geographic regions; or
significant adverse effects on competition, employment, investment,
productivity, innovation, or on the ability of U.S.-based companies to
compete with foreign based companies in domestic and export markets.
However, pursuant to the CRA, the DEA has submitted a copy of this
interim final rule to both Houses of Congress and to the Comptroller
General.

List of Subjects in 21 CFR Part 1308

Administrative practice and procedure, Drug traffic control,
Reporting and recordkeeping requirements.

For the reasons set out above, the DEA amends 21 CFR part 1308:

PART 1308--SCHEDULES OF CONTROLLED SUBSTANCES

0
1. The authority citation for 21 CFR part 1308 continues to read as
follows:

Authority: 21 U.S.C. 811, 812, 871(b), unless otherwise noted.

0
2. Amend Sec. 1308.15 by redesignating paragraphs (e)(1) through
(e)(3) as paragraphs (e)(2) through (e)(4) and adding new paragraph
(e)(1) to read as follows:

Sec. 1308.15 Schedule V.

* * * * *
(e) * * *

[[Page 29492]]

(1) Brivaracetam ((2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl] 2710
butanamide) (also referred to as BRV; UCB-34714; Briviact)
(including its salts).........................................

* * * * *

Dated: May 6, 2016.
Chuck Rosenberg,
Acting Administrator.
[FR Doc. 2016-11245 Filed 5-11-16; 8:45 am]
BILLING CODE 4410-09-P

Federal Register / Vol. 81, No. 92 / Thursday, May 12, 2016 / Rules and Regulations 29487

et seq.; 22 U.S.C. 7210; E.O. 13026, 61 FR opportunity for a hearing or to Administration (DEA) for public
58767, 3 CFR, 1996 Comp., p. 228; E.O. participate in a hearing must be inspection online at http://
13222, 66 FR 44025, 3 CFR, 2001 Comp., p. received on or before June 13, 2016. www.regulations.gov. Such information
783; Notice of August 7, 2015, 80 FR 48233 includes personal identifying
(August 11, 2015). ADDRESSES: To ensure proper handling
of comments, please reference ‘‘Docket information (such as your name,
Supplement No. 1 to Part 774— No. DEA–435’’ on all correspondence, address, etc.) voluntarily submitted by
[Amended] including any attachments. the commenter. The Freedom of
• Electronic comments: The Drug Information Act (FOIA) applies to all
■ 21. In Supplement No. 1 to Part 774 comments received. If you want to
Enforcement Administration encourages
(the Commerce Control List), ECCN submit personal identifying information
that all comments be submitted
1C981 is removed. (such as your name, address, etc.) as
electronically through the Federal
Dated: May 5, 2016. eRulemaking Portal, which provides the part of your comment, but do not want
Eric L. Hirschhorn, ability to type short comments directly it to be made publicly available, you
Under Secretary for Industry and Security. into the comment field on the Web page must include the phrase ‘‘PERSONAL
[FR Doc. 2016–11047 Filed 5–11–16; 8:45 am] or attach a file for lengthier comments. IDENTIFYING INFORMATION’’ in the
Please go to http://www.regulations.gov first paragraph of your comment. You
BILLING CODE 3510–33–P
and follow the online instructions at must also place all of the personal
that site for submitting comments. Upon identifying information you do not want
completion of your submission, you will made publicly available in the first
DEPARTMENT OF JUSTICE paragraph of your comment and identify
receive a Comment Tracking Number for
Drug Enforcement Administration your comment. Please be aware that what information you want redacted.
submitted comments are not If you want to submit confidential
instantaneously available for public business information as part of your
21 CFR Part 1308
view on Regulations.gov. If you have comment, but do not want it to be made
[Docket No. DEA–435]
received a Comment Tracking Number, publicly available, you must include the
your comment has been successfully phrase ‘‘CONFIDENTIAL BUSINESS
Schedules of Controlled Substances: INFORMATION’’ in the first paragraph
Placement of Brivaracetam Into submitted and there is no need to
resubmit the same comment. of your comment. You must also
Schedule V prominently identify the confidential
• Paper comments: Paper comments
AGENCY: Drug Enforcement that duplicate the electronic submission business information to be redacted
Administration, Department of Justice. are not necessary and are discouraged. within the comment.
Comments containing personal
ACTION: Interim final rule, with request Should you wish to mail a paper
identifying information and confidential
for comments. comment in lieu of an electronic
business information identified as
comment, it should be sent via regular
directed above will generally be made
SUMMARY: The Drug Enforcement or express mail to: Drug Enforcement
publicly available in redacted form. If a
Administration is placing the substance Administration, Attn: DEA Federal comment has so much confidential
brivaracetam ((2S)-2-[(4R)-2-oxo-4- Register Representative/ODW, 8701 business information or personal
propylpyrrolidin-1-yl] butanamide) Morrissette Drive, Springfield, VA identifying information that it cannot be
(also referred to as BRV; UCB–34714; 22152. effectively redacted, all or part of that
Briviact) (including its salts) into • Hearing requests: All requests for
comment may not be made publicly
schedule V of the Controlled Substances hearing and waivers of participation
available. Comments posted to http://
Act. This scheduling action is pursuant must be sent to: Drug Enforcement
www.regulations.gov may include any
to the Controlled Substances Act, as Administration, Attn: Administrator,
personal identifying information (such
revised by the Improving Regulatory 8701 Morrissette Drive, Springfield,
as name, address, and phone number)
Transparency for New Medical Virginia 22152. All requests for hearing
included in the text of your electronic
Therapies Act which was signed into and waivers of participation should also
submission that is not identified as
law on November 25, 2015. be sent to: (1) Drug Enforcement
directed above as confidential.
DATES: The effective date of this Administration, Attn: Hearing Clerk/LJ, An electronic copy of this document
rulemaking is May 12, 2016. Interested 8701 Morrissette Drive, Springfield, and supplemental information,
persons may file written comments on Virginia 22152; and (2) Drug including the complete Department of
this rulemaking in accordance with 21 Enforcement Administration, Attn: DEA Health and Human Services and Drug
CFR 1308.43(g). Electronic comments Federal Register Representative/ODW, Enforcement Administration eight-factor
must be submitted, and written 8701 Morrissette Drive, Springfield, analyses, to this interim final rule are
comments must be postmarked, on or Virginia 22152. available at http://www.regulations.gov
before June 13, 2016. Commenters FOR FURTHER INFORMATION CONTACT: for easy reference.
should be aware that the electronic Barbara J. Boockholdt, Office of
Federal Docket Management System Diversion Control, Drug Enforcement Request for Hearing, Notice of
will not accept comments after 11:59 Administration; Mailing Address: 8701 Appearance at Hearing, or Waiver of
p.m. Eastern Time on the last day of the Morrissette Drive, Springfield, Virginia Participation in Hearing
comment period. 22152; Telephone: (202) 598–6812. Pursuant to 21 U.S.C. 811(a), this
Interested persons, defined at 21 CFR SUPPLEMENTARY INFORMATION: action is a formal rulemaking ‘‘on the
jstallworth on DSK7TPTVN1PROD with RULES

1300.01 as those ‘‘adversely affected or record after opportunity for a hearing.’’
aggrieved by any rule or proposed rule Posting of Public Comments Such proceedings are conducted
issuable pursuant to section 201 of the Please note that all comments pursuant to the provisions of the
Act (21 U.S.C. 811),’’ may file a request received are considered part of the Administrative Procedure Act (APA), 5
for hearing or waiver of hearing public record. They will, unless U.S.C. 551–559. 21 CFR 1308.41–
pursuant to 21 CFR 1308.44. Requests reasonable cause is given, be made 1308.45; 21 CFR part 1316, subpart D.
for hearing and waivers of an available by the Drug Enforcement In accordance with 21 CFR 1308.44(a)–

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29488 Federal Register / Vol. 81, No. 92 / Thursday, May 12, 2016 / Rules and Regulations

(c), requests for a hearing, notices of treatment in the United States, and the within 90 days, issue an interim final
appearance, and waivers of an degree of dependence the substance rule controlling the drug in accordance
opportunity for a hearing or to may cause. 21 U.S.C. 812. The initial with such subsections and 21 U.S.C.
participate in a hearing may be schedules of controlled substances 812(b) using the specified procedures.
submitted only by interested persons, established by Congress are found at 21 For purposes of calculating the 90 days,
defined as those ‘‘adversely affected or U.S.C. 812(c), and the current list of all Public Law 114–89 states that such date
aggrieved by any rule or proposed rule scheduled substances is published at 21 shall be the later of the date on which
issuable pursuant to section 201 of the CFR part 1308. the Attorney General receives the
Act (21 U.S.C. 811).’’ 21 CFR 1300.01. Pursuant to 21 U.S.C. 811(a)(1), the scientific and medical evaluation and
Requests for a hearing and notices of Attorney General may, by rule, ‘‘add to the scheduling recommendation from
participation must conform to the such a schedule or transfer between
the Secretary in accordance with
requirements of 21 CFR 1308.44(a) or such schedules any drug or other
subsection (b), or the date on which the
(b), as applicable, and include a substance if he * * * finds that such
drug or other substance has a potential Attorney General receives notification
statement of the interest of the person in
for abuse, and * * * makes with respect from the Secretary that the Secretary has
the proceeding and the objections or
to such drug or other substance the approved an application under section
issues, if any, concerning which the
person desires to be heard. Any waiver findings prescribed by subsection (b) of 505(c), 512, or 571 of the Federal Food,
of an opportunity for a hearing must section 812 of this title for the schedule Drug, and Cosmetic Act or section
conform to the requirements of 21 CFR in which such drug is to be placed 351(a) of the Public Health Service Act,
1308.44(c) including a written statement * * *’’ The Attorney General has or indexed a drug under section 572 of
regarding the interested person’s delegated this scheduling authority the Federal Food, Drug, and Cosmetic
position on the matters of fact and law under 21 U.S.C. 811 to the Act, with respect to the drug described
involved in any hearing. Administrator of the DEA. 28 CFR in paragraph (1). Public Law 114–89
Please note that pursuant to 21 U.S.C. 0.100. further stipulates that a rule issued by
811(a), the purpose and subject matter The CSA provides that scheduling of the Attorney General under paragraph
of the hearing are restricted to ‘‘(A) any drug or other substance may be (1) becomes immediately effective as an
find[ing] that such drug or other initiated by the Attorney General (1) on interim final rule without requiring the
substance has a potential for abuse, and her own motion; (2) at the request of the Attorney General to demonstrate good
(B) mak[ing] with respect to such drug Secretary of Health and Human Services cause and requires that the interim final
or other substance the findings (HHS); or (3) on the petition of any rule give interested persons the
prescribed by subsection (b) of section interested party. 21 U.S.C. 811(a). This opportunity to comment and to request
812 of this title for the schedule in action imposes the regulatory controls a hearing. After the conclusion of such
which such drug is to be placed. * * *’’ and administrative, civil, and criminal proceedings, the Attorney General must
Requests for a hearing and waivers of sanctions of schedule V controlled issue a final rule in accordance with the
participation in the hearing should be substances for any person who handles scheduling criteria of subsections 21
submitted to DEA using the address or proposes to handle BRV. U.S.C. 811(b), (c), and (d) of this section
information provided above. The Improving Regulatory and 21 U.S.C. 812(b).
Transparency for New Medical
Legal Authority Therapies Act (Pub. L. 114–89) was Background
The DEA implements and enforces signed into law on November 25, 2015.
titles II and III of the Comprehensive This law amended 21 U.S.C. 811 and Brivaracetam ((2S)-2-[(4R)-2-oxo-4-
Drug Abuse Prevention and Control Act states that in cases where a new drug is propylpyrrolidin-1-yl] butanamide)
of 1970, as amended. 21 U.S.C. 801–971. (1) approved by the Department of (also referred to as BRV; UCB–34714;
Titles II and III are referred to as the Health and Human Services (HHS) and Briviact) is a new molecular entity with
‘‘Controlled Substances Act’’ and the (2) HHS recommends control in CSA central nervous system (CNS)
‘‘Controlled Substances Import and schedule II–V, DEA shall issue an depressant properties. BRV is known to
Export Act,’’ respectively, and are interim final rule scheduling the drug, be a high affinity ligand for the synaptic
collectively referred to as the within 90 days. vesicle protein, SV2A, which is found
‘‘Controlled Substances Act’’ or the The law further states that the 90-day on excitatory synapses in the brain. On
‘‘CSA’’ for the purpose of this action. timeframe starts the later of (1) the date November 22, 2014, UCB Inc. (Sponsor)
The DEA publishes the implementing DEA receives the HHS scientific and submitted three New Drug Applications
regulations for these statutes in title 21 medical evaluation/scheduling (NDAs) to the U.S. Food and Drug
of the Code of Federal Regulations recommendation or (2) the date DEA Administration (FDA) for the tablet,
(CFR), chapter II. The CSA and its receives notice of drug approval by oral, and intravenous formulations of
implementing regulations are designed HHS. In addition, the law specifies that BRV. The FDA accepted the NDA filings
to prevent, detect, and eliminate the the rulemaking shall become for BRV on January 21, 2015.
diversion of controlled substances and immediately effective as an interim final On March 28, 2016 the DEA received
listed chemicals into the illicit market rule without requiring the DEA to
notification that HHS/FDA approved
while providing for the legitimate demonstrate good cause therefor.
Specifically, Public Law 114–89 BRV as an add-on treatment to other
medical, scientific, research, and
revised section 201 of the CSA (21 medications to treat partial onset
industrial needs of the United States.
U.S.C. 811) by inserting after subsection seizures in patients age 16 years and
Controlled substances have the potential
jstallworth on DSK7TPTVN1PROD with RULES

(i) a new paragraph (j), which requires older with epilepsy.
for abuse and dependence and are
controlled to protect the public health that with respect to a drug referred to in Determination to Schedule BRV
and safety. subsection (f), if the Secretary
Under the CSA, controlled substances recommends that the Attorney General Pursuant to 21 U.S.C. 811(a)(1),
are classified into one of five schedules control the drug in schedule II, III, IV, proceedings to add a drug or substance
based upon their potential for abuse, or V pursuant to subsections (a) and (b), to those controlled under the CSA may
their currently accepted medical use in the Attorney General is required to, be initiated by request of the Secretary

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of the HHS.1 On September 8, 2015, the action to lacasamide and ezogabine, BRV, there was an increase of drug
HHS provided the DEA with a scientific which are both schedule V CNS likability, feeling of a high, and taking
and medical evaluation document depressant anti-epileptics (AEDs). Based the drug again in comparison to
prepared by the FDA entitled ‘‘Basis for on data submitted by the Sponsor in placebo. The HHS mentioned that
the Recommendation to Place their NDAs, the HHS indicated that individuals who took BRV had fewer
Brivaracetam in Schedule V of the administration of BRV in mice, rats, and sedative, euphoric, stimulant, dizziness,
Controlled Substances Act.’’ Pursuant to dogs resulted in CNS depressant effects, and overall negative subjective effects
21 U.S.C. 811(b), this document including decreased locomotor activity compared to ALP.
contained an eight-factor analysis of the and reactivity, motor incoordination, 3. The State of Current Scientific
abuse potential of BRV as a new drug, and ataxia. Knowledge Regarding Brivaracetam:
along with the HHS’ recommendation to BRV is not self-administered in The chemical name for brivaracetam is
control BRV under schedule V of the animals and, unlike schedule IV (2S)-2-[(4R)-2-oxo-4-propylpyrrolidin-1-
CSA. benzodiazepines and the schedule III yl] butanamide. Other names include
In response, in December 2015, the AED perampanel, lacks pentobarbital- BRV and UCB–34714. The Chemical
DEA reviewed the scientific and like (schedule II) discriminative Abstract Services number (CAS #) of
medical evaluation and scheduling stimulus and reinforcing effects (HHS BRV is: 357336–20–0. BRV is a racetam
recommendation provided by the HHS, review, 2015). In humans, BRV is most derivative.3 As the HHS noted, BRV
along with all other relevant data, and similar to the schedule V AEDs does not have structural similarities to
completed its own eight-factor review lacosamide, ezogabine, and pregabalin any other scheduled AED or to any
document pursuant to 21 U.S.C. 811(c). in producing positive subjective effects major classes of abused sedative drugs
The DEA concluded that BRV met the without producing sedation and with noted euphoric effects. Chemical
21 U.S.C. 812(b)(5) criteria for withdrawal following drug synthesis of BRV is considered highly
placement in schedule V of the CSA. discontinuation that is observed with complex and includes several steps,
Subsequently, on March 28, 2016, the schedule IV benzodiazepines. Based on reagents and specialized equipment.
DEA received notification that HHS/ this collective evidence, the HHS BRV is readily soluble in water at up
FDA approved three NDAs for BRV (see concluded that BRV has an abuse to 700 mg/mL. In an in vitro oral tablet
Background section). potential that is most similar to AEDs in dissolution evaluation, BRV oral tablets
Pursuant to the provisions of the schedule V. were placed in a buffer (pH 6.4) for 16
Improving Regulatory Transparency for 2. Scientific Evidence of the Drug’s hours. Approximately 86–96% of BRV
New Medical Therapies Act (Pub. L. Pharmacological Effects, if Known: BRV was released after 16 hours in the buffer;
114–89), and based on the HHS selectively binds with high affinity to 14–30% of BRV was released following
recommendation, NDA approvals by synaptic vesicle protein 2A (SV2A). It 1 hour and 40–66% BRV was released
HHS/FDA, and DEA’s determination, produces reverse inhibition caused by after 4 hours.
DEA is issuing this interim final rule to negative modulators of gamma Following oral ingestion, BRV is
schedule brivaracetam ((2S)-2-[(4R)-2- aminobutyric acid (GABA) and glycine rapidly and completely absorbed. In
oxo-4-propylpyrrolidin-1-yl] and inhibits sodium (Na+) channels. healthy young males, the half-life of
butanamide) (including its salts) as a These sites appear to underlie BRV was determined to be
controlled substance under the CSA. pharmacological activity of BRV. approximately 9 hours. According to the
Included below is a brief summary of In rats, BRV at high doses partially HHS, the half-life of BRV is decreased
each factor as analyzed by the HHS and generalizes to the schedule IV to 6 hours when a repeated oral dose of
the DEA, and as considered by the DEA benzodiazepine chlordiazepoxide. BRV, 800 mg/day BRV is administered. The
in its scheduling action. Please note that across a wide range of doses, neither HHS noted that BRV binds weakly to
both the DEA and HHS analyses are initiates nor maintains self- plasma proteins and is extensively
available in their entirety under administration in rats trained to self- metabolized through several pathways.
‘‘Supporting Documents’’ in the public administer cocaine. Human studies have Clearance through the kidneys
docket for this interim final rule at reported that healthy individuals may represents 5–10% of the total clearance
http://www.regulations.gov, under experience euphoria, sedation, and a and only 3–7% of the parent compound
Docket Number ‘‘DEA–435.’’ Full drunken-like feeling following BRV (BRV) was detected in the urine. The
analysis of, and citations to, the administration. When treatment- three main metabolites of BRV were
information referenced in the summary emergent adverse events (TEAEs) 2 were detected in urine and according to the
may also be found in the supporting and pooled across several clinical BRV HHS, these metabolites are relatively
related material. studies, the most common TEAEs were inactive. One BRV metabolite was
1. The Drug’s Actual or Relative dizziness and sedative-related events characterized as having a potency that
Potential for Abuse: BRV is a new such as fatigue, extreme drowsiness, was 20 times less than BRV, and this
chemical entity and has not been and extreme weakness. In a human metabolite was not detected in human
marketed in the United States or in any abuse potential study, the oral abuse plasma and represented less than 3% of
other country; information on actual potential, safety, tolerability, and the dose in urine.
abuse of BRV is not available. The HHS pharmacokinetics of BRV (50 mg, 200 4. Its History and Current Pattern of
characterized BRV as related in its mg, and 1000 mg) were compared to 1.5 Abuse: As noted by the HHS,
and 3.0 mg of the schedule IV CNS information on the history and current
1 As set forth in a memorandum of understanding
depressant alprazolam (ALP) and pattern of abuse of BRV is not available
entered into by the HHS, the FDA, and the National
placebo. When surveyed, for all doses of since this drug is currently not marketed
jstallworth on DSK7TPTVN1PROD with RULES

Institute on Drug Abuse (NIDA), the FDA acts as the
lead agency within the HHS in carrying out the in any country. A review of the animal
Secretary’s scheduling responsibilities under the 2 Treatment-emergent adverse event (TEAE): An
and human data indicates that BRV has
CSA, with the concurrence of the NIDA. 50 FR event or unexpected medical occurrence (e.g. an abuse potential similar to other
9518, Mar. 8, 1985. The Secretary of the HHS has adverse event) which first appears during treatment
delegated to the Assistant Secretary for Health of with a drug or substance. TEAEs are typically schedule V AEDs. If BRV were to be
the HHS the authority to make domestic drug absent prior to the onset of treatment or would have
scheduling recommendations. 58 FR 35460, July 1, been exacerbated relative to pre-treatment 3 Racetams are a class of drugs that have a

1993. conditions. pyrrolidoline center.

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29490 Federal Register / Vol. 81, No. 92 / Thursday, May 12, 2016 / Rules and Regulations

approved for medical use, the HHS Clinical studies have reported Requirements for Handling
indicated that BRV would be abused for individuals experiencing increasing Brivaracetam
its euphoric properties and other abuse- euphoria with increasing doses of BRV. BRV is subject to the CSA’s schedule
related TEAEs that were reported in Tolerance does not appear to develop V regulatory controls and
human clinical studies. Based on the with respect to BRV treatment on administrative, civil, and criminal
available information, the HHS epileptic seizure reduction. sanctions applicable to the manufacture,
concluded that the history and pattern 8. Whether the Substance is an distribution, reverse distribution,
of abuse of BRV will be similar to other Immediate Precursor of a Substance dispensing, importing, exporting,
schedule V CNS depressants. Already Controlled under the CSA: BRV research, and conduct of instructional
5. The Scope, Duration, and is not an immediate precursor of any activities and chemical analysis with,
Significance of Abuse: As noted by the controlled substance. and possession involving schedule V
HHS, information on the scope, Conclusion: After considering the
duration, and significance of abuse of substances, including the following:
scientific and medical evaluation 1. Registration. Any person who
BRV is not available since this drug is conducted by the HHS, the HHS’ handles (manufactures, distributes,
currently not marketed in any country. recommendation, and its own eight-
Results from animal and human studies reverse distributes, dispenses, imports,
factor analysis, the DEA has determined exports, engages in research, or
suggest that there is abuse potential that these facts and all relevant data
associated with BRV and if marketed in conducts instructional activities or
constitute substantial evidence of a chemical analysis with, or possesses)
the United States, it is likely that BRV potential for abuse of BRV. As such, the
will be abused similar to other AEDs BRV, or who desires to handle BRV,
DEA hereby schedules BRV as a must be registered with the DEA to
that are CNS depressants. The HHS controlled substance under the CSA.
stated that it is unlikely that epileptic conduct such activities pursuant to 21
individuals (the population expected to Determination of Appropriate Schedule U.S.C. 822, 823, 957, and 958 and in
take this drug) will abuse BRV. The accordance with 21 CFR parts 1301 and
The CSA outlines the findings 1312. Any person who currently
HHS concluded that based on abuse required to place a drug or other
potential similarities between BRV and handles BRV, and is not registered with
substance in any particular schedule (I, the DEA, must submit an application for
other schedule V AEDs, it is likely that II, III, IV, or V). 21 U.S.C. 812(b). After
the scope, duration, and significance of registration and may not continue to
consideration of the analysis and handle BRV, unless the DEA has
abuse of BRV will be similar to these recommendation of the Assistant
compounds. approved that application for
Secretary for Health of the HHS and registration, pursuant to 21 U.S.C. 822,
6. What, if any, Risk There is to the
review of all available data, the Acting 823, 957, and 958, and in accordance
Public Health: The HHS characterized
Administrator of the DEA, pursuant to with 21 CFR parts 1301 and 1312.
BRV’s drug abuse potential to be similar
21 U.S.C. 812(b)(5), finds that: 2. Disposal of stocks. Any person who
to schedule V AEDs. As such, the public
health risk with BRV will also be similar 1. BRV has a low potential for abuse does not desire or is not able to obtain
to other schedule V AEDs. The HHS relative to the drugs or other substances a schedule V registration must surrender
noted that if BRV were approved for in schedule IV. The overall abuse all quantities of currently held BRV, or
medical use, it would be abused for its potential of BRV is comparable to may transfer all quantities of currently
rewarding properties. In healthy schedule V controlled substances such held BRV to a person registered with the
volunteers administered 600 mg or as ezogabalin, pregabalin, and DEA in accordance with 21 CFR part
higher of BRV, cognitive and motor lacosamide; 1317, in additional to all other
impairment and sedation were 2. With FDA’s approval of the new applicable federal, state, local, and tribal
observed. It is unknown how BRV drug applications, BRV has a currently laws.
would interact in combination with accepted medical use in the United 3. Security. BRV is subject to schedule
other CNS depressants and if the States as adjunctive treatment of partial III–V security requirements and must be
sedative effects would be additive or onset seizures in epileptic individuals handled and stored pursuant to 21
even a lethal combination. In an ages 16 and older; and U.S.C. 821, 823, and 871(b), and in
interaction study with BRV and 3. Human and animal studies accordance with 21 CFR 1301.71–
intravenous ethanol in healthy demonstrate that BRV has limited 1301.93.
individuals, it was determined that BRV psychological dependence and does not 4. Labeling and Packaging. All labels,
enhanced the effects of ethanol. appear to have physical dependence. labeling, and packaging for commercial
7. Its Psychic or Physiological There was no evidence of physical containers of BRV must comply with 21
Dependence Liability: BRV has limited dependence associated with BRV in U.S.C. 825 and 958(e), and be in
psychological dependence and does not human and animal studies since there accordance with 21 CFR part 1302.
appear to have physical dependence. have been no reports of withdrawal 5. Inventory. Every DEA registrant
When rats were administered BRV for syndromes or other physical who possesses any quantity of BRV
30 days, no signs of physical dependence effects. Based on these data, must take an inventory of BRV on hand,
dependence were noted in comparison abuse of BRV may lead to limited pursuant to 21 U.S.C. 827 and 958, and
to the schedule IV comparator, psychological dependence similar to in accordance with 21 CFR 1304.03,
chlordiazepoxide. Similarly, in human schedule V AEDs but less than that of 1304.04, and 1304.11.
clinical studies with healthy volunteers, drugs in schedule IV. Any person who becomes registered
there were no reports or adverse events Based on these findings, the Acting with the DEA must take an initial
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that noted physical dependence or a Administrator of the DEA concludes inventory of all stocks of controlled
withdrawal syndrome associated with that brivaracetam ((2S)-2-[(4R)-2-oxo-4- substances (including BRV) on hand on
BRV use. The low potential for physical propylpyrrolidin-1-yl] butanamide) the date the registrant first engages in
dependence observed with BRV is (also referred to as BRV; UCB–34714; the handling of controlled substances,
consistent with other schedule V AEDs. Briviact), including its salts, warrants pursuant to 21 U.S.C. 827 and 958, and
There is limited evidence for control in schedule V of the CSA. 21 in accordance with 21 CFR 1304.03,
psychological dependence with BRV. U.S.C. 812(b)(5). 1304.04, and 1304.11.

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Federal Register / Vol. 81, No. 92 / Thursday, May 12, 2016 / Rules and Regulations 29491

After the initial inventory, every DEA principles reaffirmed in Executive Order private sector, of $100,000,000 or more
registrant must take a new inventory of 13563. (adjusted for inflation) in any one year.’’
all stocks of controlled substances Therefore, neither a Small Government
Executive Order 12988, Civil Justice
(including BRV) on hand every two Agency Plan nor any other action is
Reform
years, pursuant to 21 U.S.C. 827 and required under UMRA of 1995.
958, and in accordance with 21 CFR This regulation meets the applicable
standards set forth in sections 3(a) and Paperwork Reduction Act of 1995
1304.03, 1304.04, and 1304.11.
6. Records and Reports. Every DEA 3(b)(2) of Executive Order 12988 to This action does not impose a new
registrant must maintain records and eliminate drafting errors and ambiguity, collection of information requirement
submit reports for BRV, or products minimize litigation, provide a clear legal under the Paperwork Reduction Act of
containing BRV, pursuant to 21 U.S.C. standard for affected conduct, and 1995. 44 U.S.C. 3501–3521. This action
827 and 958(e), and in accordance with promote simplification and burden would not impose recordkeeping or
21 CFR parts 1304, 1312, and 1317. reduction. reporting requirements on State or local
7. Prescriptions. All prescriptions for Executive Order 13132, Federalism governments, individuals, businesses, or
BRV or products containing BRV must organizations. An agency may not
comply with 21 U.S.C. 829, and be This rulemaking does not have conduct or sponsor, and a person is not
issued in accordance with 21 CFR parts federalism implications warranting the required to respond to, a collection of
1306 and 1311, subpart C. application of Executive Order 13132. information unless it displays a
8. Importation and Exportation. All The rule does not have substantial currently valid OMB control number.
importation and exportation of BRV direct effects on the States, on the
must be in compliance with 21 U.S.C. relationship between the national Congressional Review Act
952, 953, 957, and 958, and in government and the States, or on the
This rule is not a major rule as
accordance with 21 CFR part 1312. distribution of power and
defined by section 804 of the Small
9. Liability. Any activity involving responsibilities among the various
Business Regulatory Enforcement
BRV not authorized by, or in violation levels of government.
Fairness Act of 1996 (Congressional
of, the CSA or its implementing Executive Order 13175, Consultation Review Act (CRA)). This rule will not
regulations, is unlawful, and may and Coordination With Indian Tribal result in: An annual effect on the
subject the person to administrative, Governments economy of $100,000,000 or more; a
civil, and/or criminal sanctions. major increase in costs or prices for
This rule does not have tribal
Regulatory Analyses implications warranting the application consumers, individual industries,
of Executive Order 13175. It does not Federal, State, or local government
Administrative Procedure Act agencies, or geographic regions; or
have substantial direct effects on one or
Public Law 114–89 was signed into more Indian tribes, on the relationship significant adverse effects on
law, amending 21 U.S.C. 811. This between the Federal government and competition, employment, investment,
amendment provides that in cases Indian tribes, or on the distribution of productivity, innovation, or on the
where a new drug is (1) approved by the power and responsibilities between the ability of U.S.-based companies to
Department of Health and Human Federal government and Indian tribes. compete with foreign based companies
Services (HHS) and (2) HHS in domestic and export markets.
recommends control in CSA schedule Regulatory Flexibility Act However, pursuant to the CRA, the DEA
II–V, the DEA shall issue an interim In accordance with 5 U.S.C. 603(a), has submitted a copy of this interim
final rule scheduling the drug within 90 ‘‘[w]henever an agency is required by [5 final rule to both Houses of Congress
days. Additionally, the law specifies U.S.C. 553], or any other law, to publish and to the Comptroller General.
that the rulemaking shall become general notice of proposed rulemaking List of Subjects in 21 CFR Part 1308
immediately effective as an interim final for any proposed rule, or publishes a
rule without requiring the DEA to notice of proposed rulemaking for an Administrative practice and
demonstrate good cause. Therefore, the interpretive rule involving the internal procedure, Drug traffic control,
DEA has determined that the notice and revenue laws of the United States, the Reporting and recordkeeping
comment requirements of section 553 of agency shall prepare and make available requirements.
the APA, 5 U.S.C. 553, do not apply to for public comment an initial regulatory For the reasons set out above, the DEA
this scheduling action. flexibility analysis.’’ As noted in the amends 21 CFR part 1308:
above discussion regarding applicability
Executive Orders 12866, Regulatory
of the Administrative Procedure Act, the PART 1308—SCHEDULES OF
Planning and Review, and 13563,
DEA has determined that the notice and CONTROLLED SUBSTANCES
Improving Regulation and Regulatory
comment requirements of section 553 of
Review
the APA, 5 U.S.C. 553, do not apply to ■ 1. The authority citation for 21 CFR
In accordance with Public Law 114– this scheduling action. Consequently, part 1308 continues to read as follows:
89, this scheduling action is subject to the RFA does not apply to this interim Authority: 21 U.S.C. 811, 812, 871(b),
formal rulemaking procedures final rule. unless otherwise noted.
performed ‘‘on the record after
opportunity for a hearing,’’ which are Unfunded Mandates Reform Act of 1995 ■ 2. Amend § 1308.15 by redesignating
conducted pursuant to the provisions of In accordance with the Unfunded paragraphs (e)(1) through (e)(3) as
jstallworth on DSK7TPTVN1PROD with RULES

5 U.S.C. 556 and 557. The CSA sets Mandates Reform Act (UMRA) of 1995, paragraphs (e)(2) through (e)(4) and
forth the procedures and criteria for 2 U.S.C. 1501 et seq., the DEA has adding new paragraph (e)(1) to read as
scheduling a drug or other substance. determined and certifies that this action follows:
Such actions are exempt from review by would not result in any Federal
the Office of Management and Budget mandate that may result ‘‘in the § 1308.15 Schedule V.
(OMB) pursuant to section 3(d)(1) of expenditure by State, local, and tribal * * * * *
Executive Order 12866 and the governments, in the aggregate, or by the (e) * * *

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29492 Federal Register / Vol. 81, No. 92 / Thursday, May 12, 2016 / Rules and Regulations

(1) Brivaracetam ((2S)-2-[(4R)-2- FOR FURTHER INFORMATION CONTACT: substance under section 505 of the
oxo-4-propylpyrrolidin-1-yl] Barbara J. Boockholdt, Office of Federal Food, Drug, and Cosmetic Act
butanamide) (also referred to as Diversion Control, Drug Enforcement (FDCA), 21 U.S.C. 355. 21 U.S.C.
BRV; UCB–34714; Briviact) (in- Administration; Mailing Address: 8701 811(h)(1). The Attorney General has
cluding its salts) ........................... 2710 Morrissette Drive, Springfield, Virginia delegated her scheduling authority
* * * * * 22152; Telephone: (202) 598–6812. under 21 U.S.C. 811 to the
SUPPLEMENTARY INFORMATION: Administrator of the DEA. 28 CFR
Dated: May 6, 2016. 0.100.
Chuck Rosenberg, Legal Authority
Acting Administrator. Background
The Drug Enforcement
[FR Doc. 2016–11245 Filed 5–11–16; 8:45 am] Administration (DEA) implements and Section 201(h)(4) of the CSA, 21
BILLING CODE 4410–09–P enforces titles II and III of the U.S.C. 811(h)(4), requires the
Comprehensive Drug Abuse Prevention Administrator to notify the Secretary of
and Control Act of 1970, as amended. 21 the Department of Health and Human
DEPARTMENT OF JUSTICE U.S.C. 801–971. Titles II and III are Services (HHS) of his intention to
referred to as the ‘‘Controlled temporarily place a substance into
Drug Enforcement Administration Substances Act’’ and the ‘‘Controlled schedule I of the CSA.1 The
Substances Import and Export Act,’’ Administrator transmitted the notice of
21 CFR Part 1308 respectively, and are collectively intent to place butyryl fentanyl and
referred to as the ‘‘Controlled beta-hydroxythiofentanyl into schedule
[Docket No. DEA–434F] Substances Act’’ or the ‘‘CSA’’ for the I on a temporary basis to the Assistant
purpose of this action. The DEA Secretary by letter dated December 21,
Schedules of Controlled Substances: 2015. The Assistant Secretary
publishes the implementing regulations
Temporary Placement of Butyryl responded to this notice by letter dated
for these statutes in title 21 of the Code
Fentanyl and Beta-Hydroxythiofentanyl January 13, 2016, and advised that
of Federal Regulations (CFR), chapter II.
Into Schedule I The CSA and its implementing based on review by the Food and Drug
AGENCY: Drug Enforcement regulations are designed to prevent, Administration (FDA), there are
Administration, Department of Justice. detect, and eliminate the diversion of currently no investigational new drug
controlled substances and listed applications or approved new drug
ACTION: Final order.
chemicals into the illicit market while applications for butryl fentanyl or beta-
SUMMARY: The Administrator of the Drug ensuring an adequate supply is available hydroxythiofentanyl. The Assistant
Enforcement Administration is issuing for the legitimate medical, scientific, Secretary also stated that the HHS has
this final order to temporarily schedule research, and industrial needs of the no objection to the temporary placement
the synthetic opioids, N-(1- United States. Controlled substances of butryl fentanyl or beta-
phenethylpiperidin-4-yl)-N- have the potential for abuse and hydroxythiofentanyl into schedule I of
phenylbutyramide, also known as N-(1- dependence and are controlled to the CSA. The DEA has taken into
phenethylpiperidin-4-yl)-N- protect the public health and safety. consideration the Assistant Secretary’s
phenylbutanamide, (butyryl fentanyl) Under the CSA, every controlled comments as required by 21 U.S.C.
and N-[1-[2-hydroxy-2-(thiophen-2- substance is classified into one of five 811(h)(4). Neither butryl fentanyl nor
yl)ethyl]piperidin-4-yl]-N- schedules based upon its potential for beta-hydroxythiofentanyl is currently
phenylpropionamide, also known as N- abuse, its currently accepted medical listed in any schedule under the CSA,
[1-[2-hydroxy-2-(2-thienyl)ethyl]-4- use in treatment in the United States, and no exemptions or approvals are in
piperidinyl]-N-phenylpropanamide, and the degree of dependence the drug effect for butryl fentanyl or beta-
(beta-hydroxythiofentanyl), and their or other substance may cause. 21 U.S.C. hydroxythiofentanyl under section 505
isomers, esters, ethers, salts and salts of 812. The initial schedules of controlled of the FDCA, 21 U.S.C. 355. The DEA
isomers, esters and ethers, into schedule substances established by Congress are has found that the control of butryl
I pursuant to the temporary scheduling found at 21 U.S.C. 812(c), and the fentanyl and beta-hydroxythiofentanyl
provisions of the Controlled Substances current list of all scheduled substances in schedule I on a temporary basis is
Act. This action is based on a finding by is published at 21 CFR part 1308. necessary to avoid an imminent hazard
Section 201 of the CSA, 21 U.S.C. 811, to public safety, and as required by 21
the Administrator that the placement of
provides the Attorney General with the U.S.C. 811(h)(1)(A), a notice of intent to
butyryl fentanyl and beta-
authority to temporarily place a temporarily schedule butryl fentanyl
hydroxythiofentanyl into schedule I of
substance into schedule I of the CSA for and beta-hydroxythiofentanyl was
the Controlled Substances Act is
two years without regard to the published in the Federal Register on
necessary to avoid an imminent hazard
requirements of 21 U.S.C. 811(b) if she March 23, 2016. 81 FR 15485.
to the public safety. As a result of this
finds that such action is necessary to To find that placing a substance
order, the regulatory controls and
avoid an imminent hazard to the public temporarily into schedule I of the CSA
administrative, civil, and criminal
safety. 21 U.S.C. 811(h)(1). In addition, is necessary to avoid an imminent
sanctions applicable to schedule I
if proceedings to control a substance are hazard to the public safety, the
controlled substances will be imposed
initiated under 21 U.S.C. 811(a)(1), the
on persons who handle (manufacture,
Attorney General may extend the 1 As discussed in a memorandum of
distribute, reverse distribute, import, understanding entered into by the Food and Drug
temporary scheduling for up to one
export, engage in research, conduct
jstallworth on DSK7TPTVN1PROD with RULES

Administration (FDA) and the National Institute on
year. 21 U.S.C. 811(h)(2). Drug Abuse (NIDA), the FDA acts as the lead agency
instructional activities or chemical Where the necessary findings are within the HHS in carrying out the Secretary’s
analysis, or possess), or propose to made, a substance may be temporarily scheduling responsibilities under the CSA, with the
handle, butyryl fentanyl and beta- scheduled if it is not listed in any other concurrence of NIDA. 50 FR 9518, Mar. 8, 1985.
hydroxythiofentanyl. schedule under section 202 of the CSA, The Secretary of the HHS has delegated to the
Assistant Secretary for Health of the HHS the
DATES:This final order is effective on 21 U.S.C. 812, or if there is no authority to make domestic drug scheduling
May 12, 2016. exemption or approval in effect for the recommendations. 58 FR 35460, July 1, 1993.

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Document Created: 2016-05-12 01:07:30
Document Modified: 2016-05-12 01:07:30

Category		Regulatory Information
Collection		Federal Register
sudoc Class		AE 2.7: GS 4.107: AE 2.106:
Publisher		Office of the Federal Register, National Archives and Records Administration
Section		Rules and Regulations
Action		Interim final rule, with request for comments.
Dates		The effective date of this rulemaking is May 12, 2016. Interested persons may file written comments on this rulemaking in accordance with 21 CFR 1308.43(g). Electronic comments must be submitted, and written comments must be postmarked, on or before June 13, 2016. Commenters should be aware that the electronic Federal Docket Management System will not accept comments after 11:59 p.m. Eastern Time on the last day of the comment period.
Contact		Barbara J. Boockholdt, Office of
FR Citation		81 FR 29487
CFR Associated		Administrative Practice and Procedure; Drug Traffic Control and Reporting and Recordkeeping Requirements

81 FR 29487 - Schedules of Controlled Substances: Placement of Brivaracetam Into Schedule V

DEPARTMENT OF JUSTICEDrug Enforcement Administration

Federal Register Volume 81, Issue 92 (May 12, 2016)

DEPARTMENT OF JUSTICE
Drug Enforcement Administration