[Federal Register Volume 77, Number 244 (Wednesday, December 19, 2012)]
[Proposed Rules]
[Pages 75075-75079]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2012-30531]
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DEPARTMENT OF JUSTICE
Drug Enforcement Administration
21 CFR Part 1308
[Docket No. DEA-369]
Schedules of Controlled Substances: Placement of Lorcaserin Into
Schedule IV
AGENCY: Drug Enforcement Administration, Department of Justice.
ACTION: Notice of proposed rulemaking.
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SUMMARY: The Drug Enforcement Administration (DEA) proposes placing the
substance lorcaserin, including its salts, isomers, and salts of
isomers whenever the existence of such salts, isomers, and salts of
isomers is possible, into Schedule IV of the Controlled Substances Act
(CSA). This proposed action is based on a recommendation from the
Assistant Secretary for Health of the Department of Health and Human
Services (HHS) and on an evaluation of all other relevant data by DEA.
If finalized, this action would impose the regulatory controls and
criminal sanctions of Schedule IV on the manufacture, distribution,
dispensing, importation, exportation, and possession of lorcaserin and
products containing lorcaserin.
DATES: DEA will permit interested persons to file written comments on
this proposal pursuant to 21 CFR 1308.43(g). Electronic comments must
be submitted and written comments must be postmarked on or before
January 18, 2013. Commenters should be aware that the electronic
Federal Docket Management System will not accept comments after
midnight Eastern Time on the last day of the comment period.
[[Page 75076]]
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),'' \1\ may file a request for hearing or
waiver of participation pursuant to 21 CFR 1308.44 and in accordance
with 21 CFR 1316.45. Requests for hearing and waivers of participation
must be received on or before January 18, 2013.
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\1\ 21 CFR 1300.01.
ADDRESSES: To ensure proper handling of comments, please reference
``Docket No. DEA-369'' on all electronic and written correspondence.
DEA encourages all comments be submitted electronically through http://www.regulations.gov using the electronic comment form provided on that
site. An electronic copy of this document and supplemental information
to this proposed rule are also available at the http://www.regulations.gov Web site for easy reference. Paper comments that
duplicate the electronic submission are not necessary as all comments
submitted to www.regulations.gov will be posted for public review and
are part of the official docket record. Should you, however, wish to
submit written comments via regular or express mail, they should be
sent to the Drug Enforcement Administration, Attention: DEA Federal
Register Representative/OD, 8701 Morrissette Drive, Springfield, VA
22152. All requests for hearing and waivers of participation must be
sent to Drug Enforcement Administration, Attention: Hearing Clerk/LJ,
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8701 Morrissette Drive, Springfield, VA 22152.
FOR FURTHER INFORMATION CONTACT: John W. Partridge, Executive
Assistant, Office of Diversion Control, Drug Enforcement
Administration; Mailing Address: 8701 Morrissette Drive, Springfield,
Virginia 22152. Telephone: (202) 307-7165.
SUPPLEMENTARY INFORMATION:
Posting of Public Comments
Please note that all comments received are considered part of the
public record and made available for public inspection online at http://www.regulations.gov and in the DEA's public docket. Such information
includes personal identifying information (such as your name, address,
etc.) voluntarily submitted by the commenter.
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 posted online or made available in the public docket, you must
include the phrase ``PERSONAL IDENTIFYING INFORMATION'' in the first
paragraph of your comment. You must also place all the personal
identifying information you do not want posted online or made available
in the public docket 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 posted online or made available
in the public docket, you must include the phrase ``CONFIDENTIAL
BUSINESS INFORMATION'' in the first paragraph of your comment. You must
also prominently identify confidential business information to be
redacted within the comment. If a comment has so much confidential
business information that it cannot be effectively redacted, all or
part of that comment may not be posted online or made available in the
public docket.
Personal identifying information and confidential business
information identified and located as set forth above will be redacted
and the comment, in redacted form, will be posted online and placed in
the DEA's public docket file. Please note that the Freedom of
Information Act applies to all comments received. If you wish to
inspect the agency's public docket file in person by appointment,
please see the ``For Further Information Contact'' paragraph, above.
Requests for Hearing or Waiver of Participation in Hearing
In accordance with the provisions of the CSA (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 (5 U.S.C. 556 and 557)
and 21 CFR 1308.41. Pursuant to 21 CFR 1308.44(a) and (c), requests for
a hearing and waivers of participation 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).'' \2\ Requests for a hearing must conform to the
requirements of 21 CFR 1308.44(a) and 1316.47. A request should state,
with particularity, 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 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.
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\2\ 21 CFR 1300.01.
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Please note that pursuant to 21 U.S.C. 811(a), the purpose and
subject matter of the hearing is 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
hearing and waivers of participation in the hearing should be submitted
to DEA using the address information provided above. DEA may grant a
hearing only ``for the purpose of receiving factual evidence and expert
opinion regarding the issues involved in the issuance, amendment or
repeal of a rule issuable'' pursuant to 21 U.S.C. 811(a).
Legal Authority
DEA implements and enforces Titles II and III of the Comprehensive
Drug Abuse Prevention and Control Act of 1970, often referred to as the
Controlled Substances Act (CSA) and the Controlled Substances Import
Export Act (CSIEA) (21 U.S.C. 801-971), as amended (hereinafter,
``CSA'').
Under the CSA, controlled substances are classified in one of five
schedules based upon their potential for abuse, their currently
accepted medical use, safety and the degree of dependence the substance
may cause. 21 U.S.C. 812. The initial schedules of controlled
substances are found at 21 U.S.C. 812(c). 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
(A) finds that such drug or other substance has a potential for abuse,
and (B) 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* * *'' Pursuant to 28 CFR
0.100(b), the Attorney General has delegated this scheduling authority
to the Administrator of DEA.
Background
Lorcaserin ((R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzepine
hydrochloride hemihydrate) is a new chemical entity which has central
nervous system hallucinogenic properties. Lorcaserin is a serotonin
receptor agonist, at the 5HT2C and 5HT2A receptor
subtypes. Lorcaserin was approved by the Food and Drug Administration
(FDA) on June 27, 2012, as an addition to a reduced-calorie diet and
exercise, for chronic weight
[[Page 75077]]
management and it will be marketed under the trade name BELVIQ[supreg].
Proposed Determination To Schedule Lorcaserin
Pursuant to the CSA, 21 U.S.C. 811(a), proceedings to add a drug or
substance to those controlled under the CSA may be initiated by request
of the Secretary of HHS. On June 25, 2012, HHS provided DEA with a
scientific and medical evaluation document prepared by FDA entitled
``Basis for the Recommendation for Control of Lorcaserin in Schedule IV
of the Controlled Substances Act.'' Pursuant to 21 U.S.C. 811(b), (c),
and (f), this document contained an eight-factor analysis of the abuse
potential of lorcaserin as a new drug, along with HHS' recommendation
to control lorcaserin under Schedule IV of the CSA.
In response, DEA conducted an eight-factor analysis of abuse
potential of lorcaserin pursuant to 21 U.S.C. 811(c). Included below is
a brief summary of each factor as considered by HHS and DEA. Please
note that both the DEA and HHS analyses are available in whole in the
``Supporting and Related Material'' of the public docket for this rule
at www.regulations.gov under docket number DEA-369. Full analysis of
and citations to the information referenced in the summary may be found
in the supporting material.
1. The Drug's Actual or Relative Potential for Abuse: Lorcaserin is
a new chemical substance that has not been marketed in the U.S. or in
any other country. As such, there is no information available which
details actual abuse of lorcaserin. However, the legislative history of
the CSA offers another methodology for assessing a drug or substance's
potential for abuse:
The drug or drugs containing such a substance are new drugs so
related in their action to a drug or drugs already listed as having
a potential for abuse to make it likely that the drug will have the
same potentiality for abuse as such drugs, thus making it reasonable
to assume that there may be significant diversions from legitimate
channels, significant use contrary to or without medical advice, or
that it has a substantial capability of creating hazards to the
health of the user or to the safety of the community.\3\
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\3\ Comprehensive Drug Abuse Prevention and Control Act of 1970,
H.R. Rep. No. 91-1444, 91st Cong., Sess. 1 (1970); 1970 U.S.C.C.A.N.
4566, 4601.
According to HHS, lorcaserin is an agonist at the serotonin
receptor subtypes 5-HT2C and 5-HT2A. Lorcaserin
is indicated as an addition to a reduced-calorie diet and exercise, for
chronic weight management. There is evidence, described below, that
lorcaserin produces subjective effects in humans and in animals that
are similar to those produced by zolpidem (Schedule IV) and ketamine
(Schedule III)
HHS described a human abuse potential study in recreational drug
abusers of psychedelic drugs and CNS depressants, in which lorcaserin
and the comparator drugs zolpidem (Schedule IV) and ketamine (Schedule
III) produced significant increases on positive subjective measures
(visual analog scales (VAS)) for ``high'' and ``good drug effects as
well as an increase on the VAS for ``hallucinations.'' Lorcaserin, as
well as zolpidem and ketamine, significantly increased reports of
``sedation'' on the subjective scale of the Addiction Research Center
Inventory (ARCI), compared to placebo. HHS summarized that these
subjective response data suggest that lorcaserin produces subjective
effects similar to those produced by zolpidem and ketamine. According
to HHS, 20-60 mg of lorcaserin produced a high rate of euphoria in 6-
19% of the subjects in a human abuse potential study. The incidence of
euphoria following lorcaserin administration in the human abuse
potential study is similar to that reported following zolpidem
(Schedule IV) administration (13-16%) and lower than that following
ketamine (Schedule III) administration (50%).
According to HHS, lorcaserin is not available or marketed in any
country. Thus there is no evidence of lorcaserin diversion, illicit
manufacturing, or deliberate ingestion. Because lorcaserin has been
shown to produce euphoria in humans, it is anticipated that there will
be significant use contrary to or without medical advice. Lorcaserin is
not readily synthesized from available substances, and thus its
diversion will be likely from the legitimate channels.
2. Scientific Evidence of the Drug's Pharmacological Effects, If
Known: HHS stated that lorcaserin is a 5-HT2C and 5-
HT2A serotonin receptor agonist. DEA further notes that it
has been shown that lorcaserin through activation of 5-HT2C
receptors causes inositol phosphate accumulation with an
EC50 of 9 nM. Lorcaserin also activated the 5-
HT2A and 5-HT2B receptors, with EC50s
of 168 nM and 943 nM, respectively.
HHS stated that acutely, lorcaserin decreases locomotor activity in
rats. Tolerance does develop to this effect, because after 21 days,
lorcaserin does not affect the locomotor activity of the rats. DEA
further notes that a study showed that food intake in rats was reduced
after a single administration of lorcaserin. The doses administered
were 3, 6, 12, and 24 mg/kg. Lorcaserin decreased the cumulative food
intake at 2, 4, 6, and 22 hours. The ED50 for food intake
inhibition was 18 mg/kg.
According to HHS' review, a drug discrimination study conducted in
2,5-dimethoxy-4-methylamphetamine (DOM)-trained rats showed that
lorcaserin (0.1-10 mg/kg) produced full generalization (=
80%) to the DOM cue in 7 of 9 rats. DOM is a Schedule I hallucinogen
and a 5-HT2A and 5-HT2C receptor agonist. These
data suggest that lorcaserin in doses 0.1 to 10 mg/kg produces
discriminative stimulus responses similar to DOM, a hallucinogen.
As described by HHS in a human abuse potential study with
individuals with a history of abusing drugs, lorcaserin was evaluated
for its abuse potential; it was compared to ketamine (Schedule III NMDA
antagonist), zolpidem (Schedule IV GABA agonist), and a placebo. In
clinical trials, lorcaserin, similar to ketamine and zolpidem, produced
euphoric and hallucinogenic adverse events (AEs).
3. The State of the Current Scientific Knowledge Regarding the Drug
or Other Substance: HHS states that lorcaserin ((R)-8-chloro-1-methyl-
2,3,4,5-tetrahydro-1H-3-benzepine hydrochloride hemihydrate) is water-
soluble. The molecular formula is C11H14ClN and
its molecular weight is 241.6 g/mol, the CAS number is 616202-92-7.
According to HHS, in humans, lorcaserin is rapidly absorbed from
the gastrointestinal tract after oral administration, the
tmax (time to reach maximum plasma concentration) is <= 2
hours and its half-life in plasma is about 11 hours. DEA further notes
that after a single oral administration of 10 mg/kg lorcaserin to rats,
the absorption from the gastrointestinal tract was rapid, resulting in
a mean maximum plasma concentration (Cmax) of 0.76 [micro]g/
ml at 0.25 hour. The time from oral administration to brain maximal
exposure was 1 hour.
According to HHS, the major circulating metabolite of lorcaserin is
lorcaserin sulfamate (M1). Lorcaserin is metabolized by the liver and
excreted by the kidney. M1 is considered inactive and it does not bind
significantly to monoamine transporters. DEA further notes that the
major metabolite in the urine is N-carbamoyl glucuronide (M5).
4. Its History and Current Pattern of Abuse: History and current
pattern of abuse of lorcaserin is not available since it has not been
marketed in any country. As stated in HHS' review, lorcaserin produced
positive subjective effects in a human abuse potential study that are
[[Page 75078]]
similar to those produced by zolpidem (Schedule IV) and ketamine
(Schedule III). HHS states that the positive subjective effects
reported from supratherapeutic doses of lorcaserin administration, are
predictive of its potential for abuse.
5. The Scope, Duration, and Significance of Abuse: According to the
HHS review, the information on lorcaserin's scope, duration and
significance of abuse is not available since it has not been marketed
in any country. Thus, the evaluation of the significance of abuse of
lorcaserin derives from positive indicators in pre-market clinical
trials which are believed to be predictive of drug abuse. Based on the
AEs reported in the clinical efficacy studies and the data from a human
abuse potential lorcaserin study, HHS concluded that the scope and
significance of the abuse potential of lorcaserin is similar to
Schedule IV substances. HHS states that marketing lorcaserin as a
Schedule IV substance will decrease its abuse, as opposed to marketing
it as an uncontrolled or Schedule V substance.
6. What, if any, Risk There is to the Public Health: According to
HHS, the abuse potential of lorcaserin presents a risk to the public
health. HHS states that lorcaserin produces a number of AEs that are
commonly seen with other Schedule IV substances that are abused. Some
of these AEs include feeling jittery, psychomotor hyperactivity,
paresthesia, abnormal dreams, and state of confusion. Headache, nausea,
and dizziness were the most commonly reported AEs in lorcaserin
clinical studies. In a human abuse potential study, 20-60 mg lorcaserin
produced a high incidence of the AE euphoria in 6-19% of the subjects.
According to HHS, because lorcaserin binds to 5-HT2
receptors and generalizes to 5-HT2 agonists in drug
discrimination studies in rats, it is expected to have a hallucinogenic
profile. DEA further notes that in the human abuse potential study
conducted by Shram and colleagues (2011), supratherapeutic doses of
lorcaserin were associated with significantly higher peak scores on the
``Detached'' (40 and 60 mg), ``Hallucinations'' (40 mg), and ``Spaced
Out'' (40 and 60 mg) visual analog scales.
7. Its Psychic or Physiological Dependence Liability: According to
HHS' review, there were two clinical studies conducted to determine the
ability of lorcaserin to induce physical dependence. The patients in
these studies were obese and lorcaserin was administered for 4 and 12
weeks prior to drug discontinuation. Upon lorcaserin discontinuation,
there were no signs of changes in mood, food interest, or body weight.
Discontinuation of lorcaserin administration to animals also did not
produce typical withdrawal symptoms. However, according to HHS, the
ability of lorcaserin to produce hallucinations, euphoria, and positive
subjective responses at supratherapeutic doses is suggestive of its
potential to produce psychic dependence.
8. Whether the Substance is an Immediate Precursor of a Substance
Already Controlled Under the CSA: Lorcaserin is not an immediate
precursor of a substance already controlled under the CSA.
Conclusion: Based on consideration of the scientific and medical
evaluation conducted by HHS and its recommendation, and after
considering its own eight-factor analysis, DEA has determined that
these facts and all relevant data constitute substantial evidence of
potential for abuse of lorcaserin. As such, DEA hereby proposes to
schedule lorcaserin as a controlled substance under the CSA.
Proposed Determination of Appropriate Schedule
The CSA establishes five schedules of controlled substances known
as Schedules I, II, III, IV, and V. The statute outlines the findings
required in placing a drug or other substance in any schedule. 21
U.S.C. 812(b). After consideration of the analysis and recommendation
of the Assistant Secretary for Health of HHS and review of all
available data, the Administrator of DEA, pursuant to 21 U.S.C. 812(b),
finds that:
(1) Lorcaserin has a low potential for abuse relative to the drugs
or other substances in Schedule III. The overall abuse potential of
lorcaserin is comparable to the Schedule IV substances;
(2) Lorcaserin has a currently accepted medical use in treatment in
the United States. Lorcaserin was approved for marketing by FDA as an
addition to a reduced-calorie diet and exercise, for chronic weight
management; and
(3) Abuse of lorcaserin may lead to limited psychological
dependence relative to the drugs or other substances in Schedule III.
This finding is based on the ability of lorcaserin to produce positive
subjective effects at supratherapeutic doses.
Based on these findings, the Administrator of DEA concludes that
lorcaserin, including its salts, isomers, and salts of isomers whenever
the existence of such salts, isomers, and salts of isomers is possible,
warrants control in Schedule IV of the CSA (21 U.S.C. 812(b)(4)).
Requirements for Handling Lorcaserin
If this rule is finalized as proposed, lorcaserin would be subject
to CSA regulatory controls and administrative, civil and criminal
sanctions applicable to the manufacture, distribution, dispensing,
importing and exporting of a Schedule IV controlled substance,
including the following:
Registration. Any person who manufactures, distributes, dispenses,
imports, exports, engages in research or conducts instructional
activities with lorcaserin, or who desires to manufacture, distribute,
dispense, import, export, engage in instructional activities or conduct
research with lorcaserin, would need to be registered to conduct such
activities pursuant to 21 U.S.C. 822 and in accordance with 21 CFR Part
1301.
Security. Lorcaserin would be subject to Schedules III-V security
requirements and would need to be manufactured, distributed, and stored
pursuant to 21 U.S.C. 823 and in accordance with 21 CFR 1301.71,
1301.72(b), (c), and (d), 1301.73, 1301.74, 1301.75(b) and (c),
1301.76, and 1301.77.
Labeling and Packaging. All labels and labeling for commercial
containers of lorcaserin which are distributed on or after finalization
of this rule would need to be in accordance with 21 CFR 1302.03-
1302.07, pursuant to 21 U.S.C. 825.
Inventory. Every registrant required to keep records and who
possesses any quantity of lorcaserin would be required to keep an
inventory of all stocks of lorcaserin on hand pursuant to 21 U.S.C. 827
and in accordance with 21 CFR 1304.03, 1304.04, and 1304.11. Every
registrant who desires registration in Schedule IV for lorcaserin would
be required to conduct an inventory of all stocks of the substance on
hand at the time of registration.
Records. All registrants would be required to keep records pursuant
to 21 U.S.C. 827 and in accordance with 21 CFR 1304.03, 1304.04,
1304.21, 1304.22, and 1304.23.
Prescriptions. All prescriptions for lorcaserin or prescriptions
for products containing lorcaserin would be required to be issued as a
controlled substance pursuant to 21 U.S.C. 829 and in accordance with
21 CFR 1306, including but not limited to 21 CFR 1306.03-1306.06,
1306.08, 1306.09, and 1306.21-1306.27.
Importation and Exportation. All importation and exportation of
lorcaserin would need to be done in
[[Page 75079]]
accordance with 21 CFR Part 1312, pursuant to 21 U.S.C. 952, 953, 957,
and 958.
Criminal Liability. Any activity with lorcaserin not authorized by,
or in violation of, Subchapter I Part D and Subchapter II of the CSA
occurring on or after finalization of this proposed rule would be
unlawful.
Regulatory Analyses
Executive Orders 12866 and 13563
In accordance with 21 U.S.C. 811(a), this proposed scheduling
action is subject to formal rulemaking procedures done ``on the record
after opportunity for a hearing,'' which are conducted pursuant to the
provisions of 5 U.S.C. 556 and 557. Such actions are exempt from review
by the Office of Management and Budget pursuant to Section 3(d)(1) of
Executive Order 12866 and the principles reaffirmed in Executive Order
13563.
Executive Order 12988
This proposed regulation meets the applicable standards set forth
in Sections 3(a) and 3(b)(2) of Executive Order 12988 Civil Justice
Reform to eliminate ambiguity, minimize litigation, establish clear
legal standards and reduce burden.
Executive Order 13132
This proposed rulemaking does not preempt or modify any provision
of State law; nor does it impose enforcement responsibilities on any
State; nor does it diminish the power of any State to enforce its own
laws. Accordingly, this rulemaking does not have federalism
implications warranting the application of Executive Order 13132.
Executive Order 13175
This proposed rule will not have tribal implications and will not
impose substantial direct compliance costs on Indian tribal
governments.
Regulatory Flexibility Act
The Administrator, in accordance with the Regulatory Flexibility
Act (5 U.S.C. 601-612), has reviewed this proposed rule and by
approving it certifies that it will not have a significant economic
impact on a substantial number of small entities. Lorcaserin products,
as recently approved by the FDA, will be used as an adjunct treatment
of partial onset seizure. Handlers of lorcaserin will also handle other
controlled substances used as anti-seizure agents, which are already
subject to the regulatory requirements of the CSA.
Unfunded Mandates Reform Act of 1995
This rule will not result in the expenditure by State, local and
tribal governments, in the aggregate, or by the private sector, of
$136,000,000 or more (adjusted for inflation) in any one year, and will
not significantly or uniquely affect small governments. Therefore, no
actions were deemed necessary under provisions of the Unfunded Mandates
Reform Act 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.
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, 21 CFR part 1308 is proposed to be
amended as follows:
PART 1308--SCHEDULES OF CONTROLLED SUBSTANCES
1. The authority citation for part 1308 continues to read as
follows:
Authority: 21 U.S.C. 811, 812, 871(b), unless otherwise noted.
2. Section 1308.14 is amended by redesignating paragraphs (e) and
(f) as paragraphs (f) and (g) and adding a new paragraph (e) to read as
follows:
Sec. 1308.14 Schedule IV.
* * * * *
(e) Lorcaserin. Any material, compound, mixture, or preparation
which contains any quantity of the following substances, including its
salts, isomers, and salts of such isomers, whenever the existence of
such salts, isomers, and salts of isomers is possible:
(1) Lorcaserin............................................... 1625
* * * * *
Dated: December 13, 2012.
Michele M. Leonhart,
Administrator.
[FR Doc. 2012-30531 Filed 12-18-12; 8:45 am]
BILLING CODE 4410-09-P