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[Federal Register Volume 76, Number 204 (Friday, October 21, 2011)]
[Proposed Rules]
[Pages 65424-65428]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2011-27253]

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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Part 1308

[Docket No. DEA-354]

Schedules of Controlled Substances: Placement of Ezogabine Into 
Schedule V

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 ezogabine, including its salts, isomers, and salts of isomers 
whenever the existence of such salts, isomers, and salts of isomers is 
possible, into Schedule V of the Controlled Substances Act (CSA). This 
proposed action is pursuant to the CSA which requires that such actions 
be made on the record after opportunity for a hearing through formal 
rulemaking.

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 
November 21, 2011. 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.
    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 
pursuant to 21 CFR 1308.44 and in accordance with 21 CFR 1316.45 and 
1316.47. Requests for hearing, notices of appearance, and waivers of 
participation must be received on or before November 21, 2011.
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    \1\ 21 CFR 1300.01.

ADDRESSES: To ensure proper handling of comments, please reference 
``Docket No. DEA-354'' 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 http://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 must be sent to Drug 
Enforcement Administration, Attention: Hearing Clerk/LJ, 8701 
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Morrissette Drive, Springfield, VA 22152.

FOR FURTHER INFORMATION CONTACT: Rhea D. Moore, Office of Diversion 
Control, Drug Enforcement Administration, 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 of 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'' paragraph.

Request for Hearing, Notice of Appearance at 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)-(c), requests for 
hearing, notices of appearance, 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).'' Such requests or notices must 
conform to the requirements of 21 CFR 1308.44(a) or (b) and 1316.47 or 
1316.48, as applicable. A request or notice 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

[[Page 65425]]

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 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, notices of appearance at the hearing, and waivers of 
participation in the hearing should be submitted to DEA using the 
address information provided above.

Legal Authority

    Under the CSA, controlled substances are classified in one of five 
schedules based upon their potential for abuse, their currently 
accepted medical use, and the degree of dependence the substance may 
cause. 21 U.S.C. 812. The initial schedules of controlled substances by 
statute are found at 21 U.S.C. 812(c) and the current list of scheduled 
substances are 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 (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.
    The CSA provides that scheduling of any drug or other substance may 
be initiated by the Attorney General (1) on his own motion; (2) at the 
request of the Secretary of HHS, or (3) on the petition of any 
interested party. 21 U.S.C. 811(a). 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 V on the 
manufacture, distribution, dispensing, importation, and exportation of 
ezogabine and products containing ezogabine.

Background

    Ezogabine, known chemically as N-[2-amino-4-(4-fluorobenzylamino)-
phenyl]-carbamic acid ethyl ester, is a new chemical substance with 
central nervous system depressant properties and is classified as a 
sedative-hypnotic. Pharmacological studies indicate that ezogabine 
primarily acts as a ligand at ion-gated channels in the brain to 
enhance potassium currents mediated by neuronal KCNQ (Kv7) channels. 
Additionally, ezogabine indirectly enhances the gamma-aminobutyric acid 
(GABA) mediated neurotransmission. On June 10, 2011, the Food and Drug 
Administration (FDA) approved a New Drug Application (NDA) for 
ezogabine as an adjunct treatment of partial onset seizures, to be 
marketed under the trade name Potiga.[reg] \2\
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    \2\ http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022345Orig1s000TOC.cfm; as of July 21, 2011.
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Proposed Determination to Schedule Ezogabine

    Pursuant to 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 January 12, 2011, HHS provided DEA with a 
scientific and medical evaluation document prepared by FDA entitled 
``Basis for the Recommendation for Control of Ezogabine 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 
ezogabine as a new drug, along with HHS' recommendation to control 
ezogabine under Schedule V of the CSA.
    In response, DEA conducted an eight-factor analysis of ezogabine's 
abuse potential pursuant to 21 U.S.C. 811(c). Included below is a brief 
summary of each factor as analyzed by HHS and DEA, and as considered by 
DEA in the scheduling decision. Please note that both the DEA and HHS 
analyses are available in their entirety under ``Supporting and Related 
Material'' of the public docket for this rule at www.regulations.gov 
under docket number DEA-354.
    1. The Drug's Actual or Relative Potential for Abuse: Ezogabine 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 ezogabine. 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.

    Ezogabine acts as a ligand at ion-gated channels in the brain, 
similar to the Schedule V substances pregabalin and lacosamide, and, 
like those drugs, ezogabine is indicated for the treatment of epileptic 
conditions in humans. There is strong evidence, described below, that 
ezogabine produces behavioral effects in humans and in animals that are 
similar to those produced by pregabalin and lacosamide.
    Phase 1 clinical studies indicate that the rate of euphoria-related 
adverse events (AEs) resulting from administration of ezogabine was 6-
9%. This is similar to the AE rates for administration of pregabalin 
(10%) and lacosamide (>7%), while Phase \2/3\ clinical studies 
indicated similar AE rates between ezogabine (16H18FN3O2 and a molecular 
weight of 303.3 g/mol. Ezogabine is a non-hygroscopic white to slightly 
colored powder with a melting point of 140-143\0\C. It is soluble in 
0.9% saline, methanol, chloroform, but only sparingly soluble in 
ethanol and 0.1N HCL.
    Ezogabine in humans has a Tmax (time required for 
ezogabine to reach maximum plasma concentration) ranging from 1-4 hours 
following both acute and multiple dosing, and, without the involvement 
of cytochrome P450, undergoes an extensive and almost exclusively phase 
2 metabolic biotransformation. Ezogabine is predominantly metabolized 
by N-glucuronidation, resulting in the formation of two distinct N-
glucuronides of the unchanged parent drug and to a lesser extent by N-
acetylation to form N-acetyl-retigabine, the major bioactive metabolite 
of ezogabine. The half-life of both ezogabine and N-acetyl-retigabine 
is approximately eight hours and the Cmax (maximum plasma 
concentration) of both components is dose proportional after both acute 
and multiple dosing, suggesting a lack of accumulation with repeated 
administration.
    4. Its History and Current Pattern of Abuse: As stated in the 
summary of Factor 1, information on ezogabine's history and current 
pattern of abuse is unavailable as it has not been marketed in any 
country. As such, evaluation of abuse potential for ezogabine derives 
from positive indicators in clinical studies which are believed to be 
predictive of drug abuse and which are discussed in Factors 1 and 2 
above.
    5. The Scope, Duration, and Significance of Abuse: Because 
ezogabine has not been marketed in any country, information on the 
scope, duration, and significance of abuse of ezogabine is unavailable. 
However, epidemiological data on pregabalin, a Schedule V drug with an 
abuse potential similar to that of ezogabine, is available from the 
Drug Abuse Warning Network (DAWN) database.
    The ``abuse frequency ratio,'' calculated as the ratio of 
nonmedical use related annual emergency department visits (as reported 
in DAWN) to the total number of annual prescriptions for pregabalin is 
less than that for the Schedule IV drug, alprazolam. Further, because 
ezogabine has abuse-related human and animal data in its NDA similar to 
data generated for pregabalin, ezogabine is likely to have an abuse 
potential similar to pregabalin. The ``abuse frequency ratios'' for 
pregabalin range from 29 to 47, while those for alprazolam are 
approximately three to six times higher, ranging from 160 to 235. Thus, 
pregabalin was placed into Schedule V based both on abuse-related human 
and animal data submitted in its NDA and by epidemiological data which 
justified placement relative to drugs in Schedule IV. Given that 
ezogabine has abuse-related human and animal data in its NDA similar to 
the data generated by pregabalin, it is likely that ezogabine will have 
an abuse potential similar to this Schedule V drug.
    6. What, if any, Risk There is to the Public Health: The data 
indicates that ezogabine may present a serious safety risk to the 
public health, and the predicted level of risk is similar to that 
observed with pregabalin and lacosamide but less than that produced by 
Schedule IV benzodiazepines. In Phase 1 clinical safety studies, the 
overall adverse event profile following ezogabine administration was 
similar to those from pregabalin and lacosamide and includes not only 
euphoria, but also somnolence, and feeling or thinking abnormally. 
Further, the human abuse potential study showed that the majority of 
subjects receiving the 900 mg dose of ezogabine experienced multiple 
adverse events such as euphoria, somnolence, visual disturbance, 
amnesia, hypo-aesthesia, paranoia, fear, confusion and hallucination. 
Although the 900 mg dose is three times greater than the recommended 
therapeutic dose, individuals who abuse drugs typically do so at supra-
therapeutic doses.
    7. Its Psychic or Physiological Dependence Liability: Ezogabine may 
produce limited psychic or physiological dependence liability following 
extended administration. Since there are no studies detailing abrupt 
discontinuation of ezogabine, there are minimal adequate data to 
evaluate the ability of ezogabine to induce withdrawal symptoms that 
are indicative of physical dependence. Many of the adverse events 
reported from the discontinuation of ezogabine were also reported prior 
to its discontinuation, including dizziness,

[[Page 65427]]

somnolence, and a state of confusion. By comparison, abrupt or rapid 
discontinuation of pregabalin in human studies resulted in patient-
reported symptoms of nausea, headache or diarrhea, which are suggestive 
of physical dependence, while abrupt termination of lacosamide produced 
no signs or symptoms of withdrawal in diabetic neuropathic pain 
patients.
    Unlike ezogabine and pregabalin, the withdrawal syndrome following 
discontinuation of Schedule IV substances such as alprazolam can range 
from mild dysphoria and insomnia to a major syndrome including 
abdominal pain, muscle cramps, vomiting, sweating, tremors and 
convulsions. These are similar in character to those associated with 
other sedative-hypnotics.
    The study of ezogabine abuse potential in humans with histories of 
recreational abuse of sedative-hypnotics found that ezogabine produces 
euphoria (18-33%) in these individuals. Additionally, ezogabine 
produced euphoria (8.5%) in Phase 1 studies in healthy individuals. 
These euphoria-related adverse events following administration of 
ezogabine are suggestive of its ability to produce psychic dependence, 
and the adverse events appear to be less severe and occur less 
frequently than Schedule IV drugs (diazepam and alprazolam) and are 
more similar to those of Schedule V drugs, pregabalin and lacosamide.
    8. Whether the Substance is an Immediate Precursor of a Substance 
Already Controlled Under the CSA: Ezogabine is not an immediate 
precursor of any controlled substance.
    Conclusion: Based on consideration of the scientific and medical 
evaluation and accompanying recommendation of HHS, and based on DEA's 
consideration of its own eight-factor analysis, DEA finds that these 
facts and all relevant data constitute substantial evidence of 
potential for abuse of ezogabine. As such, DEA hereby proposes to 
schedule ezogabine 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 to place a drug or other substance in any particular 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)(5), finds that:
    (1) Ezogabine has a low potential for abuse relative to the drugs 
or other substances in Schedule IV. The overall abuse potential of 
ezogabine is comparable to the Schedule V substances such as pregabalin 
and lacosamide;
    (2) Ezogabine has a currently accepted medical use in treatment in 
the United States. Ezogabine was approved for marketing by FDA as an 
adjunct treatment of partial onset seizures; and
    (3) Abuse of ezogabine may lead to limited physical dependence or 
psychological dependence relative to the drugs or other substances in 
Schedule IV.
    Based on these findings, the Administrator of DEA concludes that 
ezogabine, 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 V of the CSA (21 U.S.C. 812(b)(5)).

Requirements for Handling Ezogabine

    If this rule is finalized as proposed, ezogabine would be subject 
to the CSA and the Controlled Substances Import and Export Act (CSIEA) 
regulatory controls and administrative, civil and criminal sanctions 
applicable to the manufacture, distribution, dispensing, importing and 
exporting of a Schedule V controlled substance, including the 
following:
    Registration. Any person who manufactures, distributes, dispenses, 
imports, exports, engages in research or conducts instructional 
activities with ezogabine, or who desires to manufacture, distribute, 
dispense, import, export, engage in research or conduct instructional 
activities with ezogabine, 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. Ezogabine 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 ezogabine 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 ezogabine would be required to keep an 
inventory of all stocks of ezogabine 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 V for ezogabine 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, 
1304.06, 1304.21, 1304.22, and 1304.23.
    Prescriptions. Ezogabine or products containing ezogabine would be 
required to be distributed or dispensed pursuant to 21 U.S.C. 829 and 
in accordance with 21 CFR 1306.03-1306.06, 1306.08, 1306.21, and 
1306.23-1306.27.
    Importation and Exportation. All importation and exportation of 
ezogabine would need to be done in accordance with 21 CFR part 1312, 
pursuant to 21 U.S.C. 952, 953, 957, and 958.
    Criminal Liability. Any activity with ezogabine not authorized by, 
or in violation of, Subchapter I Part D and Subchapter II of the CSA or 
the CSIEA 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. The CSA sets forth the criteria for 
scheduling a drug or other substance. 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.

[[Page 65428]]

Executive Order 13175

    This proposed rule will not have Tribal implications and will not 
impose substantial direct compliance costs on Indian Tribal 
governments.

Paperwork Reduction Act of 1995

    This action does not impose a new collection of information 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 to read as follows:

PART 1308--SCHEDULES OF CONTROLLED SUBSTANCES

    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.

    2. Section 1308.15 is amended by redesignating paragraphs (e)(1) 
and (2) as paragraphs (e)(2) and (3), and adding a new paragraph (e)(1) 
to read as follows:

Sec.  1308.15  Schedule V.

* * * * *
    (e) * * *
    (1) Ezogabine--2779
* * * * *

    Dated: October 14, 2011.
Michele M. Leonhart,
 Administrator.
[FR Doc. 2011-27253 Filed 10-20-11; 8:45 am]
BILLING CODE 4410-09-P
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