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[Federal Register Volume 76, Number 241 (Thursday, December 15, 2011)]
[Rules and Regulations]
[Pages 77895-77899]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2011-32172]

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Rules and Regulations
                                                Federal Register
________________________________________________________________________

This section of the FEDERAL REGISTER contains regulatory documents 
having general applicability and legal effect, most of which are keyed 
to and codified in the Code of Federal Regulations, which is published 
under 50 titles pursuant to 44 U.S.C. 1510.

The Code of Federal Regulations is sold by the Superintendent of Documents. 
Prices of new books are listed in the first FEDERAL REGISTER issue of each 
week.

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Federal Register / Vol. 76, No. 241 / Thursday, December 15, 2011 / 
Rules and Regulations

[[Page 77895]]

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: Final rule.

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SUMMARY: With the issuance of this final rule, the Administrator of the 
Drug Enforcement Administration (DEA) places 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 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: Effective date: December 15, 2011.

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:

Legal Authority

    The 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 and the Controlled 
Substances Import and Export Act (21 U.S.C. 801-971), as amended 
(hereinafter, ``CSA''). The implementing regulations for these statutes 
are found in Title 21 of the Code of Federal Regulations (CFR), parts 
1300 to 1321. 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 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 (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 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. This action imposes the regulatory 
controls and criminal sanctions of Schedule V on the manufacture, 
distribution, dispensing, importation, and exportation of ezogabine and 
products containing ezogabine.
    Pursuant to 21 CFR 1308.44(e), the Administrator of DEA may issue 
her final order ``[I]f all interested persons waive or are deemed to 
waive their opportunity for the hearing or to participate in the 
hearing.'' As no requests for a hearing were filed on this proposed 
scheduling action, all interested persons are deemed to have waived 
their opportunity for a hearing pursuant to 21 CFR 1308.44(d), and the 
Administrator may issue her final order without a hearing.
    Ezogabine is a new drug with a novel mechanism of action for the 
treatment of partial onset seizures. Because ezogabine is a new drug 
with possible immediate medical application to a life-threatening 
illness not always treatable with medications currently available and 
because it may not be prescribed in the United States until this final 
rulemaking action is in effect and the subsequent requirements that 
result from this final action are satisfied, the Administrator hereby 
finds that it is in the interest of public health to forego the 30 day 
period prior to this final rule taking effect. This will impose no 
hardship on any interested party and is responsive to comments intended 
to facilitate the availability of ezogabine as soon as possible for 
that population of people suffering from seizures that may benefit from 
treatment with ezogabine. Therefore, in accordance with this finding of 
conditions of public health and of good cause to waive the 30 day 
period and pursuant to 21 CFR 1308.45 and 5 U.S.C. 553(d)(3), this 
final rule is effective upon publication.

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[supreg].\1\
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    \1\ http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022345Orig1s000TOC.cfm; as of July 21, 2011.
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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

[[Page 77896]]

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).
    Following analysis, the Administrator of DEA published a Notice of 
Proposed Rulemaking entitled ``Schedules of Controlled Substances: 
Placement of Ezogabine into Schedule V'' on October 21, 2011 (76 FR 
65424), which proposed placement of ezogabine into Schedule V of the 
CSA. The proposed rule provided an opportunity for all interested 
persons to request a hearing or to submit comments on or before 
November 21, 2011.
    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 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. 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.\2\
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    \2\ 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 [deg]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

[[Page 77897]]

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 yet been marketed, 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 file 
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 file 
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, 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.

Requests for a Hearing and Comments

    DEA received no requests for a hearing on this scheduling action. 
DEA received two comments on the NPRM to schedule ezogabine.
    Comment: The first comment requested that ezogabine be placed into 
Schedule IV of the CSA instead of Schedule V as proposed. While the 
commenter stated that ezogabine may help those who have not had success 
with current epilepsy treatments, the commenter believed that 
ezogabine's new mechanism of action, including its effect on the 
central nervous system as an anticonvulsant and the potential side 
effects of the drug therein, warrant closer scrutiny and supervision 
under Schedule IV.
    DEA Response: DEA disagrees. That ezogabine has an effect on the 
central nervous system is alone not enough to merit its inclusion into 
Schedule IV of the CSA, nor is the possibility that persons to whom 
ezogabine is prescribed would need to monitor their medications 
closely. Instead, as detailed in the HHS and DEA analyses and the HHS 
recommendation, studies indicate that the abuse potential and likely 
effects of ezogabine are similar to those of the Schedule V drugs 
pregabalin and lacosamide, and, therefore, merit ezogabine's inclusion 
into Schedule V of the CSA.
    Comment: The second comment stated that because epilepsy is a 
serious and potentially life-threatening illness that may not be 
adequately treated with currently available medicines, conditions of 
public health necessitate an early effective date for the final rule 
pursuant to 21 CFR 1308.45. As such, the commenter requested an 
effective date for the rule concurrent with its publication in the 
Federal Register.
    DEA Response: As stated under ``Legal Authority,'' DEA agrees that 
this rule should become effective upon publication. Ezogabine, unlike 
the currently available anticonvulsant

[[Page 77898]]

medications, may act as an anticonvulsant through a novel mechanism of 
action. Because some patients with epilepsy do not achieve satisfactory 
seizure control from treatments currently in use, the availability of 
ezogabine becomes an important and potentially life-saving option for 
such patients. Thus, for public health reasons pursuant to 21 CFR 
1308.45 and based on finding good cause pursuant to 5 U.S.C. 553(d)(3) 
as outlined, this final rule is effective upon publication in the 
Federal Register.

Scheduling 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 will schedule ezogabine as a controlled 
substance under the CSA.

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

    Upon the effective date of this final rule, ezogabine is 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, must be registered to conduct such 
activities pursuant to 21 U.S.C. 822 and in accordance with 21 CFR Part 
1301.
    Security. Ezogabine is subject to Schedules III-V security 
requirements and must 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 the effective 
date of this final rule must 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 must 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 must conduct an inventory of 
all stocks of the substance on hand at the time of registration.
    Records. All registrants must 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 must 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 must 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 the effective date of this final rule 
is unlawful.

Regulatory Analyses

Executive Orders 12866 and 13563

    In accordance with 21 U.S.C. 811(a), this 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 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 rulemaking does not preempt or modify any provision of state 
law or impose enforcement responsibilities on any state or 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 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.

Congressional Review Act

    This rule is not a major rule as defined by Sec.  804 of the Small 
Business Regulatory Enforcement Fairness Act of 1996 (Congressional 
Review Act). 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, 
or significant adverse effects on competition, employment, investment, 
productivity, innovation, or on the ability of United States-based 
companies to compete with foreign based companies in domestic and 
export markets.

List of Subjects in 21 CFR Part 1308

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

[[Page 77899]]

    For the reasons set out above, 21 CFR Part 1308 is amended as 
follows:

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. 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 [N-[2-amino-4-(4-fluorobenzylamino)-phenyl]-
carbamic acid ethyl ester]-2779
* * * * *

    Dated: December 8, 2011.
Michele M. Leonhart,
Administrator.
[FR Doc. 2011-32172 Filed 12-14-11; 8:45 am]
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