[Federal Register Volume 72, Number 35 (Thursday, February 22, 2007)]
[Proposed Rules]
[Pages 7945-7947]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E7-2993]


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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

[Docket No. DEA-301P]

21 CFR Part 1308


Schedules of Controlled Substances: Placement of Lisdexamfetamine 
into Schedule II

AGENCY: Drug Enforcement Administration, U.S. Department of Justice.

ACTION: Notice of proposed rulemaking.

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SUMMARY: This proposed rule is issued by the Deputy Administrator of 
the Drug Enforcement Administration (DEA) to place the substance 
lisdexamfetamine, including its salts, isomers, and salts of isomers, 
into schedule II 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 (DHHS) and on an 
evaluation of the relevant data by DEA. This scheduling of 
lisdexamfetamine in schedule II will not be finalized until a New Drug 
Application (NDA) for a lisdexamfetamine product is approved by the 
Food and Drug Administration (FDA). If finalized, this action would 
impose the regulatory controls and criminal sanctions of schedule II on 
those who handle lisdexamfetamine and products containing 
lisdexamfetamine.

DATES: Written comments must be postmarked, and electronic comments 
must be sent, on or before March 26, 2007.

ADDRESSES: To ensure proper handling of comments, please reference 
``Docket No. DEA-301'' on all written and electronic correspondence. 
Written comments sent via regular mail should be sent to the Deputy 
Administrator, Drug Enforcement Administration, Washington, DC 20537, 
Attention: DEA

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Federal Register Representative/ODL. Written comments sent via express 
mail should be sent to the Deputy Administrator, Drug Enforcement 
Administration, Attention: DEA Federal Register Representative/ODL, 
2401 Jefferson-Davis Highway, Alexandria, VA 22301. Comments may be 
directly sent to DEA electronically by sending an electronic message to 
[email protected]. Comments may also be sent 
electronically through http://www.regulations.gov using the electronic 
comment form provided on that site. An electronic copy of this document 
is also available at the http://www.regulations.gov Web site. DEA will 
accept electronic comments containing MS Word, WordPerfect, Adobe PDF, 
or Excel file formats only. DEA will not accept any file format other 
than those specifically listed here.

FOR FURTHER INFORMATION CONTACT: Christine Sannerud, PhD, Chief, Drug 
and Chemical Evaluation Section, Drug Enforcement Administration, 
Washington, DC 20537, (202) 307-7183.

SUPPLEMENTARY INFORMATION: Lisdexamfetamine is a central nervous system 
stimulant drug. The Food and Drug Administration (FDA) is currently 
reviewing a New Drug Application (NDA) for lisdexamfetamine. Upon 
approval of this pending NDA, lisdexamfetamine will be marketed as a 
prescription drug product for the treatment of Attention Deficit 
Hyperactivity Disorder (ADHD).
    Lisdexamfetamine is an amide ester conjugate comprised of the amino 
acid L-lysine covalently bound to the amino group of d-amphetamine. The 
chemical name of its dimesylate salt form is (2S)-2,6-diamino-N-[(1S)-
1-methyl-2-phenethyl]hexanamide dimethanesulfonate (CAS number 608137-
32-3). Lisdexamfetamine per se is pharmacologically inactive and its 
effects are due to its in vivo metabolic conversion to d-amphetamine. 
In this regard, lisdexamfetamine acts as a prodrug.
    Lisdexamfetamine shares substantial pharmacological effects and 
abuse potential with amphetamine. Lisdexamfetamine is positively 
reinforcing in monkeys. It generalizes to the discriminative stimulus 
effects of d-amphetamine in monkeys. It produces locomotor stimulation 
in rats. In adults, the total amphetamine exposure resulting from 75 mg 
oral lisdexamfetamine is equivalent to 35 mg oral Adderall XR, an 
extended release amphetamine product. Peak plasma concentrations of d-
amphetamine following oral ingestion of 50 and 70 mg lisdexamfetamine 
correspond closely to those produced by oral ingestion of 30 and 50 mg 
immediate-release d-amphetamine product. In controlled clinical 
studies, lisdexamfetamine has been found to be similar to d-amphetamine 
in psychoactive measures. It produces euphoria in humans typical of d-
amphetamine. Lisdexamfetamine shows an adverse event profile similar to 
that of d-amphetamine. Some adverse effects of lisdexamfetamine include 
insomnia, nervousness, irritability, anorexia, weight loss, mood 
alterations, and increases in blood pressure and heart rate.
    Lisdexamfetamine has not been studied for its psychological and 
physical dependence potential. However, since lisdexamfetamine is a 
prodrug for d-amphetamine, it is expected to possess dependence 
potential similar to that of d-amphetamine. d-Amphetamine is known to 
cause both psychological and physical dependence. Some symptoms of d-
amphetamine withdrawal include depression, increase in sleep and food 
intake, drug craving, anhedonia, irritability and poor concentration.
    Lisdexamfetamine is a new molecular entity and has not been 
marketed in the United States or other countries. Therefore, there has 
been no evidence of diversion, abuse, or law enforcement encounters 
involving lisdexamfetamine. On November 14, 2006, the Assistant 
Secretary for Health, DHHS, sent the Deputy Administrator of DEA a 
scientific and medical evaluation and a letter recommending that 
lisdexamfetamine be placed into schedule II of the CSA. Enclosed with 
the November 14, 2006 letter was a document prepared by the FDA 
entitled, ``Basis for the Recommendation for Control of 
Lisdexamfetamine in Schedule II of the Controlled Substances Act.'' The 
document contained a review of the factors which the CSA requires the 
Secretary to consider (21 U.S.C. 811(b)).
    The factors considered by the Assistant Secretary of Health and DEA 
with respect to lisdexamfetamine were:
    (1) Its actual or relative potential for abuse;
    (2) Scientific evidence of its pharmacological effects;
    (3) The state of current scientific knowledge regarding the drug;
    (4) Its history and current pattern of abuse;
    (5) The scope, duration, and significance of abuse;
    (6) What, if any, risk there is to the public health;
    (7) Its psychic or physiological dependence liability; and
    (8) Whether the substance is an immediate precursor of a substance 
already controlled under this subchapter. (21 U.S.C. 811(c))
    Based on the recommendation of the Assistant Secretary for Health, 
received in accordance with section 201(b) of the Act (21 U.S.C. 
811(b)), and the independent review of the available data by DEA, the 
Deputy Administrator of DEA, pursuant to sections 201(a) and 201(b) of 
the Act (21 U.S.C. 811(a) and 811(b)), finds that:
    (1) Lisdexamfetamine has a high potential for abuse;
    (2) Upon approval of the pending NDA, lisdexamfetamine will have a 
currently accepted medical use in treatment in the United States; and
    (3) Abuse of lisdexamfetamine may lead to severe psychological or 
physical dependence.
    Based on these findings, the Deputy Administrator of DEA concludes 
that lisdexamfetamine, including its salts, isomers, and salts of 
isomers, warrants control in schedule II of the CSA, if and when an NDA 
for lisdexamfetamine is approved.
    Interested persons are invited to submit their comments, objections 
or requests for a hearing with regard to this proposal. Requests for a 
hearing should state, with particularity, the issues concerning which 
the person desires to be heard. All correspondence regarding this 
matter should be submitted to the Deputy Administrator, Drug 
Enforcement Administration, Washington, DC, 20537, Attention: DEA 
Federal Register Representative/ODL. In the event that comments, 
objections, or requests for a hearing raise one or more issues which 
the Deputy Administrator finds warrant a hearing, the Deputy 
Administrator shall order a public hearing by notice in the Federal 
Register, summarizing the issues to be heard and setting the time for 
the hearing.

Requirements for Handling Lisdexamfetamine

    If this rule is finalized as proposed, lisdexamfetamine 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 II controlled 
substance, including the following:
    Registration. Any person who manufactures, distributes, dispenses, 
imports, exports, engages in research or conducts instructional 
activities with lisdexamfetamine, or who desires to manufacture, 
distribute, dispense, import, export, engage in instructional 
activities or conduct research with

[[Page 7947]]

lisdexamfetamine, would be required to be registered to conduct such 
activities in accordance with Part 1301 of Title 21 of the Code of 
Federal Regulations.
    Security. Lisdexamfetamine would be subject to schedule II security 
requirements and must be manufactured, distributed and stored in 
accordance with Sec. Sec.  1301.71, 1301.72(a), (c), and (d), 1301.73, 
1301.74, 1301.75(b) and (c), 1301.76 and 1301.77 of Title 21 of the 
Code of Federal Regulations.
    Labeling and Packaging. All labels and labeling for commercial 
containers of lisdexamfetamine which are distributed after finalization 
of this rule would be required to comply with requirements of 
Sec. Sec.  1302.03-1302.07 of Title 21 of the Code of Federal 
Regulations.
    Quotas. Quotas for lisdexamfetamine would be established pursuant 
to part 1303 of Title 21 of the Code of Federal Regulations.
    Inventory. Every registrant required to keep records and who 
possesses any quantity of lisdexamfetamine would be required to keep an 
inventory of all stocks of lisdexamfetamine on hand pursuant to 
Sec. Sec.  1304.03, 1304.04 and 1304.11 of Title 21 of the Code of 
Federal Regulations. Every registrant who desires registration in 
schedule II for lisdexamfetamine 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 Sec. Sec.  1304.03, 1304.04, 1304.21, 1304.22, and 1304.23 of Title 
21 of the Code of Federal Regulations.
    Reports. All registrants required to submit reports to the 
Automation of Reports and Consolidated Order System (ARCOS) in 
accordance with Sec.  1304.33 of Title 21 of the Code of Federal 
Regulations would be required to do so for lisdexamfetamine.
    Orders for Lisdexamfetamine. All registrants involved in the 
distribution of lisdexamfetamine would be required to comply with the 
order form requirements of part 1305 of Title 21 of the Code of Federal 
Regulations.
    Prescriptions. All prescriptions for lisdexamfetamine or 
prescriptions for products containing lisdexamfetamine would be 
required to be issued pursuant to 21 CFR 1306.03-1306.06 and 1306.11-
1306.15.
    Importation and Exportation. All importation and exportation of 
lisdexamfetamine would need to be in compliance with part 1312 of Title 
21 of the Code of Federal Regulations.
    Criminal Liability. Any activity with lisdexamfetamine not 
authorized by, or in violation of, the Controlled Substances Act or the 
Controlled Substances Import and Export Act occurring on or after 
finalization of this proposed rule would be unlawful.

Regulatory Certifications

Executive Order 12866

    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 5 U.S.C. 556 and 557 and, as such, are exempt from review 
by the Office of Management and Budget pursuant to Executive Order 
12866, section 3(d)(1).

Regulatory Flexibility Act

    The Deputy Administrator, in accordance with the Regulatory 
Flexibility Act (5 U.S.C. 605(b)), 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. Lisdexamfetamine 
products will be prescription drugs used for the treatment of Attention 
Deficit Hyperactivity Disorder (ADHD). Handlers of lisdexamfetamine 
will also handle other controlled substances used to treat ADHD which 
are already subject to the regulatory requirements of the CSA.

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.

Executive Order 13132

    This 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.

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 
$118,000,000 or more 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.

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, 
Narcotics, Prescription drugs.
    Under the authority vested in the Attorney General by section 
201(a) of the CSA (21 U.S.C. 811(a)), and delegated to the 
Administrator of DEA by U.S. Department of Justice regulations (28 CFR 
0.100), and redelegated to the Deputy Administrator pursuant to 28 CFR 
0.104, the Deputy Administrator hereby proposes that 21 CFR part 1308 
be amended as follows:

PART 1308--SCHEDULES OF CONTROLLED SUBSTANCES [AMENDED]

    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 1308.12 is proposed to be amended by adding a new 
paragraph (d)(5) to read as follows:


Sec.  1308.12  Schedule II.

* * * * *
    (d) * * *
    (5) Lisdexamfetamine, its salts, isomers, and salts of its isomers 
1205
* * * * *

    Dated: February 12, 2007.
Michele M. Leonhart,
Deputy Administrator.
[FR Doc. E7-2993 Filed 2-21-07; 8:45 am]
BILLING CODE 4410-09-P