[Federal Register Volume 74, Number 140 (Thursday, July 23, 2009)]
[Proposed Rules]
[Pages 36424-36427]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-17538]


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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Part 1308

[Docket No. DEA-327]


Schedules of Controlled Substances: Placement of Fospropofol Into 
Schedule IV

AGENCY: Drug Enforcement Administration, 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 
fospropofol, 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 Acting Assistant Secretary 
for Health of the Department of Health and Human Services (DHHS) and on 
an evaluation of the relevant data by DEA. If finalized, this action 
would impose the regulatory controls and criminal sanctions of schedule 
IV on those who handle fospropofol and products containing fospropofol.

DATES: Written comments must be postmarked on or before August 24, 
2009, and electronic comments must be sent on or before midnight 
Eastern time August 24, 2009.

ADDRESSES: To ensure proper handling of comments, please reference 
``Docket No. DEA-327'' on all written and electronic correspondence. 
Written comments sent via regular or express mail should be sent to the 
Drug Enforcement Administration, Attention: DEA Federal Register 
Representative/ODL, 8701 Morrissette Drive, Springfield, Virginia 
22152. Comments may be sent to DEA 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 Microsoft Word, WordPerfect, 
Adobe PDF, or Excel file formats only. DEA will not accept any file 
format other than those specifically listed here.
    Please note that DEA is requesting that electronic comments be 
submitted before midnight Eastern Time on the day the comment period 
closes because http://www.regulations.gov terminates the public's 
ability to submit comments at midnight Eastern time on the day the 
comment period closes. Commenters in time zones other than Eastern time 
may want to consider this so that their electronic comments are 
received. All comments sent via regular or express mail will be 
considered timely if postmarked on the day the comment period closes.

FOR FURTHER INFORMATION CONTACT: Christine A. Sannerud, Ph.D., Chief, 
Drug and Chemical Evaluation Section, Office of Diversion Control, Drug 
Enforcement Administration, 8701 Morrissette Drive, Springfield, 
Virginia 22152, Telephone: (202) 307-7183.

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

[[Page 36425]]

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.

Background

    On December 12, 2008, the Food and Drug Administration (FDA) 
approved fospropofol for marketing under the trade name Lusedra[reg] in 
the United States as a drug product indicated for monitored anesthesia 
care (MAC) sedation in adult patients undergoing diagnostic or 
therapeutic procedures. Lusedra[reg] will be available as 35 
milligrams/ml of fospropofol disodium solution for intravenous (i.v.) 
use. Fospropofol acts as a central nervous system (CNS) depressant and 
is classified as a sedative-hypnotic.
    Fospropofol, 2,6-diisopropopylphenoxymethyl phosphate disodium, is 
a water soluble, phosphono-O-methyl prodrug of propofol. It is 
metabolized in the body to propofol, the active metabolite. Propofol 
has been available for medical use in the United States since 1989 and 
is not currently a controlled substance.
    The pharmacological effects of fospropofol are attributed to the 
pharmacological actions of propofol. Fospropofol elicits behavioral 
effects similar to methohexital and midazolam, schedule IV sedative-
hypnotics.
    The receptor binding profile of fospropofol has been shown to be 
similar to that of propofol (DHHS evaluation, 2008). Propofol binds to 
[gamma]-aminobutyric acid (GABAA) receptor and acts as a 
modulator by potentiating the activity of GABA at this receptor. Other 
psychoactive drugs, e.g., barbiturates, benzodiazepines, and volatile 
anesthetics, potentiate activity of GABA at the GABAA 
receptor. Propofol also inhibits the activity of the N-methyl-D-
asparate (NMDA) receptor; as does ketamine, another anesthetic with 
significant abuse potential.
    Since propofol is the active metabolite of fospropofol, the abuse 
potential of fospropofol is comparable to that of propofol. Animal 
self-administration studies demonstrated that the reinforcing effects 
of propofol are relatively low and comparable to midazolam and other 
schedule IV benzodiazepines. Both drug-naive and methohexital-trained 
(schedule IV barbiturate) rats self-administer propofol under a fixed 
ratio schedule. In baboons after substituting for cocaine, 
subanesthetic doses of propofol maintained low-to-high levels of self-
administration.
    Schedule IV sedative-hypnotics like methohexital and midazolam are 
known to produce euphoric moods as adverse events and have histories of 
abuse in the U.S. and elsewhere. The adverse events associated with 
fospropofol are similar to those experienced with schedule IV sedative-
hypnotics. In humans, the most commonly reported adverse events were 
paresthesia (abnormal skin sensations, e.g., burning, itching), 
pruritus (itching), headache, and dizziness. In nine clinical studies 
in healthy humans (n = 273), subjects were administered intravenous 
(i.v.) fospropofol. Within that population, 0.7 percent reported 
euphoria and disorientation adverse events (DHHS evaluation, 2008).
    The current abuse profiles of propofol, the active metabolite of 
fospropofol, indicate that propofol is abused by medical professionals 
since they have access to the drug in medical facilities which perform 
anesthesia, according to the Adverse Event Reporting System (AERS) 
DataMart database (DHHS evaluation, 2008). Although the fospropofol 
product Lusedra[supreg] will be marketed as an i.v. dosage form, in the 
New Drug Application (NDA) submitted to the DHHS, it has been 
demonstrated that after oral administration fospropofol is active in 
the body. The oral activity of fospropofol increases the likelihood of 
its abuse by other routes of administration and its use to commit other 
crimes (e.g., date-rape).
    Withdrawal symptoms observed upon ceasing long-term administration 
of a substance are indicative of a substance's ability to produce 
physical dependence. The effects of long-term administration of 
fospropofol were not studied in the clinical trials so the dependence 
potential of fospropofol is best demonstrated by the withdrawal 
syndrome associated with long-term use of propofol. There have been 
published reports of withdrawal symptoms upon abrupt cessation of 
administration of propofol after several days of treatment. The 
symptoms included agitation, tremors, tachycardia, tachypnea, 
hyperpyrexia, confusion, and hallucinations. These symptoms are similar 
to the symptoms observed upon withdrawal from benzodiazepines. 
Withdrawal symptoms improve once administration of propofol is 
reinitiated. A delusional state lasting up to seven days may occur 
before full mental functioning returns.
    References to the above studies may be found in the Health and 
Human Services scheduling recommendation and DEA's independent 
analysis, both of which are available on the electronic docket 
associated with this rule making.
    Since fospropofol is a new molecular entity, there has been no 
evidence of diversion, abuse, or law enforcement encounters involving 
the drug. On February 27, 2009, the Acting Assistant Secretary for 
Health, Department of Health and Human Services (DHHS), sent the Deputy 
Administrator of DEA a scientific and medical evaluation and a letter 
recommending that fospropofol be placed into schedule IV of the CSA. 
Enclosed with the February 27, 2009, letter was a document prepared by 
the FDA entitled, ``Basis for the Recommendation for Control of 
Fospropofol and Its Salts in Schedule IV of the CSA.'' 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 fospropofol 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. Fospropofol has a low potential for abuse relative to the drugs 
or substances in schedule III. Although there is no direct comparison 
to a schedule III substance, this finding is based on the demonstration 
of the abuse potential of propofol, the active metabolite, relative to 
the schedule IV substances, methohexital and midazolam;
    2. Fospropofol has a currently accepted medical use in treatment in 
the U.S.; Fospropofol under the trade name Lusedra[supreg] was approved 
for marketing as a product indicated for monitored anesthesia care by 
FDA on December 12, 2008; and
    3. Abuse of fospropofol may lead to limited physical dependence or 
psychological dependence relative to the drugs or other substances in 
schedule III. This finding is based on

[[Page 36426]]

the symptoms exhibited upon withdrawal from propofol.
    Based on these findings, the Deputy Administrator of DEA concludes 
that fospropofol, 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))

Comments and Requests for 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). 
All persons are invited to submit their comments or objections with 
regard to this proposal. Requests for a hearing may be submitted by 
interested persons and must conform to the requirements of 21 CFR 
1308.44 and 1316.47. The request should state, with particularity, the 
issues concerning which the person desires to be heard and the 
requestor's interest in the proceeding. Only interested persons, 
defined in the regulations as those ``adversely affected or aggrieved 
by any rule or proposed rule issuable pursuant to section 201 of the 
Act (21 U.S.C. 811),'' may request a hearing. 21 CFR 1308.42. Please 
note that 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). All correspondence regarding this matter including 
comments, objections, and requests for hearing should be submitted to 
DEA using the address information provided above.

Requirements for Handling Fospropofol

    If this rule is finalized as proposed, fospropofol 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 fospropofol, or who desires to manufacture, distribute, 
dispense, import, export, engage in instructional activities or conduct 
research with fospropofol, would need to be registered to conduct such 
activities in accordance with 21 CFR part 1301.
    Security. Fospropofol would be subject to Schedules III-V security 
requirements and would need to be manufactured, distributed, and stored 
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 fospropofol which are distributed on or after 
finalization of this rule would need to comply with requirements of 21 
CFR 1302.03-1302.07.
    Inventory. Every registrant required to keep records and who 
possesses any quantity of fospropofol would be required to keep an 
inventory of all stocks of fospropofol on hand pursuant to 21 CFR 
1304.03, 1304.04 and 1304. Every registrant who desires registration in 
schedule IV for fospropofol 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 CFR 1304.03, 1304.04, 1304.21, 1304.22, and 1304.23.
    Prescriptions. All prescriptions for fospropofol or prescriptions 
for products containing fospropofol would be required to be issued 
pursuant to 21 CFR 1306.03-1306.06 and 1306.21, 1306.22-1306.27.
    Importation and Exportation. All importation and exportation of 
fospropofol would need to be in compliance with 21 CFR part 1312.
    Criminal Liability. Any activity with fospropofol not authorized 
by, or in violation of, the CSA 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. 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. Fospropofol products 
will be used for monitored anesthesia care (MAC) sedation in adult 
patients undergoing diagnostic or therapeutic procedures. Handlers of 
fospropofol will also handle other controlled substances used for 
sedation 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 
$120,000,000 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.

Congressional Review Act

    This rule is not a major rule as defined by section 804 of the 
Small Business Regulatory Enforcement Fairness Act of 1996 
(Congressional Review Act). 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 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:

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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 1308.14 is amended in paragraph (c), by redesignating 
paragraphs (c)(23) through (c)(51) as paragraphs (c)(24) through 
(c)(52) and adding a new paragraph (c)(23) as follows:


Sec.  1308.14  Schedule IV.

* * * * *
    (c) * * *

 
 
 
(23) Fospropofol.................................................   2138
 

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    Dated: July 16, 2009.
Michele M. Leonhart,
Deputy Administrator.
[FR Doc. E9-17538 Filed 7-22-09; 8:45 am]
BILLING CODE 4410-09-P