Federal
Register Notices > Rules - 200 9
>
Placement of Fospropofol Into Schedule IV
9
FR Doc E9-17538[Federal Register: July 23, 2009 (Volume 74,
Number 140)] [Proposed Rules] [Page 36424-36427] From the
Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr23jy09-10]
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.
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
dea.diversion.policy@usdoj.gov. 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:
[[Page 36427]]
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
* * * * *
Dated: July 16, 2009.
Michele M. Leonhart,
Deputy Administrator.
[FR Doc. E9-17538 Filed 7-22-09; 8:45 am]
NOTICE: This is an
unofficial version. An official version of these publications may be obtained
directly from the Government Printing Office (GPO).
|