[Federal Register Volume 75, Number 207 (Wednesday, October 27, 2010)]
[Proposed Rules]
[Pages 66196-66199]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-27193]
[[Page 66195]]
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Part II
Department of Justice
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Drug Enforcement Administration
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21 CFR Part 1308
Schedules of Controlled Substances: Placement of Propofol Into Schedule
IV; Proposed Rule
Federal Register / Vol. 75, No. 207 / Wednesday, October 27, 2010 /
Proposed Rules
[[Page 66196]]
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DEPARTMENT OF JUSTICE
Drug Enforcement Administration
21 CFR Part 1308
[Docket No. DEA-338]
Schedules of Controlled Substances: Placement of Propofol Into
Schedule IV
AGENCY: Drug Enforcement Administration, 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
propofol, 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 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 propofol and products containing propofol.
DATES: Written comments must be postmarked on or before December 27,
2010, and electronic comments must be sent on or before midnight
Eastern time December 27, 2010.
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, PhD, 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 Drug
Enforcement Administration'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 Drug Enforcement Administration'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 CONTACT paragraph.
Background
On March 18, 2008, the Drug Enforcement Administration (DEA)
received a petition requesting that 21 CFR 1308.13 be amended so that
propofol be controlled as a schedule III substance under the CSA. The
basis of the petition was the reports of increased incidences of
propofol abuse during the past decade. The petitioner stated as the
main argument in support of the request that:
``Propofol is the most common intravenous anesthetic in the
United States today but over the course of the decade, documented
cases of abuse have been steadily increasing over the past 10 years
* * * Unfortunately, there is also a very high mortality rate
(greater than 33%) associated with this abuse.''
The petitioner stated that controlling propofol as a scheduled drug
would require all practitioners to strictly monitor the access and use
of propofol and possibly save lives.
Propofol was approved in 1989 and is an ultra-short acting
intravenous (i.v.) anesthetic under the commercial name,
Diprivan[supreg]. Propofol is also marketed as a generic drug under
three trade names. Two veterinary versions, Rapinovet and PropoFlo/
PropoVet were approved for marketing in 1999 and 2000, respectively.
Propofol is indicated in adults for the initiation and maintenance of
Monitored Anesthesia Care (MAC) sedation, combined sedation, and
regional anesthesia. It is also indicated for Intensive Care Unit (ICU)
sedation of intubated and mechanically ventilated patients. For
children, propofol is indicated for induction and maintenance of
general anesthesia. Diprivan[supreg] is an injectable emulsion (10 mg/
mL).
Propofol, or 2,6-diisopropylphenol, is slightly soluble in water
and is formulated in an oil-in-water emulsion that is milky-white in
appearance. Fospropofol, the water-soluble O-methyl-phosphate disodium
salt prodrug of propofol, has been recently controlled as a schedule IV
substance under the CSA.
Propofol binds to the gamma-aminobutyric acid (GABAA)
receptors and acts as a modulator by potentiating the activity of GABA
at these receptors. Other psychoactive drugs that are controlled under
the CSA, e.g., barbiturates (schedule II and III) and benzodiazepines
(schedule IV), potentiate the activity of GABA at the GABAA
receptors.
[[Page 66197]]
Animal self-administration studies demonstrate the reinforcing
effects of propofol in rat, mouse, and primate models. It has been
demonstrated that drugs that are self-administered by animals also have
drug abuse potential in humans. Propofol has been demonstrated to have
reinforcing effects comparable to methohexital, a schedule IV sedative-
hypnotic. A study found that both drug-na[iuml]ve and methohexital-
trained (a schedule IV barbiturate) rats self-administer propofol under
a fixed ratio schedule. In baboons, low-to-high levels of self-
administration were maintained by subanesthetic doses of propofol after
substituting for cocaine. There have been published abuse liability
studies of propofol in humans in which the reinforcement and reward
effects have been demonstrated. These studies showed that propofol
produces subjective effects most comparable to schedule IV sedatives.
Generally, the studies demonstrated that propofol dose-dependently
increased the reporting by the subject feeling ``high,'' relative to
the placebo.
The motivation for abuse of propofol is generally for its sedative
and relaxing properties and induction of euphoric effects. There have
also been reports that propofol's ability to induce sexual illusions
and disinhibition contributes to its appeal as a drug of abuse.
Anecdotal reports of propofol abusers described their experiences as
``pleasant,'' ``euphoric,'' and ``relaxing''.
The current abuse profiles of propofol indicate that it is abused
by medical professionals since they have access to the drug in medical
facilities which perform anesthesia (Adverse Event Reporting System
(AERS) DataMart database). In the AERS database, there are reports of
propofol diversion and abuse, some of which resulted in death. In 96
percent of these cases, the abusers were health care providers or were
in training programs to become health care professionals. Propofol is
not currently controlled by either the Federal Government or State
governments, and may not be a target or priority of law enforcement;
therefore, information on reported seizures and cases from Federal,
State and local law enforcement agencies is very limited.
Schedule IV sedative-hypnotics, such as methohexital and midazolam,
are known to produce euphoric moods and have histories of abuse in the
United States and other countries. There have been published case
reports of individuals who became dependent on propofol. These reports
indicated that the individuals expressed a ``craving'' for propofol,
causing them to compulsively self-inject daily. They were abusing
propofol for its relaxing and euphoric effects. In a survey of academic
anesthesiology programs, 18 percent reported diversion or abuse of
propofol. Twenty-eight percent of the reported abusers of propofol had
died due to propofol overdose. The individuals who died were affiliated
with health care facilities in which there were no pharmacy or security
mechanisms to control access to propofol. In a published survey of
certified registered nurse anesthetists, propofol was reported to be
the fourth most preferred drug to misuse among this population.
Propofol abuse is associated with significant adverse health effects,
including death. The known major side effects include pancreatitis,
pulmonary edema, cardiovascular depression, and respiratory depression.
The cause of death with propofol toxicity is due to severe respiratory
depression.
Withdrawal symptoms observed upon ceasing long-term administration
of a substance are indicative of a substance's ability to produce
physical dependence. There have been published reports of withdrawal
symptoms upon an abrupt cessation of administration of propofol after a
prolonged treatment. The symptoms include 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. It should be noted
that after a prolonged administration of propofol, the cessation of
administration should be done cautiously and the patient should be
monitored for any signs of a withdrawal syndrome.
Propofol has been on the market since 1989, but, due to propofol
being unavailable to the general public, the seizures of propofol on
the Federal, State and local levels are very low. Medical professionals
are the predominant population who are abusers of propofol. Subsequent
to DEA gathering and evaluating the available data on propofol, on July
2, 2009, DEA requested that DHHS provide a scientific and medical
evaluation of the available information and a scheduling recommendation
for propofol, in accordance with 21 U.S.C. 811(b). On May 14, 2010, the
Assistant Secretary for Health, DHHS, sent the Deputy Administrator of
DEA a scientific and medical evaluation and a letter recommending that
propofol be placed into schedule IV of the CSA. Enclosed with the April
30, 2010, letter was a document prepared by the Food and Drug
Administration (FDA) entitled, ``Basis for the Recommendation for
Control of Propofol and Its Salts in Schedule IV of the Controlled
Substances Act (CSA).'' The document contained a review of the factors
which the CSA requires the Secretary to consider (21 U.S.C. 811(b)).
The references to the studies used in the evaluations for DHHS'
scheduling recommendation and DEA's independent analysis can be found
in both documents. These documents are available on the electronic
docket associated with this rule making.
The factors considered by the Assistant Secretary of Health and DEA
with respect to propofol 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) Propofol has a low potential for abuse relative to the drugs or
substances in schedule III. The abuse potential of propofol is
comparable to the schedule IV substances, methohexital and midazolam;
(2) Propofol has a currently accepted medical use in treatment in
the United States; propofol under the trade name Diprivan[supreg] was
approved for marketing as a product indicated for monitored anesthesia
care by FDA in 1989; and
(3) Abuse of propofol may lead to limited psychological dependence
or physical dependence relative to the drugs or other substances in
schedule III.
Based on these findings, the Deputy Administrator of DEA concludes
that propofol, including its salts, isomers, and salts of isomers,
whenever the existence of such salts, isomers, and salts of isomers is
possible, warrants
[[Page 66198]]
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 Propofol
If this rule is finalized as proposed, propofol 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 propofol, or who desires to manufacture, distribute,
dispense, import, export, engage in instructional activities, or
conduct research with propofol, would need to be registered to conduct
such activities in accordance with 21 CFR part 1301.
Security. Propofol 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 propofol 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 propofol would be required to keep an
inventory of all stocks of propofol on hand pursuant to 21 CFR 1304.03,
1304.04 and 1304.11. Every registrant who desires registration in
schedule IV for propofol 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 propofol or prescriptions for
products containing propofol 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
propofol would need to be in compliance with 21 CFR part 1312.
Criminal Liability. Any activity with propofol 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. Propofol products are
used for the initiation and maintenance of MAC sedation, combined
sedation, and regional anesthesia for adult and pediatric patients
undergoing diagnostic or therapeutic procedures. Handlers of propofol
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:
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 by redesignating paragraphs (c)(46)
through
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(c)(52) as paragraphs (c)(47) through (c)(53) and adding a new
paragraph (c)(46) as follows:
Sec. 1308.14 Schedule IV.
* * * * *
(c) * * *
(46) Propofol.................................................. 2139
* * * * *
Dated: October 19, 2010.
Michele M. Leonhart,
Deputy Administrator.
[FR Doc. 2010-27193 Filed 10-26-10; 8:45 am]
BILLING CODE 4410-09-P