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[Federal Register: October 27, 2010 (Volume 75, Number 207)]
[Proposed Rules]               
[Page 66195-66199]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr27oc10-24]                         

[[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

[[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 
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, 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
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