66196 Federal Register / Vol. 75, No. 207 / Wednesday, October 27, 2010 / Proposed Rules 

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. 

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®. 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® 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 Omethyl-phosphate disodium salt 

prodrug of propofol, has been recently 

controlled as a schedule IV substance 

under the CSA. 

Propofol binds to the gammaaminobutyric 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. 


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Federal Register / Vol. 75, No. 207 / Wednesday, October 27, 2010 / Proposed Rules 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-naı ̈ve and methohexitaltrained (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® 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 


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66198 Federal Register / Vol. 75, No. 207 / Wednesday, October 27, 2010 / Proposed Rules 

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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Federal Register / Vol. 75, No. 207 / Wednesday, October 27, 2010 / Proposed Rules 66199 

(c)(52) as paragraphs (c)(47) through 

(c)(53) and adding a new paragraph 

(c)(46) as follows: 

§ 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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