Federal Register / Vol. 78, No. 57 / Monday, March 25, 2013 / Proposed Rules 17895 

22,109 hours due to this proposed 

regulatory change. 

IX. Proposed Effective Date 

FDA is proposing that any final order 

based on this proposal become effective 

on the date of its publication in the 

Federal Register or at a later date if 

stated in the final order. 

X. Codification of Orders 

Prior to the amendments by FDASIA, 

section 515(b) of the FD&C Act provided 

for FDA to issue regulations to require 

approval of an application for premarket 

approval for preamendments devices or 

devices found substantially equivalent 

to preamendments devices. Section 

515(b) of the FD&C Act, as amended by 

FDASIA, provides for FDA to require 

approval of an application for premarket 

approval for such devices by issuing a 

final order, following the issuance of a 

proposed order in the Federal Register. 

FDA will continue to codify the 

requirement for an application for 

premarket approval, resulting from 

changes issued in a final order, in the 

Code of Federal Regulations (CFR). 

Therefore, under section 515(b)(1)(A) of 

the FD&C Act, as amended by FDASIA, 

in this proposed order, we are proposing 

to require approval of an application for 

premarket approval for AEDs and if this 

proposed order is finalized, we will 

make the language in 21 CFR 870.5310 

consistent with the final version of this 

proposed order. 

XI. Comments 

Interested persons may submit either 

electronic comments regarding this 

document to http://www.regulations.gov 

or written comments to the Division of 

Dockets Management (see ADDRESSES). It 

is only necessary to send one set of 

comments. Identify comments with the 

docket number found in brackets in the 

heading of this document. Received 

comments may be seen in the Division 

of Dockets Management between 9 a.m. 

and 4 p.m., Monday through Friday, and 

will be posted to the docket at http:// 

www.regulations.gov. 

XII. Reference 

The following reference has been 

placed on display in the Division of 

Dockets Management (see ADDRESSES) 

and may be seen by interested persons 

between 9 a.m. and 4 p.m., Monday 

through Friday, and is available 

electronically at http:// 

www.regulations.gov. (FDA has verified 

the Web site address in this reference 

section, but FDA is not responsible for 

any subsequent changes to the Web site 

after this document publishes in the 

Federal Register.) 

1. The panel transcript and other 

meeting materials are available on 

FDA’s Web site at http://www.fda.gov/ 

AdvisoryCommittees/ 

CommitteesMeetingMaterials/ 

MedicalDevices/ 

MedicalDevicesAdvisoryCommittee/ 

CirculatorySystemDevicesPanel/ 

ucm240575.htm. 

List of Subjects in 21 CFR Part 870 

Medical devices. 

Therefore, under the Federal Food, 

Drug, and Cosmetic Act and under 

authority delegated to the Commissioner 

of Food and Drugs, it is proposed that 

21 CFR part 870 be amended as follows: 

PART 870—CARDIOVASCULAR 

DEVICES 

■ 1. The authority citation for 21 CFR 

part 870 continues to read as follows: 

Authority: 21 U.S.C. 351, 360, 360c, 360e, 

360j, 371. 

■ 2. Section 870.5310 is amended by 

revising the section heading and 

paragraphs (a) and (c) to read as follows: 

§ 870.5310 Automated external defibrillator 

system. 

(a) Identification. An automated 

external defibrillator (AED) system 

consists of an AED device and its 

accessories, i.e., battery, pad electrode 

and, if applicable, an adapter. An AED 

system analyzes the patient’s 

electrocardiogram, interprets the cardiac 

rhythm, and automatically delivers an 

electrical shock (fully automated AED), 

or advises the user to deliver the shock 

(semi-automated or shock advisory 

AED) to treat ventricular fibrillation or 

pulseless ventricular tachycardia. 

* * * * * 

(c) Date PMA or notice of completion 

of PDP is required. A PMA is required 

to be submitted to the Food and Drug 

Administration by [A DATE WILL BE 

ADDED 90 DAYS AFTER DATE OF 

PUBLICATION OF A FUTURE FINAL 

ORDER IN THE FEDERAL REGISTER], 

for any automated external defibrillator 

that was in commercial distribution 

before May 28, 1976, or that has, by [A 

DATE WILL BE ADDED 90 DAYS 

AFTER DATE OF PUBLICATION OF A 

FUTURE FINAL ORDER IN THE 

FEDERAL REGISTER], been found to be 

substantially equivalent to any 

automated external defibrillator that 

was in commercial distribution before 

May 28, 1976. Any other automated 

external defibrillator and automated 

external defibrillator accessories, i.e., 

pad electrodes, adaptors, and batteries 

shall have an approved PMA or 

declared completed PDP in effect before 

being placed in commercial 

distribution. 

Dated: March 19, 2013. 

Leslie Kux, 

Assistant Commissioner for Policy. 

[FR Doc. 2013–06723 Filed 3–22–13; 8:45 am] 

BILLING CODE 4160–01–P 

DEPARTMENT OF JUSTICE 

Drug Enforcement Administration 

21 CFR Part 1308 

[Docket No. DEA–370] 

Schedules of Controlled Substances: 

Placement of Alfaxalone into Schedule 

IV 

AGENCY: Drug Enforcement 

Administration, Department of Justice. 

ACTION: Notice of proposed rulemaking. 

SUMMARY: The Drug Enforcement 

Administration (DEA) proposes the 

placement of 5a-pregnan-3a-ol-11,20- 

dione (alfaxalone) 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 pursuant to the CSA which 

requires that such actions be made on 

the record after opportunity for a 

hearing through formal rulemaking. 

DATES: DEA will permit interested 

persons to file written comments on this 

proposal pursuant to 21 CFR 1308.43(g). 

Electronic comments must be submitted 

and written comments must be 

postmarked on or before April 24, 2013. 

Commenters should be aware that the 

electronic Federal Docket Management 

System will not accept comments after 

midnight Eastern Time on the last day 

of the comment period. 

Interested persons, defined at 21 CFR 

1300.01 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 file a request 

for hearing pursuant to 21 CFR 1308.44 

and in accordance with 21 CFR 1316.45 

and 1316.47. Requests for hearing and 

waivers of participation must be 

received on or before April 24, 2013. 

ADDRESSES: To ensure proper handling 

of comments, please reference ‘‘Docket 

No. DEA 370’’ on all electronic and 

written correspondence. DEA 

encourages all comments be submitted 

electronically through http:// 

www.regulations.gov using the 

electronic comment form provided on 

that site. An electronic copy of this 

document and supplemental 


srobinson on DSK4SPTVN1PROD with PROPOSALS
17896 Federal Register / Vol. 78, No. 57 / Monday, March 25, 2013 / Proposed Rules 

information to this proposed rule are 

also available at the http:// 

www.regulations.gov Web site for easy 

reference. Paper comments that 

duplicate the electronic submission are 

not necessary as all comments 

submitted to www.regulations.gov will 

be posted for public review and are part 

of the official docket record. Should 

you, however, wish to submit written 

comments via regular or express mail, 

they should be sent to the Drug 

Enforcement Administration, Attention: 

DEA Federal Register Representative/ 

OD, 8701 Morrissette Drive, Springfield, 

Virginia 22152. All requests for hearing 

and waivers of participation must be 

sent to Drug Enforcement 

Administration, Attention: Hearing 

Clerk/LJ, 8701 Morrissette Drive, 

Springfield, Virginia 22152. 

FOR FURTHER INFORMATION CONTACT: John 

W. Partridge, Executive Assistant, Office 

of Diversion Control, Drug Enforcement 

Administration; Mailing Address: 8701 

Morrissette Drive, Springfield, Virginia 

22152; Telephone: (202) 307–7165. 

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 of 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 

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, 

above. 

Request for Hearing, Notice of 

Appearance at or Waiver of 

Participation in Hearing 

In accordance with the CSA, this 

action is a formal rulemaking ‘‘on the 

record after opportunity for a hearing.’’ 

21 U.S.C. 811(a). Such proceedings are 

conducted pursuant to the provisions of 

the Administrative Procedure Act (5 

U.S.C. 556 and 557) and 21 CFR 

1308.41. Pursuant to 21 CFR 1308.44(a)– 

(c), requests for hearings, notices of 

appearances, and waivers of 

participation may be submitted only by 

interested persons, defined at 21 CFR 

1300.01 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).’’ Such requests or 

notices must conform to the 

requirements of 21 CFR 1308.44(a) or (b) 

and 1316.47 or 1317.48, as applicable. A 

request or notice should state, with 

particularity, the interest of the person 

in the proceeding and the objections or 

issues, if any, concerning which the 

person desires to be heard. Any waiver 

must conform to the requirements of 21 

CFR 1308.44(c) and 1316.49, including 

a written statement regarding the 

interested person’s position on the 

matters of fact and law involved in any 

hearing. 

Please note that pursuant to 21 U.S.C. 

811(a), the purpose and subject matter 

of the hearing is restricted to ‘‘(A) 

find[ing] that such drug or other 

substance has a potential for abuse, and 

(B) mak[ing] with respect to such drug 

or other substance the findings 

prescribed by subsection (b) of section 

812 of this title for the schedule in 

which such drug is to be placed* * *.’’ 

Requests for hearing, notices of 

appearance at the hearing, and waivers 

of participation in the hearing should be 

submitted to DEA using the address 

information provided above. 

Legal Authority 

The DEA implements and enforces 

Titles II and III of the Comprehensive 

Drug Abuse Prevention and Control Act 

of 1970, often referred to as the 

Controlled Substances Act and the 

Controlled Substances Import and 

Export Act (21 U.S.C. 801–971), as 

amended (hereinafter, ‘‘CSA’’). The 

implementing regulations for these 

statutes are found in Title 21 of the 

Code of Federal Regulations (CFR), parts 

1300 to 1321. Under the CSA, controlled 

substances are classified in one of five 

schedules based upon their potential for 

abuse, their currently accepted medical 

use, and the degree of dependence the 

substance may cause. 21 U.S.C. 812. The 

initial schedules of controlled 

substances by statute are found at 21 

U.S.C. 812(c) and the current list of 

scheduled substances are published at 

21 CFR Part 1308. 

The CSA permits these schedules to 

be modified by providing that 

scheduling of any drug or other 

substance may be initiated by the 

Attorney General: (1) On his own 

motion; (2) at the request of the 

Secretary of Health and Human Services 

(HHS); or (3) on the petition of any 

interested party. 21 U.S.C. 811(a). The 

Attorney General may, by rule, ‘‘add to 

such a schedule or transfer between 

such schedules any drug or other 

substance if he (A) finds that such drug 

or other substance has a potential for 

abuse, and (B) makes with respect to 

such drug or other substance the 

findings prescribed by subsection (b) of 

section 812 of this title for the schedule 

in which such drug is to be 

placed* * *.’’ 21 U.S.C. 811(a). The 

findings required for the placement of a 

controlled substance in Schedule IV are: 

the drug or other substance has a low 

potential for abuse relative to the drugs 

or other substances in Schedule III; the 

drug or substance has a currently 

accepted medical use in treatment in the 

United States; and abuse of the drug or 

other substance may lead to limited 

physical dependence or psychological 

dependence relative to the drugs or 

other substances in Schedule III. 21 

U.S.C. 812(b)(4). 

Background 

Alfaxalone (5a-pregnan-3a-ol-11,20- 

dione, previously spelled alphaxalone), 

a substance with central nervous system 

(CNS) depressant properties, is a 

neurosteroid that is a derivative of 11- 

alpha-hydroxy-progesterone. A New 

Animal Drug Application (NADA) for 

alfaxalone, as an intravenous injectable 

anesthetic, was recently approved by 

the Food and Drug Administration 

(FDA) for the induction and 

maintenance of anesthesia and for 

induction of anesthesia followed by 

maintenance of anesthesia with an 

inhalant anesthetic, in cats and dogs. 


srobinson on DSK4SPTVN1PROD with PROPOSALS
Federal Register / Vol. 78, No. 57 / Monday, March 25, 2013 / Proposed Rules 17897 

1Comprehensive Drug Abuse Prevention and 

Control Act of 1970, H.R. Rep. No. 91–1444, 91st 

Cong., Sess. 1 (1970); 1970 U.S.C.C.A.N. 4566, 4601. 

Alfaxalone primarily acts as an agonist 

at the gamma-aminobutyric acid 

(GABA) receptor-channel complex, with 

a mechanism of action at this site 

similar to that of barbiturates like 

phenobarbital (Schedule IV) and 

methohexital (Schedule IV), 

benzodiazepines such as diazepam 

(Schedule IV) and midazolam (Schedule 

IV), as well as the anesthetic agents, 

propofol (Schedule IV under 

consideration) and fospropofol 

(Schedule IV). 

Proposed Determination to Schedule 

Alfaxalone 

Pursuant to 21 U.S.C. 811(a), 

proceedings to add a drug or substance 

to those controlled under the CSA may 

be initiated by request of the Secretary 

of HHS. On July 17, 2012, HHS 

provided DEA with a scientific and 

medical evaluation document prepared 

by FDA entitled ‘‘Basis for the 

Recommendation for Control of 

alfaxalone in Schedule IV of the 

Controlled Substances Act.’’ Pursuant to 

21 U.S.C. 811(b), this document 

contained an eight-factor analysis of the 

abuse potential of alfaxalone, along with 

HHS’ recommendation to control 

alfaxalone under Schedule IV of the 

CSA. 

In response, DEA conducted an eightfactor analysis of alfaxalone’s abuse 

potential pursuant to 21 U.S.C. 811(c). 

Included below is a brief summary of 

each factor as analyzed by HHS and 

DEA, and as considered by DEA in the 

scheduling decision. Please note that 

both the DEA and HHS analyses are 

available in their entirety under 

‘‘Supporting and Related Material’’ of 

the public docket for this rule at 

www.regulations.gov under docket 

number DEA–370. 

1. The Drug’s Actual or Relative 

Potential for Abuse: The abuse potential 

of alfaxalone is associated with its 

ability to evoke pharmacological effects 

similar to those evoked by the Schedule 

IV substances such as fospropfol, 

propofol (Schedule IV under 

consideration), and midazolam. 

Since alfaxalone is a new veterinary 

product and has not been marketed in 

the United States, information on actual 

abuse of alfaxalone in the United States 

is not available. However, the legislative 

history of the CSA offers another 

methodology for assessing a drug or 

substance’s potential for abuse: 

The drug or drugs containing such a 

substance are new drugs so related in their 

action to a drug or drugs already listed as 

having a potential for abuse to make it likely 

that the drug will have the same potentiality 

for abuse as such drugs, thus making it 

reasonable to assume that there may be 

significant diversions from legitimate 

channels, significant use contrary to or 

without medical advice, or that it has a 

substantial capability of creating hazards to 

the health of the user or to the safety of the 

community.1

According to HHS, alfaxalone is 

thought to interact with the gammaaminobutyric acid subtype A (GABA)-A 

receptors, and to enhance the activity of 

GABA, the principal inhibitory 

neurotransmitter in the central nervous 

system (CNS). This pharmacological 

evidence suggests that the abuse 

potential of alfaxalone is comparable to 

other drugs with a similar mechanism of 

action, and similar anesthetic 

properties, such as midazolam 

(Schedule IV), methohexital (Schedule 

IV), fospropofol (Schedule IV) and 

propofol (Schedule IV under 

consideration). Similar to the above 

mentioned Schedule IV sedativehypnotics, alfaxalone acts as an 

inhibitor on the CNS and produces 

sedation and anesthesia. Based on the 

similarities between propofol and 

alfaxalone regarding their mechanisms 

of action and their intended routes of 

administration for clinical use, and the 

fact that 96% of propofol abuse reports 

involved abuse by medical 

professionals, HHS reasoned that 

alfaxalone abuse might be by medical 

professionals who have access to the 

drug and have knowledge in the 

intravenous administration of drugs. 

There are no published studies of 

abuse potential for alfaxalone in 

humans. However, there is evidence 

that alfaxalone produces the sedativehypnotic midazolam-like discriminative 

stimulus effects in rats and monkeys, as 

well as some ethanol-like effects in rats. 

Based on the pharmacological 

similarities to other Schedule IV potent 

sedative-hypnotic drugs, such as 

midazolam, methohexital and 

fospropofol, the consequences of abuse 

of alfaxalone can be predicted to be 

similar to those drugs mentioned above. 

Furthermore, abuse and misuse of these 

drugs might result in death. The overt 

behavioral effects and adverse events 

produced by alfaxalone in animals are 

similar to those caused by Schedule IV 

benzodiazepines and barbiturates. 

In summary, the relative abuse 

potential of alfaxalone can be 

considered no greater than the Schedule 

IV substances such as fospropfol, 

propofol, and midazolam and less than 

that of other sedatives in Schedule III. 

2. Scientific Evidence of the Drug’s 

Pharmacological Effects, If Known: 

According to the HHS review, 

alfaxalone acts directly through the 

GABA–A receptor-channel complex and 

increases the probability that the 

channel will enter into naturallyoccurring open states of relatively long 

duration. The activity of alfaxalone on 

GABA receptors is similar to that of 

barbiturates like phenobarbital and 

methohexital (Schedule IV) as well as 

anesthetic agents like propofol 

(Schedule IV under consideration) and 

fospropofol (Schedule IV). Furthermore, 

similar to benzodiazepines such as 

diazepam and midazolam, alfaxalone 

can also increase the frequency of single 

channel openings. Additionally 

alfaxalone has been shown to inhibit Ttype calcium channels. Alfaxalone does 

not affect cannabinoid (CB1 subtype), 

dopamine (D1-, D2-, D3-, D4- and D5- 

subtype), glutamate (AMPA, kainate, 

and NMDA subtype), opioid (mu, kappa 

and delta subtype), and serotonin (1A, 

2B, 2C, 3, 5A and 6 subtype) receptors, 

nor does it affect the transporters for 

dopamine, norepinephrine and 

serotonin. In addition, alfaxalone does 

not significantly bind to major steroid 

nuclear receptors including androgens, 

estrogens, glucocorticoids or 

progesterone receptors. 

Pre-clinical behavioral studies 

showed that, similar to 

chlordiazepoxide (Schedule IV), 

alfaxalone produces anxiolytic-like 

behavioral effects in rat models of 

anxiety, such as the elevated plus maze, 

the conflict test and restraint stress. In 

a published drug discrimination study, 

in which rats were trained to 

discriminate midazolam (Schedule IV) 

from saline, alfaxalone fully generalized 

to the midazolam discriminative cue. 

These results are consistent with 

previously published studies showing 

ethanol-like discriminative stimulus 

effects of alfaxalone and with other 

studies showing that other 

neurosteroids have barbiturate-like or 

benzodiazepine-like discriminative 

stimulus effects in rats and monkeys. 

This pharmacological profile of 

alfaxalone is consistent with 

neurosteroids with GABAergic effects. 

According to the HHS review, the oral 

administration of alfaxalone as 

compared to its intravenous 

administration is 100 times less potent 

for producing midazolam-like effects. 

Alfaxalone has a low oral bioavailability 

(about 2%). It has been shown that an 

intravenous dose of about 50 mg of 

alfaxalone results in anesthesia in 

humans with a plasma level of 3 mg/L. 

Accordingly, an oral dose of about 2500 

mg might be expected to result in 

anesthesia at the plasma level of 3 mg/ 

L in humans, and thus oral doses of 250 


srobinson on DSK4SPTVN1PROD with PROPOSALS
17898 Federal Register / Vol. 78, No. 57 / Monday, March 25, 2013 / Proposed Rules 

to 800 mg of alfaxalone should be 

needed to produce a sub-anesthetic 

intoxication at plasma levels in a range 

of 0.3 to 1.0 mg/L. For a vial containing 

100 mg of alfaxalone for an oral use, an 

amount of 2.5 to 8 vials would be 

needed to produce a ‘‘high’’. 

As stated in the HHS review, selfadministration studies in animals with 

pregnanolone, allopregnanolone, 

endogenous metabolites of progesterone 

and a neuroactive steroid, Co 8–7071, 

showed that these substances produce 

some positive reinforcing effects in rats 

and rhesus monkeys. These substances, 

similar to alfaxalone, positively 

modulate GABA–A receptors by binding 

at the neurosteroid modulatory site. 

HHS stated that these data are 

predictive of abuse potential of 

alfaxalone. HHS review also cited recent 

evidence that alpha4, beta3 and delta 

GABA–A receptors are modulated by 

both THDOC, a neurosteroid, and 

propofol. Based on this potential 

overlap in cellular targets, comparable 

kinetic profiles, and similar clinical 

indications for propofol and alfaxalone, 

HHS reasoned that alfaxalone may 

produce reinforcing effects similar to 

those of propofol. 

In summary, alfaxalone, similar to 

chlordiazepoxide (Schedule IV), has 

anxiolytic activity in animals. 

Alfaxalone produced midazolam-like 

(Schedule IV) discriminative stimulus 

effects in rats, and it may share 

propofol’s reinforcing effects. The 

abuse-related neuropharmacology 

profile of alfaxalone is similar to that of 

Schedule IV substances. 

3. The State of Current Scientific 

Knowledge Regarding the Drug or Other 

Substance: The chemical name of 

alfaxalone is 5a-pregnan-3a-ol-11, 20- 

dione. Alfaxalone has a molecular 

formula of C21H32O3 and a molecular 

weight of 332.5 g/mol, and a melting 

point of 165° to 171°C. Alfaxalone has 

a poor water solubility (< 5 mg/ml), but 

its water solubility increases to 80 mg/ 

ml via complexation with cyclodextrins, 

especially 2-hydroxypropyl-betacyclodextrin (2HPCD). According to the 

HHS review, the alfaxalone product for 

veterinary anesthesia will be formulated 

as a 10 mg/ml solution of alfaxalone in 

2HPCD (80 mg/ml), sodium phosphate 

buffer and water, adjusted to a pH of 6.5 

to 7. According to the Sponsor’s 

information cited by the HHS review, 

the processes involved in the synthesis 

and purification of alfaxalone are highly 

complex and require expertise in 

chemistry manufacture. 

According to the HHS, the half-lives 

of alfaxalone are 24–37 and 45–77 

minutes in dogs and cats, respectively. 

The clearance of alfaxalone is 59 ml/ 

min/kg in dogs and 28 ml/min/kg in 

cats. The primary routes of elimination 

in the rat are biliary (65%) and renal 

(35%) routes. The half-life of alfaxalone 

in humans is about 35 minutes. The 

major metabolites in humans are 

glucuronidated and the primary route of 

elimination is through renal (80%). Oral 

bioavailability of alfaxalone is about 2% 

as compared to its intravenous 

administration in humans. A clinical 

study showed that an intravenous 

administration of 30 mg alfaxalone 

produced plasma levels of about 3 mg/ 

L, accompanied by anesthesia in 

humans. The veterinary alfaxalone 

product that is recently approved by the 

FDA contains 100 mg/vial (a vial of 10 

ml formulated solution, 10 mg/ml of 

alfaxalone) which would be sufficient to 

produce anesthesia in two individuals 

when administered intravenously. HHS 

also states that because alfaxalone can 

be abused at subanesthetic doses, a 100 

mg vial of alfaxalone drug product 

administered intravenously could be 

used repeatedly by the same individual, 

or by multiple individuals, who 

intended to abuse the substance. 

4. Its History and Current Pattern of 

Abuse: Since alfaxalone is a new 

veterinary product and has not been 

marketed in the United States, 

information on actual abuse of 

alfaxalone in the United States is not 

available. Because alfaxalone has been 

marketed under the trade name 

Alfaxan® in the United Kingdom (UK) 

since 2007, the Sponsor submitted to 

HHS the results of a search of 

pharmacovigilance reports to the UK 

Veterinary Medicines Directorate. 

According to HHS, the Sponsor also 

provided information obtained from 

several other sources regarding 

diversion and abuse of alfaxalone. None 

of the above sources contained evidence 

of abuse of alfaxalone by humans. 

According to the HHS review, a search 

conducted by the Sponsor of the 

publically-available pharmacovigilance 

database provided by the UK’s 

Medicines and Healthcare Products 

Regulatory Agency (MHRA) Web site 

also did not produce reports related to 

alfaxalone abuse. DEA conducted a 

comprehensive search of several major 

national drug abuse monitoring 

programs and found no evidence of 

alfaxalone abuse. It may be due to the 

fact that alfaxalone-containing products 

have not been marketed in the United 

States to date. However, alfaxalone’s 

pharmacological properties suggest that 

its pattern of abuse would be similar to 

other drugs used in maintenance and 

induction of anesthesia, such as 

midazolam (Schedule IV) and propofol 

(Schedule IV under consideration). 

5. The Scope, Duration, and 

Significance of Abuse: As mentioned 

above, a comprehensive search by DEA 

of the major national drug abuse 

monitoring programs found no evidence 

of human abuse of alfaxalone in the U.S. 

However, as stated in the HHS review, 

the ‘‘suspicious order monitor system’’ 

of the U.S. distributor of alfaxalone, will 

be utilized to monitor the diversion of 

this product. This monitoring system of 

evaluates order quantities, buying 

patterns, and customer class regarding 

orders of unusual volume that could 

indicate diversion. As part of their 

monitoring, daily searches of the DEA 

Web site for new abuse issues and for 

abuse-related data from HHS’s 

Substance Abuse and Mental Health 

Administration Services (SAMHSA) 

will be conducted. Additionally, the 

Sponsor will provide FDA with 

pharmacovigilance information for both 

animal and human adverse events from 

all markets. 

6. What, if any, Risk There is to the 

Public Health: According to the HHS 

review, the public health risks of 

alfaxalone are mostly risks to the 

individual abuser and the risks are 

similar to those associated with the 

abuse of other sedative hypnotics and 

CNS depressants, such as midazolam 

and methohexital. Abuse of alfaxalone 

may lead to the death of the abuser or 

other adverse events that affect 

behavior, reaction ability and timing in 

operating a motor vehicle or machinery. 

As an anesthetic, the adverse events 

(AEs) that are likely to result from 

alfaxalone use are usually similar to 

those arising from the use of most 

general anesthetics. These events 

include apnea, bradycardia, bradypnea, 

hypertension, hypotension, 

hypothermia, hypoxia, unacceptable 

anesthesia quality, tachycardia and 

emesis. These AEs were found in animal 

studies involving cats and dogs. 

Alfaxalone, as anesthetic product if 

used in excess, carries potential for 

overdose. 

HHS cited two cases involving the 

accidental overdose of the alfaxalone 

human product, Althesin®, a human 

product containing combination of 

alfaxalone/alfadolone which was 

previously withdrawn from market. 

HHS stated that the occurrence of an 

accidental or purposeful overdose of 

Alfaxan® (containing 10 mg/ml of 

alfaxalone) is unlikely. HHS reasoned 

that if a person were trying to duplicate 

the same accidental overdose of 

injectable alfaxalone solution, he or she 

would be required to draw up a large 

volume of alfaxalone solution into the 


srobinson on DSK4SPTVN1PROD with PROPOSALS
Federal Register / Vol. 78, No. 57 / Monday, March 25, 2013 / Proposed Rules 17899 

syringe. The intravenous selfadministration of such large volume of 

Alfaxan® would be a very difficult if not 

impossible to perform, as the person 

would likely be anesthetized after the 

first 4.2 ml of the injection. If a person 

were to drink Alfaxan® to try to cause 

overdose, it would require 100 times 

more drug because of alfaxalone’s poor 

oral bioavailability (1–2%). According 

to HHS, little is known about other 

health effects that might occur in 

someone abusing the drug chronically. 

In summary, the public health risks of 

alfaxalone abuse are similar to those 

associated with the abuse of other 

sedative hypnotics and CNS 

depressants, such as midazolam and 

methohexital which are controlled in 

Schedule IV of the CSA and propofol 

(Schedule IV under consideration). The 

major adverse events of these 

anesthetics include respiratory 

depression and deaths. 

7. Its Psychic or Physiological 

Dependence Liability: According to 

HHS, studies of abrupt discontinuation 

of alfaxalone were not conducted. 

However, a study cited (McMohan et al., 

2007) by the HHS review suggested the 

ability of alfaxalone to produce physical 

dependence. McMahon and his 

associates found that alfaxalone reduced 

the discriminative cue produced by 

flumazenil-precipitated withdrawal 

following chronic administration of 

benzodiazepines such as diazepam or 

lorazepam (both Schedule IV) in Rhesus 

monkeys (McMahon et al., 2007). The 

HHS review concludes that alfaxalone 

can decrease withdrawal resulting from 

chronic administration of other positive 

GABA–A receptor modulators. 

According to HHS, there is no data 

available on the effects of abrupt 

discontinuation of alfaxalone because, 

as an anesthetic, it is not used 

chronically and not available for 

chronic use. 

8. Whether the Substance is an 

Immediate Precursor of a Substance 

Already Controlled Under the CSA: 

Alfaxalone is not considered an 

immediate precursor of any controlled 

substance of the CSA as defined by 21 

U.S.C 802(23). 

Conclusion: Based on consideration of 

the scientific and medical evaluation 

and accompanying recommendation of 

HHS, and based on DEA’s consideration 

of its own eight-factor analysis, DEA 

finds that these facts and all relevant 

data constitute substantial evidence of 

potential for abuse of alfaxalone. As 

such, DEA hereby proposes to schedule 

alfaxalone as a controlled substance 

under the CSA. 

Proposed Determination of Appropriate 

Schedule 

The CSA establishes five schedules of 

controlled substances known as 

Schedules I, II, III, IV, and V. The statute 

outlines the findings required to place a 

drug or other substance in any 

particular schedule. 21 U.S.C. 812(b). 

After consideration of the analysis and 

recommendations of the Assistant 

Secretary for Health of HHS and review 

of all available data, the Administrator 

of DEA, pursuant to 21 U.S.C. 812(b)(4), 

finds that: 

(1) 5a-pregnan-3a-ol-11,20-dione 

(alfaxalone) has a low potential for 

abuse relative to the drugs or other 

substances in Schedule III; 

(2) 5a-pregnan-3a-ol-11,20-dione 

(alfaxalone) has a currently accepted 

medical use in treatment in the United 

States. Alfaxalone was approved for 

marketing by FDA as a veterinary 

anesthetic product for the induction and 

maintenance of anesthesia in cats and in 

dogs; and 

(3) abuse of 5a-pregnan-3a-ol-11,20- 

dione (alfaxalone) may lead to limited 

physical dependence or psychological 

dependence relative to the drugs or 

other substances in Schedule III. 

Based on these findings, the 

Administrator of DEA concludes that 

5a-pregnan-3a-ol-11,20-dione 

(alfaxalone) 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)). 

Requirements for Handling Alfaxalone 

If this rule is finalized as proposed, 

alfaxalone would be subject to the CSA 

and the Controlled Substances Import 

and Export Act (CSIEA) 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 

alfaxalone or who desires to 

manufacture, distribute, dispense, 

import, export, engage in research or 

conduct instructional activities with 

alfaxalone would need to be registered 

to conduct such activities pursuant to 

21 U.S.C. 822 and 958 and in 

accordance with 21 CFR part 1301. 

Security. Alfaxalone would be subject 

to Schedule 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 alfaxalone which is distributed on or 

after the effective date of the finalization 

of this rule would need to be in 

accordance with 21 CFR 1302.03– 

1302.07, pursuant to 21 U.S.C. 825. 

Inventory. Every registrant required to 

keep records and who possesses any 

quantity of alfaxalone would be 

required to keep an inventory of all 

stocks of alfaxalone on hand pursuant to 

21 U.S.C. 827 and in accordance with 21 

CFR 1304.03, 1304.04, and 1304.11. 

Every registrant who desires registration 

in Schedule IV for alfaxalone 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 

U.S.C. 827 and in accordance with 21 

CFR 1304.03, 1304.04, 1304.21, 1304.22, 

and 1304.23. 

Prescriptions. Alfaxalone or products 

containing alfaxalone would be required 

to be distributed or dispensed pursuant 

to 21 U.S.C. 829 and in accordance with 

21 CFR 1306.03–1306.06, 1306.08, 

1308.09, and 1306.21–1306.27. 

Importation and Exportation. All 

importation and exportation of 

alfaxalone would need to be done in 

accordance with 21 CFR part 1312, 

pursuant to 21 U.S.C. 952, 953, 957, and 

958. 

Criminal Liability. Any activity with 

alfaxalone not authorized by, or in 

violation of, the CSA occurring on or 

after effective date of the finalization of 

this proposed rule would be unlawful. 

Regulatory Analyses 

Executive Orders 12866 and 13563 

In accordance with 21 U.S.C. 811(a), 

this proposed scheduling action is 

subject to formal rulemaking procedures 

done ‘‘on the record after opportunity 

for a hearing,’’ which are conducted 

pursuant to the provisions of 5 U.S.C. 

556 and 557. The CSA sets forth the 

criteria for scheduling a drug or other 

substance. Such actions are exempt 

from review by the Office of 

Management and Budget pursuant to 

Section 3(d)(1) of Executive Order 

12866 and the principles reaffirmed in 

Executive Order 13563. 

Executive Order 12988 

This proposed regulation meets the 

applicable standards set forth in 

Sections 3(a) and 3(b)(2) of Executive 

Order 12988 Civil Justice Reform to 

eliminate ambiguity, minimizes 


srobinson on DSK4SPTVN1PROD with PROPOSALS
17900 Federal Register / Vol. 78, No. 57 / Monday, March 25, 2013 / Proposed Rules 

litigation, establish clear legal 

standards, and reduce burden. 

Executive Order 13132 

This proposed 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. 

Executive Order 13175 

This proposed rule will not have 

tribal implications and will not impose 

substantial direct compliance costs on 

Indian tribal governments. 

Paperwork Reduction Act of 1995 

This action does not impose a new 

collection of information under the 

Paperwork Reduction Act of 1995, 44 

U.S.C. 3501–3521. 

List of Subjects in 21 CFR Part 1308 

Administrative practice and 

procedure, Drug traffic control, 

Reporting and recordkeeping 

requirements. 

For the reasons set out above, 21 CFR 

part 1308 is proposed to be amended to 

read 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)(1) through 

(c)(53) as paragraphs (c)(2) through 

(c)(54) and adding a new paragraph 

(c)(1) as follows: 

§ 1308.14 Schedule IV. 

* * * * * 

(c) * * * 

(1) 5a-pregnan-3a-ol-11,20-dione 

(Alfaxalone) * * * (2731) 

* * * * * 

Dated: March 15, 2013. 

Michele M. Leonhart, 

Administrator. 

[FR Doc. 2013–06651 Filed 3–22–13; 8:45 am] 

BILLING CODE 4410–09–P 

DEPARTMENT OF THE TREASURY 

Internal Revenue Service 

26 CFR Part 1 

[REG–148500–12] 

RIN 1545–BL36 

Shared Responsibility Payment for Not 

Maintaining Minimum Essential 

Coverage; Correction 

AGENCY: Internal Revenue Service (IRS), 

Treasury. 

ACTION: Correction to notice of proposed 

rulemaking and notice of public 

hearing. 

SUMMARY: This document contains 

corrections to a notice of proposed 

rulemaking and notice of public hearing 

(REG–148500–12) that was published in 

the Federal Register on Friday, 

February 1, 2013 (78 FR 7314). The 

proposed regulations relate to the 

requirement to maintain minimum 

essential coverage enacted by the 

Patient Protection and Affordable Care 

Act and the Health Care and Education 

Reconciliation Act of 2010, as amended 

by the TRICARE Affirmation Act and 

Public Law 111–173. These proposed 

regulations provide guidance on the 

liability for the shared responsibility 

payment for not maintaining minimum 

essential coverage. 

FOR FURTHER INFORMATION CONTACT: SueJean Kim or John B. Lovelace, (202) 

622–4960 (not a toll free number). 

SUPPLEMENTARY INFORMATION: 

Background 

The notice of proposed rulemaking 

and notice of public hearing (REG– 

148500–12) that is the subject of these 

corrections are under Section 5000A of 

the Internal Revenue Code. 

Need for Correction 

As published, the notice of proposed 

rulemaking and notice of public hearing 

(REG–148500–12) contains errors that 

may prove to be misleading and are in 

need of clarification. 

Correction of Publication 

Accordingly, the notice of proposed 

rulemaking and notice of public hearing 

(REG–148500–12), that was the subject 

of FR Doc. 2013–02141, is corrected as 

follows: 

1. On page 7316, in the preamble, 

column 1, under the paragraph heading 

‘‘Exempt Individuals’’, line 7 of the 

third full paragraph, the language 

‘‘consultation with the Secretary of ’’ is 

corrected to read ‘‘consultation with the 

Secretary of the’’. 

2. On page 7316, in the preamble, 

column 3, under the paragraph heading 

‘‘Computation of Shared Responsibility 

Payment’’, lines 5 and 6 from the top of 

the column, the language ‘‘the following 

amounts: (1) The flat dollar amount, or 

(2) the percentage of’’ is corrected to 

read ‘‘the following amounts: (1) the flat 

dollar amount, or (2) the percentage of’’. 

3. On page 7316, in the preamble, 

column 3, under the paragraph heading 

‘‘Minimum Essential Coverage’’, lines 3 

through 32 of the third and fourth full 

paragraph of the column, the language 

‘‘following: (1) Coverage under a 

specified government sponsored 

program, (2) coverage under an eligible 

employer-sponsored plan, (3) coverage 

under a health plan offered in the 

individual market within a State, (4) 

coverage under a grandfathered health 

plan, and (5) other health benefits 

coverage that the Secretary of Health 

and Human Services, in coordination 

with the Secretary, recognizes for 

purposes of section 5000A(f). 

Under section 5000A(f)(1)(A), 

specified government sponsored 

programs include the following: (1) The 

Medicare program under part A of title 

XVIII of the Social Security Act, (2) the 

Medicaid program under title XIX of the 

Social Security Act, (3) the Children’s 

Health Insurance Program (CHIP) under 

title XXI of the Social Security Act, (4) 

medical coverage under chapter 55 of 

title 10, United States Code, including 

the TRICARE program, (5) veterans 

health care programs under chapter 17 

or 18 of title 38, as determined by the 

Secretary of Veterans Affairs, in 

coordination with the Secretary of 

Health and Human Services and the 

Secretary of Treasury, (6) a health plan’’ 

is corrected to read ‘‘following: (1) 

coverage under a specified government 

sponsored program; (2) coverage under 

an eligible employer-sponsored plan; (3) 

coverage under a health plan offered in 

the individual market within a State; (4) 

coverage under a grandfathered health 

plan; and (5) other health benefits 

coverage that the Secretary of Health 

and Human Services, in coordination 

with the Secretary, recognizes for 

purposes of section 5000A(f). 

Under section 5000A(f)(1)(A), 

specified government sponsored 

programs include the following: (1) the 

Medicare program under part A of title 

XVIII of the Social Security Act; (2) the 

Medicaid program under title XIX of the 

Social Security Act; (3) the Children’s 

Health Insurance Program (CHIP) under 

title XXI of the Social Security Act; (4) 

medical coverage under chapter 55 of 

title 10, United States Code, including 

the TRICARE program; (5) veterans 

health care programs under chapter 17 


srobinson on DSK4SPTVN1PROD with PROPOSALS