Schedules of Controlled Substances: Placement of Alfaxalone into Schedule IV
Federal Register, Volume 78 Issue 57 (Monday, March 25, 2013)
Federal Register Volume 78, Number 57 (Monday, March 25, 2013)
Proposed Rules
Pages 17895-17900
From the Federal Register Online via the Government Printing Office www.gpo.gov
FR Doc No: 2013-06651
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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.
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SUMMARY: The Drug Enforcement Administration (DEA) proposes the placement of 5alpha-pregnan-3alpha-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
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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) finding that such drug or other substance has a potential for abuse, and (B) making 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 (5alpha-pregnan-3alpha-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.
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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 eight-factor 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.
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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\
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\1\ Comprehensive 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.
According to HHS, alfaxalone is thought to interact with the gamma-
aminobutyric 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 sedative-
hypnotics, 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 sedative-hypnotic 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.
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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 naturally-occurring 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 T-type 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
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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, self-administration 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.
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The State of Current Scientific Knowledge Regarding the Drug or Other Substance: The chemical name of alfaxalone is 5alpha-pregnan-
3alpha-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 165deg to 171degC. Alfaxalone has a poor water solubility (
