Schedules of Controlled Substances: Placement of Alfaxalone into Schedule IV, 17895-17900 [2013-06651]

Download as PDF Federal Register / Vol. 78, No. 57 / Monday, March 25, 2013 / Proposed Rules 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. srobinson on DSK4SPTVN1PROD with PROPOSALS 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.) VerDate Mar<15>2010 17:07 Mar 22, 2013 Jkt 229001 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 17895 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 Drug Enforcement Administration, Department of Justice. ACTION: Notice of proposed rulemaking. ■ AGENCY: Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 371. SUMMARY: 1. The authority citation for 21 CFR part 870 continues to read as follows: 2. Section 870.5310 is amended by revising the section heading and paragraphs (a) and (c) to read as follows: ■ § 870.5310 system. Automated external defibrillator (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 PO 00000 Frm 00008 Fmt 4702 Sfmt 4702 The Drug Enforcement Administration (DEA) proposes the placement of 5a-pregnan-3a-ol-11,20dione (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 E:\FR\FM\25MRP1.SGM 25MRP1 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. John W. Partridge, Executive Assistant, Office of Diversion Control, Drug Enforcement Administration; Mailing Address: 8701 Morrissette Drive, Springfield, Virginia 22152; Telephone: (202) 307–7165. FOR FURTHER INFORMATION CONTACT: srobinson on DSK4SPTVN1PROD with PROPOSALS 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 VerDate Mar<15>2010 17:07 Mar 22, 2013 Jkt 229001 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 PO 00000 Frm 00009 Fmt 4702 Sfmt 4702 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-11,20dione, previously spelled alphaxalone), a substance with central nervous system (CNS) depressant properties, is a neurosteroid that is a derivative of 11alpha-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. E:\FR\FM\25MRP1.SGM 25MRP1 Federal Register / Vol. 78, No. 57 / Monday, March 25, 2013 / Proposed Rules srobinson on DSK4SPTVN1PROD with PROPOSALS 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 VerDate Mar<15>2010 17:07 Mar 22, 2013 Jkt 229001 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: 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. PO 00000 Frm 00010 Fmt 4702 Sfmt 4702 17897 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 D5subtype), 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 E:\FR\FM\25MRP1.SGM 25MRP1 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, 20dione. 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/ VerDate Mar<15>2010 17:07 Mar 22, 2013 Jkt 229001 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 PO 00000 Frm 00011 Fmt 4702 Sfmt 4702 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 E:\FR\FM\25MRP1.SGM 25MRP1 srobinson on DSK4SPTVN1PROD with PROPOSALS Federal Register / Vol. 78, No. 57 / Monday, March 25, 2013 / Proposed Rules 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. VerDate Mar<15>2010 17:07 Mar 22, 2013 Jkt 229001 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-11,20dione (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 PO 00000 Frm 00012 Fmt 4702 Sfmt 4702 17899 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 E:\FR\FM\25MRP1.SGM 25MRP1 17900 Federal Register / Vol. 78, No. 57 / Monday, March 25, 2013 / Proposed Rules litigation, establish clear legal standards, and reduce burden. DEPARTMENT OF THE TREASURY Internal Revenue Service 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. srobinson on DSK4SPTVN1PROD with PROPOSALS * * * * * (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 VerDate Mar<15>2010 17:07 Mar 22, 2013 Jkt 229001 26 CFR Part 1 [REG–148500–12] RIN 1545–BL36 Shared Responsibility Payment for Not Maintaining Minimum Essential Coverage; Correction Internal Revenue Service (IRS), Treasury. ACTION: Correction to notice of proposed rulemaking and notice of public hearing. AGENCY: 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: SUMMARY: 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’’. PO 00000 Frm 00013 Fmt 4702 Sfmt 4702 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 E:\FR\FM\25MRP1.SGM 25MRP1

Agencies

[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]


=======================================================================
-----------------------------------------------------------------------

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 5[alpha]-pregnan-3[alpha]-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

[[Page 17896]]

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 (5[alpha]-pregnan-3[alpha]-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.

[[Page 17897]]

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.
    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\
---------------------------------------------------------------------------

    \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.
    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 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

[[Page 17898]]

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.
    3. The State of Current Scientific Knowledge Regarding the Drug or 
Other Substance: The chemical name of alfaxalone is 5[alpha]-pregnan-
3[alpha]-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[deg] to 171[deg]C. Alfaxalone 
has a poor water solubility (< 5 [micro]g/ml), but its water solubility 
increases to 80 mg/ml via complexation with cyclodextrins, especially 
2-hydroxypropyl-beta-cyclodextrin (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[supreg] 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[supreg], 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[supreg] (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

[[Page 17899]]

syringe. The intravenous self-administration of such large volume of 
Alfaxan[supreg] 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[supreg] 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) 5[alpha]-pregnan-3[alpha]-ol-11,20-dione (alfaxalone) has a low 
potential for abuse relative to the drugs or other substances in 
Schedule III;
    (2) 5[alpha]-pregnan-3[alpha]-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 5[alpha]-pregnan-3[alpha]-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 
5[alpha]-pregnan-3[alpha]-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

[[Page 17900]]

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

0
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.

0
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:


Sec.  1308.14  Schedule IV.

* * * * *
    (c) * * *
    (1) 5[alpha]-pregnan-3[alpha]-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