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Home , Alfadolone, Alfaxalone

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

22,109 hours due to this proposed 1. The panel transcript and other being placed in commercial regulatory change. meeting materials are available on distribution. FDA’s Web site at http://www.fda.gov/ IX. Proposed Effective Date Dated: March 19, 2013. AdvisoryCommittees/ Leslie Kux, FDA is proposing that any final order CommitteesMeetingMaterials/ Assistant Commissioner for Policy. based on this proposal become effective MedicalDevices/ on the date of its publication in the MedicalDevicesAdvisoryCommittee/ [FR Doc. 2013–06723 Filed 3–22–13; 8:45 am] Federal Register or at a later date if CirculatorySystemDevicesPanel/ BILLING CODE 4160–01–P stated in the final order. ucm240575.htm. X. Codification of Orders List of Subjects in 21 CFR Part 870 DEPARTMENT OF JUSTICE Prior to the amendments by FDASIA, Medical devices. section 515(b) of the FD&C Act provided Drug Enforcement Administration Therefore, under the Federal Food, for FDA to issue regulations to require Drug, and Cosmetic Act and under approval of an application for premarket 21 CFR Part 1308 authority delegated to the Commissioner approval for preamendments devices or of Food and Drugs, it is proposed that [Docket No. DEA–370] devices found substantially equivalent 21 CFR part 870 be amended as follows: to preamendments devices. Section Schedules of Controlled Substances: 515(b) of the FD&C Act, as amended by PART 870—CARDIOVASCULAR Placement of into Schedule FDASIA, provides for FDA to require DEVICES IV approval of an application for premarket AGENCY: approval for such devices by issuing a ■ 1. The authority citation for 21 CFR Drug Enforcement final order, following the issuance of a part 870 continues to read as follows: Administration, Department of Justice. ACTION: Notice of proposed rulemaking. proposed order in the Federal Register. Authority: 21 U.S.C. 351, 360, 360c, 360e, FDA will continue to codify the 360j, 371. SUMMARY: The Drug Enforcement requirement for an application for ■ 2. Section 870.5310 is amended by Administration (DEA) proposes the premarket approval, resulting from placement of 5a-pregnan-3a-ol-11,20- changes issued in a final order, in the revising the section heading and paragraphs (a) and (c) to read as follows: dione (alfaxalone) including its salts, Code of Federal Regulations (CFR). isomers, and salts of isomers whenever Therefore, under section 515(b)(1)(A) of § 870.5310 Automated external defibrillator the existence of such salts, isomers, and the FD&C Act, as amended by FDASIA, system. salts of isomers is possible, into in this proposed order, we are proposing (a) Identification. An automated Schedule IV of the Controlled to require approval of an application for external defibrillator (AED) system Substances Act (CSA). This proposed premarket approval for AEDs and if this consists of an AED device and its action is pursuant to the CSA which proposed order is finalized, we will accessories, i.e., battery, pad electrode requires that such actions be made on make the language in 21 CFR 870.5310 and, if applicable, an adapter. An AED the record after opportunity for a consistent with the final version of this system analyzes the patient’s hearing through formal rulemaking. proposed order. electrocardiogram, interprets the cardiac DATES: DEA will permit interested XI. Comments rhythm, and automatically delivers an persons to file written comments on this Interested persons may submit either electrical shock (fully automated AED), proposal pursuant to 21 CFR 1308.43(g). electronic comments regarding this or advises the user to deliver the shock Electronic comments must be submitted document to http://www.regulations.gov (semi-automated or shock advisory and written comments must be or written comments to the Division of AED) to treat ventricular fibrillation or postmarked on or before April 24, 2013. Dockets Management (see ADDRESSES). It pulseless ventricular tachycardia. Commenters should be aware that the is only necessary to send one set of * * * * * electronic Federal Docket Management comments. Identify comments with the (c) Date PMA or notice of completion System will not accept comments after docket number found in brackets in the of PDP is required. A PMA is required midnight Eastern Time on the last day heading of this document. Received to be submitted to the Food and Drug of the comment period. comments may be seen in the Division Administration by [A DATE WILL BE Interested persons, defined at 21 CFR of Dockets Management between 9 a.m. ADDED 90 DAYS AFTER DATE OF 1300.01 as those ‘‘adversely affected or and 4 p.m., Monday through Friday, and PUBLICATION OF A FUTURE FINAL aggrieved by any rule or proposed rule will be posted to the docket at http:// ORDER IN THE FEDERAL REGISTER], issuable pursuant to section 201 of the www.regulations.gov. for any automated external defibrillator Act (21 U.S.C. 811),’’ may file a request that was in commercial distribution for hearing pursuant to 21 CFR 1308.44 XII. Reference before May 28, 1976, or that has, by [A and in accordance with 21 CFR 1316.45 The following reference has been DATE WILL BE ADDED 90 DAYS and 1316.47. Requests for hearing and placed on display in the Division of AFTER DATE OF PUBLICATION OF A waivers of participation must be Dockets Management (see ADDRESSES) FUTURE FINAL ORDER IN THE received on or before April 24, 2013. and may be seen by interested persons FEDERAL REGISTER], been found to be ADDRESSES: To ensure proper handling between 9 a.m. and 4 p.m., Monday substantially equivalent to any of comments, please reference ‘‘Docket through Friday, and is available automated external defibrillator that No. DEA 370’’ on all electronic and electronically at http:// was in commercial distribution before written correspondence. DEA www.regulations.gov. (FDA has verified May 28, 1976. Any other automated encourages all comments be submitted the Web site address in this reference external defibrillator and automated electronically through http:// section, but FDA is not responsible for external defibrillator accessories, i.e., www.regulations.gov using the any subsequent changes to the Web site pad electrodes, adaptors, and batteries electronic comment form provided on after this document publishes in the shall have an approved PMA or that site. An electronic copy of this Federal Register.) declared completed PDP in effect before document and supplemental

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information to this proposed rule are may not be posted online or made of 1970, often referred to as the also available at the http:// available in the public docket. Controlled Substances Act and the www.regulations.gov Web site for easy Personal identifying information and Controlled Substances Import and reference. Paper comments that confidential business information Export Act (21 U.S.C. 801–971), as duplicate the electronic submission are identified and located as set forth above amended (hereinafter, ‘‘CSA’’). The not necessary as all comments will be redacted, and the comment, in implementing regulations for these submitted to www.regulations.gov will redacted form, will be posted online and statutes are found in Title 21 of the be posted for public review and are part placed in the DEA’s public docket file. Code of Federal Regulations (CFR), parts of the official docket record. Should Please note that the Freedom of 1300 to 1321. Under the CSA, controlled you, however, wish to submit written Information Act applies to all comments substances are classified in one of five comments via regular or express mail, received. If you wish to inspect the schedules based upon their potential for they should be sent to the Drug agency’s public docket file in person by abuse, their currently accepted medical Enforcement Administration, Attention: appointment, please see the ‘‘For use, and the degree of dependence the DEA Federal Register Representative/ Further Information Contact’’ paragraph, substance may cause. 21 U.S.C. 812. The OD, 8701 Morrissette Drive, Springfield, above. initial schedules of controlled Virginia 22152. All requests for hearing Request for Hearing, Notice of substances by statute are found at 21 and waivers of participation must be Appearance at or Waiver of U.S.C. 812(c) and the current list of sent to Drug Enforcement Participation in Hearing scheduled substances are published at Administration, Attention: Hearing 21 CFR Part 1308. Clerk/LJ, 8701 Morrissette Drive, In accordance with the CSA, this The CSA permits these schedules to Springfield, Virginia 22152. action is a formal rulemaking ‘‘on the be modified by providing that record after opportunity for a hearing.’’ scheduling of any drug or other FOR FURTHER INFORMATION CONTACT: John 21 U.S.C. 811(a). Such proceedings are substance may be initiated by the W. Partridge, Executive Assistant, Office conducted pursuant to the provisions of Attorney General: (1) On his own of Diversion Control, Drug Enforcement the Administrative Procedure Act (5 motion; (2) at the request of the Administration; Mailing Address: 8701 U.S.C. 556 and 557) and 21 CFR Secretary of Health and Human Services Morrissette Drive, Springfield, Virginia 1308.41. Pursuant to 21 CFR 1308.44(a)– (HHS); or (3) on the petition of any 22152; Telephone: (202) 307–7165. (c), requests for hearings, notices of interested party. 21 U.S.C. 811(a). The SUPPLEMENTARY INFORMATION: appearances, and waivers of Attorney General may, by rule, ‘‘add to Posting of Public Comments: Please participation may be submitted only by such a schedule or transfer between note that all comments received are interested persons, defined at 21 CFR such schedules any drug or other considered part of the public record and 1300.01 as those ‘‘adversely affected or substance if he (A) finds that such drug made available for public inspection aggrieved by any rule or proposed rule or other substance has a potential for online at http://www.regulations.gov issuable pursuant to section 201 of the abuse, and (B) makes with respect to and in the DEA’s public docket. Such Act (21 U.S.C. 811).’’ Such requests or such drug or other substance the information includes personal notices must conform to the findings prescribed by subsection (b) of identifying information (such as your requirements of 21 CFR 1308.44(a) or (b) section 812 of this title for the schedule name, address, etc.) voluntarily and 1316.47 or 1317.48, as applicable. A in which such drug is to be submitted by the commenter. request or notice should state, with placed* * *.’’ 21 U.S.C. 811(a). The particularity, the interest of the person findings required for the placement of a If you want to submit personal in the proceeding and the objections or controlled substance in Schedule IV are: identifying information (such as your issues, if any, concerning which the the drug or other substance has a low name, address, etc.) as part of your person desires to be heard. Any waiver potential for abuse relative to the drugs comment, but do not want it to be must conform to the requirements of 21 or other substances in Schedule III; the posted online or made available in the CFR 1308.44(c) and 1316.49, including drug or substance has a currently public docket, you must include the a written statement regarding the accepted medical use in treatment in the phrase ‘‘PERSONAL IDENTIFYING interested person’s position on the United States; and abuse of the drug or INFORMATION’’ in the first paragraph matters of fact and law involved in any other substance may lead to limited of your comment. You must also place hearing. physical dependence or psychological all of the personal identifying Please note that pursuant to 21 U.S.C. dependence relative to the drugs or information you do not want posted 811(a), the purpose and subject matter other substances in Schedule III. 21 online or made available in the public of the hearing is restricted to ‘‘(A) U.S.C. 812(b)(4). docket in the first paragraph of your find[ing] that such drug or other Background comment and identify what information substance has a potential for abuse, and you want redacted. (B) mak[ing] with respect to such drug Alfaxalone (5a-pregnan-3a-ol-11,20- If you want to submit confidential or other substance the findings dione, previously spelled alphaxalone), business information as part of your prescribed by subsection (b) of section a substance with central nervous system comment, but do not want it to be 812 of this title for the schedule in (CNS) properties, is a posted online or made available in the which such drug is to be placed* * *.’’ that is a derivative of 11- public docket, you must include the Requests for hearing, notices of alpha-hydroxy-. A New phrase ‘‘CONFIDENTIAL BUSINESS appearance at the hearing, and waivers Animal Drug Application (NADA) for INFORMATION’’ in the first paragraph of participation in the hearing should be alfaxalone, as an intravenous injectable of your comment. You must also submitted to DEA using the address , was recently approved by prominently identify confidential information provided above. the Food and Drug Administration business information to be redacted (FDA) for the induction and within the comment. If a comment has Legal Authority maintenance of and for so much confidential business The DEA implements and enforces induction of anesthesia followed by information that it cannot be effectively Titles II and III of the Comprehensive maintenance of anesthesia with an redacted, all or part of that comment Drug Abuse Prevention and Control Act inhalant anesthetic, in and .

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Alfaxalone primarily acts as an agonist significant diversions from legitimate According to the HHS review, at the gamma-aminobutyric acid channels, significant use contrary to or alfaxalone acts directly through the (GABA) -channel complex, with without medical advice, or that it has a GABA–A receptor-channel complex and a mechanism of action at this site substantial capability of creating hazards to increases the probability that the the health of the user or to the safety of the channel will enter into naturally- similar to that of like community.1 (Schedule IV) and occurring open states of relatively long (Schedule IV), According to HHS, alfaxalone is duration. The activity of alfaxalone on such as thought to interact with the gamma- GABA receptors is similar to that of (Schedule IV) and (Schedule aminobutyric acid subtype A (GABA)-A barbiturates like phenobarbital and IV), as well as the anesthetic agents, receptors, and to enhance the activity of methohexital (Schedule IV) as well as (Schedule IV under GABA, the principal inhibitory anesthetic agents like propofol consideration) and neurotransmitter in the central nervous (Schedule IV under consideration) and (Schedule IV). system (CNS). This pharmacological fospropofol (Schedule IV). Furthermore, evidence suggests that the abuse similar to benzodiazepines such as Proposed Determination to Schedule potential of alfaxalone is comparable to diazepam and midazolam, alfaxalone Alfaxalone other drugs with a similar mechanism of can also increase the frequency of single Pursuant to 21 U.S.C. 811(a), action, and similar anesthetic channel openings. Additionally proceedings to add a drug or substance properties, such as midazolam alfaxalone has been shown to inhibit T- to those controlled under the CSA may (Schedule IV), methohexital (Schedule type calcium channels. Alfaxalone does be initiated by request of the Secretary IV), fospropofol (Schedule IV) and not affect (CB1 subtype), of HHS. On July 17, 2012, HHS propofol (Schedule IV under dopamine (D1-, D2-, D3-, D4- and D5- provided DEA with a scientific and consideration). Similar to the above subtype), glutamate (AMPA, kainate, medical evaluation document prepared mentioned Schedule IV - and NMDA subtype), (mu, kappa by FDA entitled ‘‘Basis for the , alfaxalone acts as an and delta subtype), and serotonin (1A, Recommendation for Control of inhibitor on the CNS and produces 2B, 2C, 3, 5A and 6 subtype) receptors, alfaxalone in Schedule IV of the sedation and anesthesia. Based on the nor does it affect the transporters for Controlled Substances Act.’’ Pursuant to similarities between propofol and dopamine, norepinephrine and 21 U.S.C. 811(b), this document alfaxalone regarding their mechanisms serotonin. In addition, alfaxalone does contained an eight-factor analysis of the of action and their intended routes of not significantly bind to major abuse potential of alfaxalone, along with administration for clinical use, and the nuclear receptors including androgens, HHS’ recommendation to control fact that 96% of propofol abuse reports estrogens, or alfaxalone under Schedule IV of the involved abuse by medical progesterone receptors. CSA. professionals, HHS reasoned that Pre-clinical behavioral studies In response, DEA conducted an eight- alfaxalone abuse might be by medical showed that, similar to factor analysis of alfaxalone’s abuse professionals who have access to the (Schedule IV), potential pursuant to 21 U.S.C. 811(c). drug and have knowledge in the alfaxalone produces anxiolytic-like Included below is a brief summary of intravenous administration of drugs. behavioral effects in rat models of each factor as analyzed by HHS and There are no published studies of anxiety, such as the elevated plus maze, DEA, and as considered by DEA in the abuse potential for alfaxalone in the conflict test and restraint stress. In scheduling decision. Please note that humans. However, there is evidence a published drug discrimination study, both the DEA and HHS analyses are that alfaxalone produces the sedative- in which rats were trained to available in their entirety under midazolam-like discriminative discriminate midazolam (Schedule IV) ‘‘Supporting and Related Material’’ of stimulus effects in rats and monkeys, as from saline, alfaxalone fully generalized the public docket for this rule at well as some ethanol-like effects in rats. to the midazolam discriminative cue. www.regulations.gov under docket Based on the pharmacological These results are consistent with number DEA–370. similarities to other Schedule IV potent previously published studies showing 1. The Drug’s Actual or Relative sedative-hypnotic drugs, such as ethanol-like discriminative stimulus Potential for Abuse: The abuse potential midazolam, methohexital and effects of alfaxalone and with other of alfaxalone is associated with its fospropofol, the consequences of abuse studies showing that other ability to evoke pharmacological effects of alfaxalone can be predicted to be have -like or similar to those evoked by the Schedule similar to those drugs mentioned above. -like discriminative IV substances such as fospropfol, Furthermore, abuse and misuse of these stimulus effects in rats and monkeys. propofol (Schedule IV under drugs might result in death. The overt This pharmacological profile of consideration), and midazolam. behavioral effects and adverse events alfaxalone is consistent with Since alfaxalone is a new veterinary produced by alfaxalone in animals are neurosteroids with GABAergic effects. product and has not been marketed in similar to those caused by Schedule IV According to the HHS review, the oral the United States, information on actual benzodiazepines and barbiturates. administration of alfaxalone as abuse of alfaxalone in the United States In summary, the relative abuse compared to its intravenous is not available. However, the legislative potential of alfaxalone can be administration is 100 times less potent history of the CSA offers another considered no greater than the Schedule for producing midazolam-like effects. methodology for assessing a drug or IV substances such as fospropfol, Alfaxalone has a low oral bioavailability substance’s potential for abuse: propofol, and midazolam and less than (about 2%). It has been shown that an intravenous dose of about 50 mg of The drug or drugs containing such a that of other in Schedule III. 2. Scientific Evidence of the Drug’s alfaxalone results in anesthesia in substance are new drugs so related in their humans with a plasma level of 3 mg/L. action to a drug or drugs already listed as Pharmacological Effects, If Known: having a potential for abuse to make it likely Accordingly, an oral dose of about 2500 that the drug will have the same potentiality 1 Comprehensive Drug Abuse Prevention and mg might be expected to result in for abuse as such drugs, thus making it Control Act of 1970, H.R. Rep. No. 91–1444, 91st anesthesia at the plasma level of 3 mg/ reasonable to assume that there may be Cong., Sess. 1 (1970); 1970 U.S.C.C.A.N. 4566, 4601. L in humans, and thus oral doses of 250

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to 800 mg of alfaxalone should be min/kg in dogs and 28 ml/min/kg in midazolam (Schedule IV) and propofol needed to produce a sub-anesthetic cats. The primary routes of elimination (Schedule IV under consideration). intoxication at plasma levels in a range in the rat are biliary (65%) and renal 5. The Scope, Duration, and of 0.3 to 1.0 mg/L. For a vial containing (35%) routes. The half-life of alfaxalone Significance of Abuse: As mentioned 100 mg of alfaxalone for an oral use, an in humans is about 35 minutes. The above, a comprehensive search by DEA amount of 2.5 to 8 vials would be major metabolites in humans are of the major national drug abuse needed to produce a ‘‘high’’. glucuronidated and the primary route of monitoring programs found no evidence As stated in the HHS review, self- elimination is through renal (80%). Oral of human abuse of alfaxalone in the U.S. administration studies in animals with bioavailability of alfaxalone is about 2% However, as stated in the HHS review, , , as compared to its intravenous the ‘‘suspicious order monitor system’’ endogenous metabolites of progesterone administration in humans. A clinical of the U.S. distributor of alfaxalone, will and a neuroactive steroid, Co 8–7071, study showed that an intravenous be utilized to monitor the diversion of showed that these substances produce administration of 30 mg alfaxalone this product. This monitoring system of some positive reinforcing effects in rats evaluates order quantities, buying produced plasma levels of about 3 mg/ and rhesus monkeys. These substances, patterns, and customer class regarding L, accompanied by anesthesia in similar to alfaxalone, positively orders of unusual volume that could humans. The veterinary alfaxalone modulate GABA–A receptors by binding indicate diversion. As part of their at the neurosteroid modulatory site. product that is recently approved by the monitoring, daily searches of the DEA HHS stated that these data are FDA contains 100 mg/vial (a vial of 10 Web site for new abuse issues and for predictive of abuse potential of ml formulated solution, 10 mg/ml of abuse-related data from HHS’s alfaxalone. HHS review also cited recent alfaxalone) which would be sufficient to Substance Abuse and Mental Health evidence that alpha4, beta3 and delta produce anesthesia in two individuals Administration Services (SAMHSA) GABA–A receptors are modulated by when administered intravenously. HHS will be conducted. Additionally, the both THDOC, a neurosteroid, and also states that because alfaxalone can Sponsor will provide FDA with propofol. Based on this potential be abused at subanesthetic doses, a 100 pharmacovigilance information for both overlap in cellular targets, comparable mg vial of alfaxalone drug product animal and human adverse events from kinetic profiles, and similar clinical administered intravenously could be all markets. indications for propofol and alfaxalone, used repeatedly by the same individual, 6. What, if any, Risk There is to the HHS reasoned that alfaxalone may or by multiple individuals, who Public Health: According to the HHS produce reinforcing effects similar to intended to abuse the substance. review, the public health risks of those of propofol. 4. Its History and Current Pattern of alfaxalone are mostly risks to the In summary, alfaxalone, similar to Abuse: Since alfaxalone is a new individual abuser and the risks are chlordiazepoxide (Schedule IV), has veterinary product and has not been similar to those associated with the anxiolytic activity in animals. marketed in the United States, abuse of other sedative hypnotics and Alfaxalone produced midazolam-like information on actual abuse of CNS , such as midazolam (Schedule IV) discriminative stimulus alfaxalone in the United States is not and methohexital. Abuse of alfaxalone effects in rats, and it may share available. Because alfaxalone has been may lead to the death of the abuser or propofol’s reinforcing effects. The marketed under the trade name other adverse events that affect abuse-related neuropharmacology Alfaxan® in the (UK) behavior, reaction ability and timing in profile of alfaxalone is similar to that of operating a motor vehicle or machinery. since 2007, the Sponsor submitted to Schedule IV substances. As an anesthetic, the adverse events HHS the results of a search of 3. The State of Current Scientific (AEs) that are likely to result from pharmacovigilance reports to the UK Knowledge Regarding the Drug or Other alfaxalone use are usually similar to Veterinary Medicines Directorate. Substance: The chemical name of those arising from the use of most According to HHS, the Sponsor also alfaxalone is 5a-pregnan-3a-ol-11, 20- general . These events dione. Alfaxalone has a molecular provided information obtained from include , bradycardia, bradypnea, several other sources regarding formula of C21H32O3 and a molecular hypertension, , weight of 332.5 g/mol, and a melting diversion and abuse of alfaxalone. None hypothermia, , unacceptable point of 165° to 171°C. Alfaxalone has of the above sources contained evidence anesthesia quality, tachycardia and a poor water solubility (< 5 mg/ml), but of abuse of alfaxalone by humans. emesis. These AEs were found in animal its water solubility increases to 80 mg/ According to the HHS review, a search studies involving cats and dogs. ml via complexation with , conducted by the Sponsor of the Alfaxalone, as anesthetic product if especially 2-hydroxypropyl-beta- publically-available pharmacovigilance used in excess, carries potential for (2HPCD). According to the database provided by the UK’s overdose. HHS review, the alfaxalone product for Medicines and Healthcare Products HHS cited two cases involving the veterinary anesthesia will be formulated Regulatory Agency (MHRA) Web site accidental overdose of the alfaxalone as a 10 mg/ml solution of alfaxalone in also did not produce reports related to human product, Althesin®, a human 2HPCD (80 mg/ml), sodium phosphate alfaxalone abuse. DEA conducted a product containing combination of buffer and water, adjusted to a pH of 6.5 comprehensive search of several major alfaxalone/ which was to 7. According to the Sponsor’s national drug abuse monitoring previously withdrawn from market. information cited by the HHS review, programs and found no evidence of HHS stated that the occurrence of an the processes involved in the synthesis alfaxalone abuse. It may be due to the accidental or purposeful overdose of and purification of alfaxalone are highly fact that alfaxalone-containing products Alfaxan® (containing 10 mg/ml of complex and require expertise in have not been marketed in the United alfaxalone) is unlikely. HHS reasoned chemistry manufacture. States to date. However, alfaxalone’s that if a person were trying to duplicate According to the HHS, the half-lives pharmacological properties suggest that the same accidental overdose of of alfaxalone are 24–37 and 45–77 its pattern of abuse would be similar to injectable alfaxalone solution, he or she minutes in dogs and cats, respectively. other drugs used in maintenance and would be required to draw up a large The clearance of alfaxalone is 59 ml/ induction of anesthesia, such as volume of alfaxalone solution into the

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syringe. The intravenous self- Proposed Determination of Appropriate with 21 CFR 1301.71, 1301.72(b), (c), administration of such large volume of Schedule and (d), 1301.73, 1301.74, 1301.75(b) ® Alfaxan would be a very difficult if not The CSA establishes five schedules of and (c), 1301.76, and 1301.77. impossible to perform, as the person controlled substances known as Labeling and Packaging. All labels would likely be anesthetized after the Schedules I, II, III, IV, and V. The statute and labeling for commercial containers first 4.2 ml of the . If a person of alfaxalone which is distributed on or ® outlines the findings required to place a were to drink Alfaxan to try to cause drug or other substance in any after the effective date of the finalization overdose, it would require 100 times particular schedule. 21 U.S.C. 812(b). of this rule would need to be in more drug because of alfaxalone’s poor After consideration of the analysis and accordance with 21 CFR 1302.03– oral bioavailability (1–2%). According recommendations of the Assistant 1302.07, pursuant to 21 U.S.C. 825. to HHS, little is known about other Secretary for Health of HHS and review Inventory. Every registrant required to health effects that might occur in of all available data, the Administrator keep records and who possesses any someone abusing the drug chronically. of DEA, pursuant to 21 U.S.C. 812(b)(4), quantity of alfaxalone would be In summary, the public health risks of finds that: required to keep an inventory of all alfaxalone abuse are similar to those (1) 5a-pregnan-3a-ol-11,20-dione stocks of alfaxalone on hand pursuant to associated with the abuse of other (alfaxalone) has a low potential for 21 U.S.C. 827 and in accordance with 21 sedative hypnotics and CNS abuse relative to the drugs or other CFR 1304.03, 1304.04, and 1304.11. depressants, such as midazolam and substances in Schedule III; Every registrant who desires registration methohexital which are controlled in (2) 5a-pregnan-3a-ol-11,20-dione in Schedule IV for alfaxalone would be Schedule IV of the CSA and propofol (alfaxalone) has a currently accepted required to conduct an inventory of all (Schedule IV under consideration). The medical use in treatment in the United stocks of the substance on hand at the major adverse events of these States. Alfaxalone was approved for time of registration. anesthetics include respiratory marketing by FDA as a veterinary Records. All registrants would be depression and deaths. anesthetic product for the induction and required to keep records pursuant to 21 U.S.C. 827 and in accordance with 21 7. Its Psychic or Physiological maintenance of anesthesia in cats and in dogs; and CFR 1304.03, 1304.04, 1304.21, 1304.22, Dependence Liability: According to and 1304.23. HHS, studies of abrupt discontinuation (3) abuse of 5a-pregnan-3a-ol-11,20- dione (alfaxalone) may lead to limited Prescriptions. Alfaxalone or products of alfaxalone were not conducted. containing alfaxalone would be required However, a study cited (McMohan et al., physical dependence or psychological dependence relative to the drugs or to be distributed or dispensed pursuant 2007) by the HHS review suggested the to 21 U.S.C. 829 and in accordance with ability of alfaxalone to produce physical other substances in Schedule III. Based on these findings, the 21 CFR 1306.03–1306.06, 1306.08, dependence. McMahon and his 1308.09, and 1306.21–1306.27. associates found that alfaxalone reduced Administrator of DEA concludes that 5a-pregnan-3a-ol-11,20-dione Importation and Exportation. All the discriminative cue produced by importation and exportation of -precipitated withdrawal (alfaxalone) including its salts, isomers and salts of isomers, whenever the alfaxalone would need to be done in following chronic administration of accordance with 21 CFR part 1312, benzodiazepines such as diazepam or existence of such salts, isomers, and salts of isomers is possible, warrants pursuant to 21 U.S.C. 952, 953, 957, and (both Schedule IV) in Rhesus 958. monkeys (McMahon et al., 2007). The control in Schedule IV of the CSA (21 U.S.C. 812(b)(4)). Criminal Liability. Any activity with HHS review concludes that alfaxalone alfaxalone not authorized by, or in can decrease withdrawal resulting from Requirements for Handling Alfaxalone violation of, the CSA occurring on or chronic administration of other positive If this rule is finalized as proposed, after effective date of the finalization of GABA–A receptor modulators. this proposed rule would be unlawful. According to HHS, there is no data alfaxalone would be subject to the CSA available on the effects of abrupt and the Controlled Substances Import Regulatory Analyses and Export Act (CSIEA) regulatory discontinuation of alfaxalone because, Executive Orders 12866 and 13563 as an anesthetic, it is not used controls and administrative, civil and chronically and not available for criminal sanctions applicable to the In accordance with 21 U.S.C. 811(a), chronic use. manufacture, distribution, dispensing, this proposed scheduling action is importing and exporting of a Schedule subject to formal rulemaking procedures 8. Whether the Substance is an IV controlled substance, including the done ‘‘on the record after opportunity Immediate Precursor of a Substance following: for a hearing,’’ which are conducted Already Controlled Under the CSA: Registration. Any person who pursuant to the provisions of 5 U.S.C. Alfaxalone is not considered an manufactures, distributes, dispenses, 556 and 557. The CSA sets forth the immediate precursor of any controlled imports, exports, engages in research or criteria for scheduling a drug or other substance of the CSA as defined by 21 conducts instructional activities with substance. Such actions are exempt U.S.C 802(23). alfaxalone or who desires to from review by the Office of Conclusion: Based on consideration of manufacture, distribute, dispense, Management and Budget pursuant to the scientific and medical evaluation import, export, engage in research or Section 3(d)(1) of Executive Order and accompanying recommendation of conduct instructional activities with 12866 and the principles reaffirmed in HHS, and based on DEA’s consideration alfaxalone would need to be registered Executive Order 13563. of its own eight-factor analysis, DEA to conduct such activities pursuant to finds that these facts and all relevant 21 U.S.C. 822 and 958 and in Executive Order 12988 data constitute substantial evidence of accordance with 21 CFR part 1301. This proposed regulation meets the potential for abuse of alfaxalone. As Security. Alfaxalone would be subject applicable standards set forth in such, DEA hereby proposes to schedule to Schedule III–V security requirements Sections 3(a) and 3(b)(2) of Executive alfaxalone as a controlled substance and would need to be manufactured, Order 12988 Civil Justice Reform to under the CSA. distributed, and stored in accordance eliminate ambiguity, minimizes

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litigation, establish clear legal DEPARTMENT OF THE TREASURY 2. On page 7316, in the preamble, standards, and reduce burden. column 3, under the paragraph heading Internal Revenue Service ‘‘Computation of Shared Responsibility Executive Order 13132 Payment’’, lines 5 and 6 from the top of 26 CFR Part 1 This proposed rulemaking does not the column, the language ‘‘the following preempt or modify any provision of [REG–148500–12] amounts: (1) The flat dollar amount, or (2) the percentage of’’ is corrected to State law; nor does it impose RIN 1545–BL36 read ‘‘the following amounts: (1) the flat enforcement responsibilities on any dollar amount, or (2) the percentage of’’. State; nor does it diminish the power of Shared Responsibility Payment for Not 3. On page 7316, in the preamble, any State to enforce its own laws. Maintaining Minimum Essential column 3, under the paragraph heading Accordingly, this rulemaking does not Coverage; Correction ‘‘Minimum Essential Coverage’’, lines 3 have federalism implications warranting AGENCY: Internal Revenue Service (IRS), through 32 of the third and fourth full the application of Executive Order Treasury. paragraph of the column, the language 13132. ‘‘following: (1) Coverage under a ACTION: Correction to notice of proposed specified government sponsored Executive Order 13175 rulemaking and notice of public program, (2) coverage under an eligible hearing. This proposed rule will not have employer-sponsored plan, (3) coverage tribal implications and will not impose SUMMARY: This document contains under a health plan offered in the substantial direct compliance costs on corrections to a notice of proposed individual market within a State, (4) Indian tribal governments. rulemaking and notice of public hearing coverage under a grandfathered health (REG–148500–12) that was published in plan, and (5) other health benefits Paperwork Reduction Act of 1995 the Federal Register on Friday, coverage that the Secretary of Health February 1, 2013 (78 FR 7314). The and Human Services, in coordination This action does not impose a new with the Secretary, recognizes for collection of information under the proposed regulations relate to the requirement to maintain minimum purposes of section 5000A(f). Paperwork Reduction Act of 1995, 44 Under section 5000A(f)(1)(A), essential coverage enacted by the U.S.C. 3501–3521. specified government sponsored Patient Protection and Affordable Care programs include the following: (1) The Act and the Health Care and Education List of Subjects in 21 CFR Part 1308 Medicare program under part A of title Reconciliation Act of 2010, as amended XVIII of the Social Security Act, (2) the Administrative practice and by the TRICARE Affirmation Act and procedure, Drug traffic control, Medicaid program under title XIX of the Public Law 111–173. These proposed Social Security Act, (3) the Children’s Reporting and recordkeeping regulations provide guidance on the requirements. Health Insurance Program (CHIP) under liability for the shared responsibility title XXI of the Social Security Act, (4) For the reasons set out above, 21 CFR payment for not maintaining minimum medical coverage under chapter 55 of part 1308 is proposed to be amended to essential coverage. title 10, United States Code, including read as follows: FOR FURTHER INFORMATION CONTACT: Sue- the TRICARE program, (5) veterans Jean Kim or John B. Lovelace, (202) health care programs under chapter 17 PART 1308—SCHEDULES OF 622–4960 (not a toll free number). or 18 of title 38, as determined by the CONTROLLED SUBSTANCES SUPPLEMENTARY INFORMATION: Secretary of Veterans Affairs, in coordination with the Secretary of Background ■ 1. The authority citation for 21 CFR Health and Human Services and the Part 1308 continues to read as follows: The notice of proposed rulemaking Secretary of Treasury, (6) a health plan’’ and notice of public hearing (REG– is corrected to read ‘‘following: (1) Authority: 21 U.S.C. 811, 812, 871(b), 148500–12) that is the subject of these coverage under a specified government unless otherwise noted. corrections are under Section 5000A of sponsored program; (2) coverage under ■ 2. Section 1308.14 is amended by the Internal Revenue Code. an eligible employer-sponsored plan; (3) coverage under a health plan offered in redesignating paragraphs (c)(1) through Need for Correction (c)(53) as paragraphs (c)(2) through the individual market within a State; (4) (c)(54) and adding a new paragraph As published, the notice of proposed coverage under a grandfathered health (c)(1) as follows: rulemaking and notice of public hearing plan; and (5) other health benefits (REG–148500–12) contains errors that coverage that the Secretary of Health § 1308.14 Schedule IV. may prove to be misleading and are in and Human Services, in coordination * * * * * need of clarification. with the Secretary, recognizes for purposes of section 5000A(f). (c) * * * Correction of Publication Under section 5000A(f)(1)(A), (1) 5a-pregnan-3a-ol-11,20-dione Accordingly, the notice of proposed specified government sponsored (Alfaxalone) * * * (2731) rulemaking and notice of public hearing programs include the following: (1) the * * * * * (REG–148500–12), that was the subject Medicare program under part A of title of FR Doc. 2013–02141, is corrected as XVIII of the Social Security Act; (2) the Dated: March 15, 2013. follows: Medicaid program under title XIX of the Michele M. Leonhart, 1. On page 7316, in the preamble, Social Security Act; (3) the Children’s Administrator. column 1, under the paragraph heading Health Insurance Program (CHIP) under [FR Doc. 2013–06651 Filed 3–22–13; 8:45 am] ‘‘Exempt Individuals’’, line 7 of the title XXI of the Social Security Act; (4) third full paragraph, the language medical coverage under chapter 55 of BILLING CODE 4410–09–P ‘‘consultation with the Secretary of ’’ is title 10, United States Code, including corrected to read ‘‘consultation with the the TRICARE program; (5) veterans Secretary of the’’. health care programs under chapter 17

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