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Airmen. The effective date and time will recommendation from the Assistant DEA Federal Register Representative/ thereafter be continuously published in the Secretary for Health of the Department ODW, 8701 Morrissette Drive, Airport/Facility Directory. of Health and Human Services (HHS) Springfield, Virginia 22152. All requests Paragraph 6002 Class E airspace and on an evaluation of all other for hearing and waivers of participation Designated as Surface Areas. relevant data by the DEA. If finalized, must be sent to: Drug Enforcement * * * * * this action would impose the regulatory Administration, Attention: Hearing controls and administrative, civil, and Clerk/LJ, 8701 Morrissette Drive, AWP CA E2 Salinas, CA [Removed] criminal sanctions of Schedule III Springfield, Virginia 22152. Paragraph 6004 Class E airspace areas controlled substances on persons who FOR FURTHER INFORMATION CONTACT: designated as an extension to Class D surface handle (manufacture, distribute, Ruth A. Carter, Chief, Policy Evaluation area. dispense, import, export, engage in and Analysis Section, Office of * * * * * research, conduct instructional Diversion Control, Drug Enforcement activities, and possess) or propose to AWP CA E4 Salinas, CA [Modified] Administration; Mailing Address: 8701 handle perampanel. Salinas Municipal Airport, CA Morrissette Drive, Springfield, Virginia DATES: (Lat. 36°39′46″ N., long. 121°36′23″ W.) Interested persons may file 22152; Telephone: (202) 598–6812. written comments on this proposal in That airspace extending upward from the SUPPLEMENTARY INFORMATION: surface within 1.8 miles each side of the 150° accordance with 21 CFR 1308.43(g). bearing of Salinas Municipal Airport Comments must be submitted Posting of Public Comments extending from the 4.3-mile radius of the electronically or postmarked on or Please note that comments received in airport to 8 miles southeast of the airport. before November 21, 2013. Commenters response to this docket are considered This Class E airspace area is effective during should be aware that the electronic part of the public record and will be the specific dates and times established in Federal Docket Management System made available for public inspection advance by a Notice to Airmen. The effective will not accept comments after midnight and posted at http:// date and time will thereafter be continuously Eastern Time on the last day of the published in the Airport/Facility Directory. www.regulations.gov. Such information comment period. includes personal identifying Paragraph 6005 Class E airspace areas Interested persons, defined as those information (such as your name, extending upward from 700 feet or more ‘‘adversely affected or aggrieved by any address, etc.) voluntarily submitted by above the surface of the earth. rule or proposed rule issuable pursuant the commenter. * * * * * to section 201 of the Act (21 U.S.C. If you want to submit personal AWP CA E5 Salinas, CA [New] 811),’’ 21 CFR 1300.01, may file a identifying information (such as your request for hearing or waiver of name, address, etc.) as part of your Salinas Municipal Airport, CA participation pursuant to 21 CFR (Lat. 36°39′46″ N., long. 121°36′23″ W.) comment, but do not want it to be made 1308.44 and in accordance with 21 CFR public, you must include the phrase That airspace extending upward from 700 1316.45 and 1316.47. Requests for feet above the surface within a 13.1-mile ‘‘PERSONAL IDENTIFYING radius of Salinas Municipal Airport. hearing, notices of appearance, and INFORMATION’’ in the first paragraph waivers of an opportunity for a hearing Issued in Seattle, Washington, on of your comment. You must also place or to participate in a hearing must be all the personal identifying information September 26, 2013. received on or before November 21, Johanna Forkner, you do not want made publicly 2013. available in the first paragraph of your Acting Manager, Operations Support Group, Western Service Center. ADDRESSES: To ensure proper handling comment and identify what information of comments, please reference ‘‘Docket you want redacted. [FR Doc. 2013–24744 Filed 10–21–13; 8:45 am] No. DEA–374’’ on all electronic and If you want to submit confidential BILLING CODE 4910–13–P written correspondence. The DEA business information as part of your encourages that all comments be comment, but do not want it to be made submitted through the Federal publicly available, you must include the DEPARTMENT OF JUSTICE eRulemaking Portal, which provides the phrase ‘‘CONFIDENTIAL BUSINESS Drug Enforcement Administration ability to type short comments directly INFORMATION’’ in the first paragraph into the comment field on the Web page of your comment. You must also 21 CFR Part 1308 or attach a file for lengthier comments. prominently identify confidential Go to business information to be redacted [Docket No. DEA–374] http://www.regulations.gov and follow within the comment. If a comment has the on-line instructions at that site for so much confidential business Schedules of Controlled Substances: submitting comments. An electronic information that it cannot be effectively Placement of Perampanel into copy of this document and redacted, all or part of that comment Schedule III supplemental information to this may not be made publicly available. AGENCY: Drug Enforcement proposed rule are also available at Comments containing personally Administration, Department of Justice. http://www.regulations.gov for easy identifying information or confidential ACTION: Notice of proposed rulemaking. reference. Paper comments that business information identified as duplicate electronic submissions are not directed above will be made publicly SUMMARY: The Drug Enforcement necessary. All comments submitted to available in redacted form. The Freedom Administration (DEA) proposes to place http://www.regulations.gov will be of Information Act (FOIA) applies to all the substance perampanel [2-(2-oxo-1- posted for public review and are part of comments received. If you wish to phenyl-5-pyridin-2-yl-1,2- the official docket record. Should you, personally inspect the comments and dihydropyridin-3-yl) benzonitrile however, wish to submit written materials received or the supporting hydrate], including its salts, isomers, comments, in lieu of electronic documentation the DEA used in and salts of isomers, into Schedule III of comments, they should be sent via preparing the proposed action, these the Controlled Substances Act (CSA). regular or express mail to: Drug materials will be available for public This proposed action is based on a Enforcement Administration, Attention: inspection by appointment. To arrange

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a viewing, please see the FOR FURTHER regulations are designed to prevent, marketed in the United States under the INFORMATION CONTACT paragraph, above. detect, and eliminate the diversion of trade name FYCOMPA®. Perampanel is controlled substances and listed a non-competitive AMPA (a-amino-3- Requests for Hearing, Notice of chemicals into the illicit market while hydroxy-5-methyl-4-isoxazolepropionic Appearance at Hearing, or Waiver of providing for legitimate medical, acid)-type glutamate receptor Participation in Hearing scientific, research, and industrial needs antagonist. Perampanel was approved in Pursuant to the provisions of the CSA of the United States. Controlled Europe in May 2012 and has been (21 U.S.C. 811(a)), this action is a formal substances have the potential for abuse marketed there since July 2012. rulemaking ‘‘on the record after and dependence and are controlled to Proposed Determination to Schedule opportunity for a hearing.’’ Such protect the public health and safety. proceedings are conducted pursuant to Under the CSA, controlled substances Perampanel the provisions of the Administrative are classified into one of five schedules Pursuant to 21 U.S.C. 811(a), Procedure Act (APA) (5 U.S.C. 551– based upon their potential for abuse, proceedings to add a drug or substance 559), 21 CFR 1308.41–1308.45, and 21 their currently accepted medical use, to those controlled under the CSA may CFR part 1316 subpart D. In accordance and the degree of dependence the be initiated by request of the Secretary with 21 CFR 1308.44(a)–(c), requests for substance may cause. 21 U.S.C. 812. The of the Department of Health and Human a hearing, notices of appearance, and initial schedules of controlled Services (HHS). On January 22, 2013, waivers of an opportunity for a hearing substances established by Congress are the HHS recommended that the DEA or to participate in a hearing may be found at 21 U.S.C. 812(c), and the add perampanel to Schedule III of the submitted only by interested persons, current list of all scheduled substances CSA and provided the DEA with the defined as those ‘‘adversely affected or is published at 21 CFR part 1308. scientific and medical evaluation aggrieved by any rule or proposed rule Pursuant to 21 U.S.C. 811(a)(1), the document, ‘‘Basis for the issuable pursuant to section 201 of the Attorney General may, by rule, ‘‘add to Recommendation for Control of Act (21 U.S.C. 811).’’ 21 CFR 1300.01. such a schedule or transfer between Perampanel and Its Salts in Schedule III Such requests or notices must conform such schedules any drug or other of the Controlled Substances Act.’’ to the requirements of 21 CFR substance if he (A) finds that such drug Following consideration of the eight 1308.44(a) or (b) and 1316.47 or or other substance has a potential for factors determinative of control under 1316.48, as applicable, and include a abuse, and (B) makes with respect to the CSA, with findings related to the statement of the interest of the person in such drug or other substance the substance’s abuse potential, legitimate the proceeding and the objections or findings prescribed by [21 U.S.C. 812(b)] medical use, and dependence liability, issues, if any, concerning which the for the schedule in which such drug is the HHS recommended that perampanel person desires to be heard. Any waiver to be placed . . . .’’ Pursuant to 28 CFR be controlled in Schedule III of the CSA. must conform to the requirements of 21 0.100(b), the Attorney General has In response, the DEA reviewed the CFR 1308.44(c) and 1316.49, including delegated this scheduling authority to scientific and medical evaluation and a written statement regarding the the Administrator of the DEA who has scheduling recommendation provided interested person’s position on the further delegated this authority to the by the HHS, and all other relevant data, matters of fact and law involved in any Deputy Administrator of the DEA under and completed an eight factor review hearing. 28 CFR 0.104. document pursuant to 21 U.S.C. 811(c). Please note that pursuant to 21 U.S.C. The CSA provides that scheduling of Included below is a brief summary of 811(a), the purpose and subject matter any drug or other substance may be each factor as analyzed by the HHS and of a hearing held in relation to this initiated by the Attorney General (1) on the DEA, and as considered by the DEA rulemaking is restricted to ‘‘(A) find[ing] his own motion; (2) at the request of the in its proposed scheduling decision. that such drug or other substance has a Secretary of the Department of Health Please note that the DEA and HHS potential for abuse, and (B) mak[ing] and Human Services (HHS); or (3) on analyses are available in their entirety with respect to such drug or other the petition of any interested party. 21 under ‘‘Supporting and Related substance the findings prescribed by U.S.C. 811(a). If finalized, this action Material’’ in the public docket for this subsection (b) of section 812 of [Title would impose the regulatory controls proposed rule, at http:// 21] for the schedule in which such drug and administrative, civil, and criminal www.regulations.gov, under Docket is to be placed. . . .’’ Requests for sanctions of Schedule III on the Number ‘‘DEA–374.’’ Full analysis of, hearing, notices of appearance at the manufacture, distribution, dispensing, and citations to, the information hearing, and waivers of an opportunity importation, exportation, research, referenced in the summary may also be for a hearing or to participate in a instructional activities, and possession found in the supporting and related hearing must be submitted to the DEA of perampanel. material. using the address information provided 1. The Drug’s Actual or Relative Background above. Potential for Abuse: Perampanel is a Perampanel [2-(2-oxo-1-phenyl-5- new chemical entity that has been Legal Authority pyridin-2-yl-1,2-dihydropyridin-3-yl) marketed in Europe since July 2012. The DEA implements and enforces benzonitrile hydrate] is a new chemical According to the HHS, since titles II and III of the Comprehensive entity with central nervous system perampanel has been marketed in Drug Abuse Prevention and Control Act (CNS) depressant and hallucinogenic Europe only since July 2012, there is a of 1970 and the Controlled Substances properties. The HHS states that on lack of information regarding Import and Export Act, as amended, and October 22, 2012, the Food and Drug perampanel’s actual or relative potential collectively referred to as the Controlled Administration (FDA) approved a new for abuse. However, the legislative Substances Act (CSA) (21 U.S.C. 801– drug application for perampanel as an history of the CSA offers the following 971). The DEA publishes the adjunctive therapy for the treatment of criterion for assessing a new drug or implementing regulations for these partial-onset seizures with or without substance’s potential for abuse: statutes in title 21 of the Code of Federal secondarily generalized seizures in The drug or drugs containing such a Regulations (CFR), parts 1300 to 1321. patients with epilepsy aged 12 years and substance are new drugs so related in their The CSA and its implementing older. Perampanel will initially be action to a drug or drugs already listed as

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having a potential for abuse to make it likely and lower than that reported for 100 mg Perampanel (5 mg/kg), administered that the drug will have the same potentiality ketamine (Schedule III) (89 percent). orally by gavage, decreased alertness, for abuse as such drugs, thus making it The data from the study indicated that touch response, body position, limb reasonable to assume that there may be perampanel produces behavioral and tone, grip strength, body tone, significant diversions from legitimate channels, significant use contrary to or subjective effects in humans similar to spontaneous activity, and abdominal without medical advice, or that it has a or greater than alprazolam (Schedule IV) tone, and caused staggering and substantial capability of creating hazards to and similar to ketamine (Schedule III). inhibition of palpebral opening (eyelid) the health of the user or to the safety of the According to the HHS, based on in male rats. community.1 results from the clinical study with The HHS reported on two human According to the HHS, perampanel is recreational drug users, it is reasonable abuse potential studies that were a non-competitive AMPA-type to assume that perampanel will appeal performed in healthy, adult, recreational glutamate receptor antagonist, which to individuals who prefer to abuse drugs poly-drug users. In the first study, eight has been demonstrated by various that elicit the subjective and behavioral doses of perampanel (8, 12, 16, 20, 24, groups. Antagonism of the AMPA effects of alprazolam (Schedule IV) and 28, 32, and 36 mg) were administered to receptors has been shown to produce a ketamine (Schedule III). The HHS the subjects. It was determined that 36 broad-spectrum anti-convulsant activity anticipates that abuse will result in: mg was the maximum tolerated dose of focal and generalized epilepsy in diversions of perampanel from (MTD). The most commonly reported animal models. legitimate pharmaceutical distribution AEs were psychiatric, in particular The HHS states that monkeys self- channels; significant use of perampanel euphoria, which occurred at a rate of administered perampanel at rates contrary to or without medical advice; 22.6 percent in the higher dose group similar to or greater than those for and a substantial capability to create which received 24, 28, 32, and 36 mg pentobarbital (Schedule II). These data hazards to the abuser’s health and to the doses of perampanel. indicate that perampanel may have a safety of the community. In the second human abuse potential high psychological dependence liability. 2. Scientific Evidence of the Drug’s study, perampanel produced subjective It was demonstrated in rats that Pharmacological Effects, If Known: responses similar to or greater than cessation of administration of Perampanel is a non-competitive those produced by alprazolam perampanel produced withdrawal antagonist of the AMPA glutamate (Schedule IV) and ketamine (Schedule symptoms similar to those produced receptor. According to the HHS, III). Perampanel (8, 24, and 36 mg), after cessation of diazepam (Schedule perampanel is also a direct and indirect ketamine (Schedule III) (100 mg), IV) administration. antagonist of the NMDA receptor. The alprazolam (Schedule IV) (1.5 and 3 According to the HHS, a clinical HHS states that perampanel is mg), and placebo were administered to study of recreational drug abusers (with pharmacologically similar to ketamine 34 subjects who were current histories of abuse of sedative hypnotic (Schedule III), a NMDA receptor recreational poly-drug users with and psychoactive drugs such as antagonist and a recreational drug histories of CNS depressant and ketamine (Schedule III) and alprazolam known for its euphorigenic, psychedelic drug use. The effects of (Schedule IV)) using ketamine dissociative, and hallucinogenic perampanel (24 and 36 mg) on the drug- (Schedule III), alprazolam (Schedule properties. Binding studies revealed that liking Visual Analogue Scale (VAS) IV), and perampanel produced perampanel did not inhibit binding at were higher than that of alprazolam subjective effects indicative of abuse any receptor site by more than 50 (Schedule IV) (1.5 and 3 mg) and similar potential. The subjective effects percent. to ketamine (Schedule III) (100 mg). For According to the HHS, based on reported were ‘‘euphoria,’’ ‘‘high,’’ and the Addiction Research Center electrophysiological assays performed ‘‘drug-liking.’’ For the measures of Inventory Morphine-Benzedrine Group on ion channels of GABA receptors, ‘‘floating,’’ ‘‘spaced out,’’ and A (ARCI MBG) (euphoria) measure, the perampanel would be expected to cause ‘‘detached,’’ perampanel produced responses produced by perampanel (24 sedation, muscle relaxation, impairment similar responses to those of ketamine and 36 mg) were comparable to those of motor coordination and memory, (Schedule III) and greater responses produced by alprazolam (Schedule IV) development of dependency, and than those of alprazolam (Schedule IV). (3 mg) and ketamine (Schedule III) (100 occurrence of benzodiazepine-like mg), indicating that perampanel The study used 8, 24, and 36 mg doses withdrawal symptoms after produces euphoria comparable to that of perampanel, 100 mg doses of discontinuation. produced by alprazolam (Schedule IV) ketamine (Schedule III), 1.5 and 3mg The DEA further adds that and ketamine (Schedule III). The rates doses of alprazolam (Schedule IV), or a perampanel has inhibited AMPA- reported for euphoria AEs were 37 placebo. Those that received 24 and 36 2+ induced increases in [Ca ]i in rat percent for the 8 mg dose and 46 mg doses of perampanel reported cortical neurons in a concentration- percent for the 24 and 36 mg doses of measures of ‘‘sedation,’’ ‘‘slowed dependent manner, with an IC50 of 93 perampanel. The rates reported for down,’’ ‘‘confused,’’ ‘‘clear crisp nM. Perampanel (300 nM) inhibited euphoria AEs for 3 mg alprazolam vision,’’ and ‘‘attention span’’ at levels AMPA receptor-mediated excitatory (Schedule IV) and 100 mg ketamine similar to or greater than alprazolam postsynaptic field potentials (f-EPSPs) (Schedule III), were 13 percent and 89 (Schedule IV) and greater than ketamine in rat hippocampal slices by 50 percent. percent, respectively. (Schedule III). Forty-six percent of the Perampanel inhibited AMPA receptor- For the measure of feeling ‘‘high’’ on subjects reported euphoria-type adverse mediated f-EPSPs in a dose-dependent a VAS, perampanel (24 and 36 mg) events (AEs) with the 24 and 36 mg manner, with 10 mM causing complete produced responses that were perampanel doses, which was higher inhibition; the IC50 was 230 nM. comparable to those for ketamine than the rate reported for 3 mg According to the HHS, animal studies (Schedule III) (100 mg) and alprazolam alprazolam (Schedule IV) (13 percent), indicate that perampanel is a (Schedule IV) (1.5 and 3 mg). depressant. The Irwin test is an Perampanel (36 mg) was long-acting for 1 Comprehensive Drug Abuse Prevention and Control Act of 1970, H.R. Rep. No. 91–1444, 91st observational procedure that assesses the sedation and ‘‘high’’ effects. They Cong., Sess. 1 (1970); as reprinted in 1970 and scores the effects of drugs on lasted at least 22 hours. It was U.S.C.C.A.N. 4566, 4601. rodents’ behavior and physiology. demonstrated that perampanel caused

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NMDA-antagonist specific effects, such state is reached in about 2–3 weeks. perampanel likely poses a risk to public as ‘‘floating,’’ ‘‘spaced out,’’ ‘‘detached,’’ Perampanel is slowly metabolized and health similar to or greater than that of and ‘‘feeling happy,’’ that were similar the metabolites are eliminated rapidly alprazolam (Schedule IV) and similar to to those of ketamine (Schedule III) and via urine or feces. Three metabolites of that of ketamine (Schedule III). The greater than those of alprazolam perampanel have been identified as HHS asserts that the ability of a drug to (Schedule IV) (1.5 and 3 mg). The HU1, HU2, and HU3. HU1 and HU2 are have an abuse potential is an indication duration of these effects was longer for oxygen glucuronide conjugates and HU3 of the public health risk associated with perampanel (24 and 36 mg) than for is a dihydrodiol analog. Oxidative the drug. As summarized in Factor 2, ketamine (Schedule III) (100 mg): 24 to metabolism is mediated by CYP3A4 supratherapeutic doses of perampanel 48 hours compared to 3 hours, and/or CYP3A5. (24 and 36 mg) produced euphoria-type respectively. The measures of 4. Its History and Current Pattern of AEs in 46 percent of subjects, which ‘‘sedation,’’ ‘‘confused,’’ ‘‘slowed Abuse: An assessment of the history and was greater than the rate of euphoria down,’’ ‘‘attention span,’’ and ‘‘clear current pattern of perampanel abuse is AEs in subjects given 3 mg alprazolam crisp vision’’ following doses of 24 and not available because it has only been (Schedule IV) (13 percent) and less than 36 mg perampanel were similar to, or marketed in Europe since July 2012. As that produced by 100 mg ketamine greater than, alprazolam (Schedule IV), stated in HHS’s review, the results of a (Schedule III) (89 percent). and greater than ketamine (Schedule human abuse potential study indicate Clinical studies have demonstrated III). The duration of effects of higher that perampanel has an abuse potential that perampanel does affect doses of perampanel on the majority of comparable to or greater than the abuse psychomotor performance. In a study of measures was longer than for 3 mg potential of alprazolam (Schedule IV) healthy volunteers, single and multiple alprazolam (Schedule IV) and 100 mg and similar to that of ketamine doses of 8 and 12 mg perampanel dose- ketamine (Schedule III). (Schedule III). In addition, higher doses dependently impaired psychomotor According to the HHS, in clinical of perampanel produced a high rate of performance. In the same study, healthy trials that were conducted to study the euphoria-type AEs (up to 46 percent). volunteers were given alcohol until effect of perampanel on certain chronic The HHS asserts that the positive their alcohol blood level reached 80– diseases, e.g., epilepsy, Parkinson’s subjective effects reported from 100 mg/100 ml, in addition to disease, migraines, multiple sclerosis supratherapeutic doses of perampanel perampanel. The effects of perampanel (MS), and peripheral neuropathy, administration are predictive of its on complex tasks, such as driving perampanel caused CNS depressant potential to be abused. Alprazolam ability, were additive or supra-additive effects including somnolence/sedation, (Schedule IV) and ketamine (Schedule to the impairment effects of alcohol. dizziness, ataxia, confusion, amnesia III) have histories of diversion and According to the HHS, the risk of and memory impairment, euphoria, abuse. Based on perampanel’s subjective perampanel to the public health was depression, and suicidality. The AEs AE profile and its similarity to ketamine demonstrated by the AEs of aggression, that are related to NMDA receptor (Schedule III) and alprazolam (Schedule anger, hostility, suicidal ideation and antagonists were also associated with IV), it is reasonable to assume that attempts, and homicidal ideation and perampanel. These included psychotic perampanel will produce an abuse threats associated with perampanel disorder/psychosis, hallucinations, pattern that will have features of both during the clinical trials. The dissociation, delusional behavior, ketamine (Schedule III) and alprazolam FYCOMPA® drug label includes a boxed delirium, paranoia, euphoria, agitation, (Schedule IV) abuse. warning alerting prescribers and amnesia, confusion, and catatonia. 5. The Scope, Duration, and ultimate users to these public health 3. The State of Current Scientific Significance of Abuse: According to the risks. Approximately 50 subjects from Knowledge Regarding the Drug or Other HHS review, the scope, duration, and the clinical trials, without previous Substance: Perampanel (2-(2-oxo-1- significance of abuse of perampanel are relevant psychiatric histories, developed phenyl-5-pyridin-2-yl-1,2- unknown because it has only been psychotic disorders, such as paranoia, dihydropyridin-3-yl)benzonitrile marketed in Europe since July 2012. delusion, delirium, schizophrenia, and hydrate (4:3) is a white-to-yellowish However, the scope, duration, and catatonia while taking perampanel. This powder. The molecular formula is significance of abuse of perampanel can indicates that perampanel may cause C23H15N3O • 3/4H2O. It is freely soluble be predicted from the data obtained in users to display unpredictable or in N-methylpyrrolidone, sparingly pre-market clinical studies such as aggressive behavior towards themselves soluble in acetonitrile and acetone, abuse potential studies and other or others. Based on the AEs of slightly soluble in methanol, ethanol, clinical studies. In its analysis, the HHS perampanel summarized above, the and ethyl acetate, very slightly soluble concluded that: HHS determined that the public health in 1-octanol and diethyl ether, and [I]f perampanel were marketed in the United risks of perampanel are likely to be practically insoluble in heptanes and States, the scope and significance of abuse of similar to other CNS drugs, such as water. perampanel would be similar to or greater ketamine (Schedule III). Perampanel is rapidly and almost than alprazolam [Schedule IV] and similar to 7. Its Psychic or Physiological completely absorbed, slowly or greater than ketamine [Schedule III]. If Dependence Liability: According to the metabolized, and slowly eliminated perampanel were marketed as a non- HHS, low (up to 14.7 mg/kg) and high after oral administration. In humans, the controlled antiepileptic drug, it is reasonable doses (up to 43.5 mg/kg) of oral to assume that perampanel would be abused median Tmax ranged from 0.5–2.5 hours perampanel were administered to rats to an even greater extent than it would be under fasted conditions; the Tmax when controlled in Schedule III of the CSA. for 4 weeks, followed by a 1-week increased by 2–3 hours under fed This is because individuals who abuse such withdrawal period. During the conditions. Tmax is the amount of time drugs, namely ketamine, would likely prefer withdrawal period, the rats displayed for a substance to reach maximal plasma to use a drug that is non-controlled, or in a withdrawal symptoms indicative of concentrations after administration. lower level of control, rather than drugs that dependence, such as hyper-reactivity According to the HHS, the mean half- act similarly and are controlled in [Schedule and muscle rigidity, along with reduced life of perampanel (1 mg) in the fasted III], or more restrictive schedules of the CSA. food consumption. state was 84.5 and 129.5 hours for men 6. What, if Any, Risk There Is to the According to the HHS, the physical and women, respectively. The steady Public Health: According to HHS, dependence of perampanel in humans

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has not been fully evaluated, because in control in Schedule III of the CSA. 21 perampanel) on hand, on a biennial Phase 3 clinical trials, symptoms of U.S.C. 812(b)(3). basis, pursuant to 21 U.S.C. 827, 958(e) withdrawal were collected in only a and in accordance with 21 CFR 1304.03, Requirements for Handling Perampanel small fraction of patients. Reported 1304.04, and 1304.11. withdrawal symptoms included fatigue/ If this rule is finalized as proposed, Records. All DEA registrants would be lethargy/asthenia, irritability, anxiety/ perampanel would be subject to the required to maintain records of nervousness, worsening of mood/ CSA’s Schedule III regulatory controls perampanel pursuant to 21 U.S.C. 827, tearfulness, mood swings, sleep and administrative, civil, and criminal 958(e) and in accordance with 21 CFR disorders, weight changes, changes in sanctions applicable to the manufacture, parts 1304 and 1312. appetite, muscle pain/stiffness, distribution, dispensing, importing, Prescriptions. All prescriptions for diarrhea/nausea/vomiting, rhinorrhea, exporting, research, and conduct of perampanel or prescriptions for lacrimation, headache, dizziness, instructional activities, including the products containing perampanel would hallucinations, panic, and craving/drug following: be required to be issued pursuant to 21 seeking. The HHS asserts that the Registration. Any person who handles U.S.C. 829 and in accordance with 21 limited results demonstrate that (manufactures, distributes, dispenses, CFR part 1306. discontinuation of perampanel imports, exports, engages in research, or Importation and Exportation. All administration causes signs and conducts instructional activities) importation and exportation of symptoms of withdrawal. perampanel, or who desires to handle perampanel would need to be done in perampanel, would be required to be 8. Whether the Substance Is an accordance with 21 CFR part 1312, registered with the DEA to conduct such pursuant to 21 U.S.C. 952, 953, 957, and Immediate Precursor of a Substance activities, pursuant to 21 U.S.C. 822, 958. Already Controlled Under the CSA: 823, 957, and 958, and in accordance Liability. Any activity with Perampanel is not an immediate with 21 CFR parts 1301 and 1312. Any perampanel not authorized by, or in precursor of a substance already person who handles perampanel, and is violation of, the CSA, occurring on or controlled under the CSA. not registered with the DEA, must be after finalization of this proposed rule, Conclusion: Based on consideration of registered with the DEA to conduct such would be unlawful, and may subject the the scientific and medical evaluation activities pursuant to 21 U.S.C. 822, person to administrative, civil, and/or conducted by the HHS and its 823, 957, and 958, and in accordance criminal sanctions. recommendation, and after considering with 21 CFR parts 1301 and 1312. Any Regulatory Analyses its own eight-factor analysis, the DEA person who handles perampanel, and is has determined that these facts and all not registered with the DEA, would Executive Orders 12866 and 13563 relevant data constitute substantial need to be registered with the DEA to In accordance with 21 U.S.C. 811(a), evidence of potential for abuse of conduct such activities by the effective this proposed scheduling action is perampanel. As such, the DEA hereby date of the final rule. subject to formal rulemaking procedures proposes to schedule perampanel as a Security. Perampanel would be performed ‘‘on the record after controlled substance under the CSA. subject to Schedule III–V security opportunity for a hearing,’’ which are Proposed Determination of Appropriate requirements and would need to be conducted pursuant to the provisions of Schedule handled and stored in accordance with 5 U.S.C. 556 and 557. The CSA sets 21 CFR 1301.71–1301.93, pursuant to 21 The CSA outlines the findings forth the procedures and criteria for U.S.C. 823, 821, 871(b). scheduling a drug or other substance. required to place a drug or other Labeling and Packaging. All labels substance in any particular schedule (I, Such actions are exempt from review by and labeling for commercial containers the Office of Management and Budget II, III, IV or V). 21 U.S.C. 812(b). After of perampanel distributed on or after consideration of the analysis and (OMB) pursuant to Section 3(d)(1) of finalization of this rule would need to Executive Order 12866 and the recommendation by the Assistant be in accordance with 21 CFR 1302.03– Secretary for Health of the HHS, and principles reaffirmed in Executive Order 1302.07, pursuant to 21 U.S.C. 825, 13563. review of all available data, the Deputy 958(e). Administrator of the DEA, pursuant to Inventory. Every DEA registrant who Executive Order 12988 21 U.S.C. 812(b)(3), finds that: possesses any quantity of perampanel This proposed regulation meets the 1. Perampanel has a potential for on the effective date of the final rule applicable standards set forth in abuse less than the drugs or other would be required to take an inventory Sections 3(a) and 3(b)(2) of Executive substances in Schedules I and II; of all stocks of perampanel on hand as Order 12988 Civil Justice Reform to 2. Perampanel has a currently of the effective date of the rule, pursuant eliminate drafting errors and ambiguity, accepted medical use in treatment in the to 21 U.S.C. 827, 958(e) and in minimize litigation, provide a clear legal United States. Perampanel was accordance with 21 CFR 1304.03, standard for affected conduct, and approved for marketing by the FDA as 1304.04, and 1304.11(a) and (d). promote simplification and burden an adjunctive treatment of partial-onset Any person who becomes registered reduction. seizures with or without secondarily with the DEA after the effective date of generalized seizures in patients with the final rule would be required to take Executive Order 13132 epilepsy aged 12 years and older; and an initial inventory of all stocks of This proposed rulemaking does not 3. Abuse of perampanel may lead to controlled substances (including have federalism implications warranting moderate or low physical dependence perampanel) on hand at the time of the application of Executive Order or high psychological dependence. registration pursuant to 21 U.S.C. 827, 13132. The proposed rule does not have Based on these findings, the Deputy 958(e), and in accordance with 21 CFR substantial direct effects on the States, Administrator of the DEA concludes 1304.03, 1304.04, and 1304.11(a) and on the relationship between the national that perampanel [2-(2-oxo-1-phenyl-5- (b). After the initial inventory, every government and the States, or the pyridin-2-yl-1,2-dihydropyridin-3-yl) DEA registrant would be required to distribution of power and benzonitrile hydrate], including its salts, take a biennial inventory of all responsibilities among the various isomers, and salts of isomers, warrants controlled substances (including levels of government.

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Executive Order 13175 RFA and Small Business Administration Because of these facts, this proposed This proposed rule does not have (SBA) standards. 5 U.S.C. 601(6) and 15 rule will not result in significant tribal implications warranting the U.S.C. 632. However, due to the wide economic impact on a substantial application of Executive Order 13175. It variety of unidentifiable and number of small entities. unquantifiable variables that could does not have substantial direct effects Unfunded Mandates Reform Act of potentially influence the dispensing on one or more Indian tribes, on the 1995 relationship between the Federal rates of new chemical entities, the DEA Government and Indian tribes, or on the is unable to determine the number of In accordance with the Unfunded distribution of power and small entities that might dispense Mandates Reform Act (UMRA) of 1995 responsibilities between the Federal (including administer and prescribe) (2 U.S.C. 1501 et seq.), on the basis of Government and Indian tribes. perampanel (e.g., pharmacies and information contained in the prescribers). ‘‘Regulatory Flexibility Act’’ section Regulatory Flexibility Act Despite the fact that the number of above, the DEA has determined and The Deputy Administrator, in small businesses potentially impacted certifies pursuant to UMRA that this accordance with the Regulatory by this proposed rule could not be action would not result in any federal Flexibility Act (RFA) (5 U.S.C. 601– determined at this time, the DEA mandate that may result ‘‘in the 612), has reviewed this proposed rule concludes that they would not expenditure by State, local, and tribal and by approving it certifies that it will experience a significant economic governments, in the aggregate, or by the not have a significant economic impact impact as a result of this rule. Currently, private sector, of $100,000,000 or more on a substantial number of small 98 percent of DEA registrants (most of (adjusted for inflation) in any one year. entities. The purpose of this proposed which are small businesses) are . . .’’ Therefore, neither a Small rule is to place perampanel, including authorized to handle Schedule III Government Agency Plan nor any other its salts, isomers, and salts of isomers, controlled substances. Even if we action is required under provisions of into Schedule III of the CSA. No less assume that all of the DEA registrants UMRA of 1995. restrictive measures (i.e., non-control) were to dispense perampanel, (e.g., Paperwork Reduction Act of 1995 enable the DEA to meet its statutory practitioners prescribe, administer, or obligations under the CSA. In preparing dispense the substance, and pharmacies This action does not impose a new this certification, the DEA has assessed dispense the prescriptions), the costs collection of information requirement economic impact by size category and that they would incur as a result of under the Paperwork Reduction Act of has considered costs with respect to the perampanel scheduling would be 1995 (44 U.S.C. 3501–3521). This action various DEA registrant business activity minimal. Registrants that dispense (but would not impose recordkeeping or classes. not prescribe) would incur nominal reporting requirements on State or local Perampanel is a new molecular entity, additional security, inventory, governments, individuals, businesses, or approved by the FDA on October 22, recordkeeping, and labeling costs, as organizations. An agency may not 2012. It was approved in Europe in May they have already established and conduct or sponsor, and a person is not 2012, and has been marketed in Europe implemented the required systems and required to respond to, a collection of since July 2012. According to publicly processes to handle Schedule III information unless it displays a available information reviewed by the controlled substances. For example, currently valid OMB control number. pharmacies and institutional DEA, perampanel is currently List of Subjects in 21 CFR Part 1308 anticipated to enjoy patent protection practitioners may disperse Schedule II for at least a decade before generic through V controlled substances Administrative practice and equivalents may be manufactured and throughout their stock of non-controlled procedure, Drug traffic control, marketed. Accordingly, the number of substances in such a manner as to Reporting and recordkeeping currently identifiable manufacturers, obstruct theft or diversion of the requirements. importers, and distributors for controlled substances. The inclusion of For the reasons set out above, 21 CFR perampanel is extremely small. The one additional substance to this system part 1308 is proposed to be amended as publicly available materials also specify would result in little or no additional follows: the readily identifiable persons subject burden to such practitioners. In to direct regulation by this proposed addition, because DEA-registered PART 1308—SCHEDULES OF rule. Based on guidelines utilized by the dispensers must label all Schedule II–V CONTROLLED SUBSTANCES Small Business Administration, the controlled substances dispensed, the perampanel manufacturer/distributor/ requirement to label all controlled ■ 1. The authority citation for 21 CFR importer was determined not to be a substances containing perampanel part 1308 continues to read as follows: small entity. Once generic equivalents would not impose a significant Authority: 21 U.S.C. 811, 812, 871(b), are developed and approved for economic burden upon DEA-registered unless otherwise noted. manufacturing and marketing, there dispensers (as the infrastructure and may be additional manufacturers, materials for doing so would already be ■ 2. Amend § 1308.13 by redesignating importers, and distributors of in place). Accordingly, compliance paragraphs (c)(11) through (c)(14) as perampanel, but whether they may would not require significant paragraphs (c)(12) through (c)(15) and qualify as small entities cannot be manpower, capital investments, or adding new paragraph (c)(11) to read as determined at this time. recordkeeping burdens. follows: There are approximately 1.5 million Registrants who only prescribe § 1308.13 Schedule III. controlled substance registrants, perampanel by oral or written * * * * * approximately 381,559 of which are prescription would not incur any estimated to be businesses. The DEA additional security, inventory, (c) * * * estimates that 371,588 (97 percent) of recordkeeping, or labeling costs as a (11) Perampanel, and its salts, the affected businesses are considered result of this rule as they would not isomers, and salts of isomers 2261 ‘‘small entities’’ in accordance with the physically handle perampanel. * * * * *

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Dated: October 9, 2013. Regulatory Identification Number (RIN) authorized by the MTF Commander and Thomas M. Harrigan, and title, by any of the following the MTF is unable to provide the Deputy Administrator. methods: necessary treatment of the • [FR Doc. 2013–24600 Filed 10–21–13; 8:45 am] Federal eRulemaking Portal: http:// complications. This current exception BILLING CODE P www.regulations.gov. Follow the recognizes that in order to support instructions for submitting comments. Graduate Medical Education and • Mail: Federal Docket Management maintain provider skill levels, MTF System Office, 4800 Mark Center Drive, providers are required to perform DEPARTMENT OF DEFENSE East Tower, Suite 02G09, Alexandria, medical procedures that may be Office of the Secretary VA 22350–3100. excluded from coverage under the Instructions: All submissions received TRICARE private sector program. The 32 CFR Part 199 must include the agency name and final rule at 32 CFR199.4(e)(9)(ii) was docket number or RIN for this Federal viewed as necessary to protect TRICARE [DOD–2013–HA–0164] Register document. The general policy beneficiaries from incurring financial for comments and other submissions hardships in such cases. RIN 0720–AB61 from members of the public is to make Currently, Active Duty Service members (ADSMs) may receive non- TRICARE; Coverage of Care Related to these submissions available for public covered TRICARE private sector health Non-Covered Initial Surgery or viewing on the Internet at http:// care services under the Supplemental Treatment regulations.gov as they are received without change, including any personal Health Care Program (SHCP) if a waiver AGENCY: Office of the Secretary, identifiers or contact information. is submitted through the Service and Department of Defense. FOR FURTHER INFORMATION CONTACT: approved by the Director, TMA, or ACTION: Proposed rule. Thomas Doss (703) 681–7512. designee, in accordance with § 199.6(f). While the Department wants to ensure SUPPLEMENTARY INFORMATION: SUMMARY: The Department of Defense that Service members have access to the (DoD) is publishing this proposed rule I. Executive Summary latest, promising medical technologies to allow coverage for otherwise covered and procedures, there must be assurance 1. Purpose of Regulatory Actions services and supplies required in the that the care is safe and effective, and treatment of complications (unfortunate a. Need for Regulatory Actions that members are not subjected to undue risk, or rendered unfit for continued sequelae), as well as medically Under the TRICARE private sector necessary and appropriate follow-on service, due to complications suffered as health care program, certain conditions a result of unproven medical care. care, resulting from a non-covered and treatments are excluded from incident of treatment provided pursuant Consequently, requests for non-covered coverage. For example, any drug, procedures and treatments, including to a properly granted Supplemental device, medical treatment, or procedure Health Care Program waiver. This unproven care, are carefully reviewed in whose safety and efficacy has not been conjunction with other available, proposed rule is necessary to protect established by reliable evidence is TRICARE beneficiaries from incurring proven treatments, if any exist, to considered unproven and excluded determine whether or not approval of financial hardships due to the current from coverage. This exclusion includes regulatory restrictions that prohibit the requested care is necessary to assure all services directly related to the the adequate availability of health care TRICARE coverage of the treatment of unproven drug, device, medical complications resulting from non- to the member. Currently, Service treatment or procedure. Specifically, members are counseled that the covered medical procedures, even when benefits for otherwise covered services those procedures were provided while treatment remains a non-covered and supplies that are required in the TRICARE benefit, and that any follow- the beneficiary was an active duty treatment of complications (unfortunate member and were authorized by the on care, including care for sequelae) resulting from a non-covered complications, will not be covered by Director, TRICARE Management incident of treatment, are generally Activity (TMA), based on a TRICARE once the member separates or excluded from TRICARE coverage retires. Members are left to make a determination that a waiver authorizing pursuant to title 32 of the Code of the original non-covered surgery or difficult choice between pursuing a Federal Regulation (CFR) section SHCP waiver in an effort to remain fit treatment was necessary to assure 199.4(e)(9), unless the complication adequate availability of health care to for full duty while assuming the represents a separate medical condition financial risk of any necessary follow-on the Active Duty member. Additionally, such as a systemic infection, cardiac with respect to care that is related to a care after discharge, or, electing not to arrest, and acute drug reaction. receive the care and risk separation from non-covered initial surgery or treatment, TRICARE also excludes any needed the proposed rule seeks to eliminate any the Service. follow-on care resulting from a non- Like the existing exception at 32 confusion regarding what services and covered condition or initial surgery or CFR199.4(e)(9)(ii) for non-covered care supplies will be covered by TRICARE treatment pursuant to § 199.4(g)(63). provided in a MTF, this proposed and under what circumstances they will There is currently one exception to exception is narrowly tailored to serve be covered. this general exclusion, published in the a similar government interest; namely, DATES: Comments must be received on Federal Register [76 FR 57642] on protecting former active duty members or before December 23, 2013. Do not September 16, 2011, to allow coverage who have received private sector care submit comments directly to the point of otherwise covered services and pursuant to a SHCP waiver in an effort of contact or mail your comments to any supplies required in the treatment of to ensure their fitness for duty and address other than what is shown complications (unfortunate sequelae) continued service. below. Doing so will delay the posting resulting from a non-covered incident of Additionally, some confusion has of the submission. treatment provided in a Military arisen regarding the terms ADDRESSES: You may submit comments, Treatment Facility (MTF), when the ‘complication’’ and ‘‘unfortunate identified by docket number and/or initial non-covered service has been sequelae’’ as these terms are not

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