80 FR 48044 - Schedules of Controlled Substances: Placement of Eluxadoline Into Schedule IV
DEPARTMENT OF JUSTICE
Drug Enforcement Administration Federal Register Volume 80, Issue 154 (August 11, 2015)
Drug Enforcement Administration
Federal Register Volume 80, Issue 154 (August 11, 2015)
| Page Range | 48044-48051 | |
| FR Document | 2015-19655 |
[Federal Register Volume 80, Number 154 (Tuesday, August 11, 2015)] [Proposed Rules] [Pages 48044-48051] From the Federal Register Online [www.thefederalregister.org] [FR Doc No: 2015-19655] [[Page 48044]] ======================================================================= ----------------------------------------------------------------------- DEPARTMENT OF JUSTICE Drug Enforcement Administration 21 CFR Part 1308 [Docket No. DEA-419N] Schedules of Controlled Substances: Placement of Eluxadoline Into Schedule IV AGENCY: Drug Enforcement Administration, Department of Justice. ACTION: Notice of proposed rulemaking. ----------------------------------------------------------------------- SUMMARY: The Drug Enforcement Administration proposes to place the substance eluxadoline (5-[[[(2S)-2-amino-3-[4-aminocarbonyl)-2,6- dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2- yl)ethyl]amino]methyl]-2-methoxybenzoic acid), including its salts, isomers, and salts of isomers, into schedule IV of the Controlled Substances Act (CSA). This proposed scheduling action is pursuant to the CSA which requires that such actions be made on the record after opportunity for a hearing through formal rulemaking. If finalized, this action would impose the regulatory controls and administrative, civil, and criminal sanctions applicable to schedule IV controlled substances on persons who handle (manufacture, distribute, dispense, import, export, engage in research, conduct instructional activities, or possess), or propose to handle eluxadoline. DATES: Interested persons may file written comments on this proposal in accordance with 21 CFR 1308.43(g). Electronic comments must be submitted, and written comments must be postmarked, on or before September 10, 2015. Commenters should be aware that the electronic Federal Docket Management System will not accept comments after 11:59 p.m. 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, notice of appearance, or waiver of hearing pursuant to 21 CFR 1308.44 and in accordance with 21 CFR 1316.45, 1316.47, 1316.48, or 1316.49, as applicable. Requests for hearing, notices of appearance, and waivers of an opportunity for a hearing or to participate in a hearing must be received on or before September 10, 2015. ADDRESSES: To ensure proper handling of comments, please reference ``Docket No. DEA-419N'' on all correspondence, including any attachments.Electronic comments: The Drug Enforcement Administration encourages that all comments be submitted electronically through the Federal eRulemaking Portal, which provides the ability to type short comments directly into the comment field on the Web page or to attach a file for lengthier comments. Please go to http://www.regulations.gov and follow the online instructions at that site for submitting comments. Upon completion of your submission you will receive a Comment Tracking Number for your comment. Please be aware that submitted comments are not instantaneously available for public view on Regulations.gov. If you have received a Comment Tracking Number, your comment has been successfully submitted and there is no need to resubmit the same comment. Paper comments: Paper comments that duplicate the electronic submission are not necessary and are discouraged. Should you wish to mail a paper comment in lieu of an electronic comment, it should be sent via regular or express mail to: Drug Enforcement Administration, Attn: DEA Federal Register Representative/ODL, 8701 Morrissette Drive, Springfield, Virginia 22152. Hearing requests: All requests for hearing and waivers of participation must be sent to: Drug Enforcement Administration, Attn: Federal Register Representative/ODL, 8701 Morrissette Drive, Springfield, Virginia 22152. All requests for hearing and waivers of participation should also be sent to: Drug Enforcement Administration, Attn: Hearing Clerk/LJ, 8701 Morrissette Drive, Springfield, Virginia 22152. FOR FURTHER INFORMATION CONTACT: John R. Scherbenske, Office of Diversion Control, Drug Enforcement Administration; Mailing Address: 8701 Morrissette Drive, Springfield, Virginia 22152; Telephone: (202) 598-6812. SUPPLEMENTARY INFORMATION: Posting of Public Comments Please note that all comments received in response to this docket are considered part of the public record. They will, unless reasonable cause is given, be made available by the Drug Enforcement Administration (DEA) for public inspection online at http://www.regulations.gov. Such information includes personal identifying information (such as your name, address, etc.) voluntarily submitted by the commenter. The Freedom of Information Act (FOIA) applies to all comments received. 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 made publicly available, you must include the phrase ``PERSONAL IDENTIFYING INFORMATION'' in the first paragraph of your comment. You must also place the personal identifying information you do not want made publicly available 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 made publicly available, 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. Comments containing personal identifying information and confidential business information identified as directed above will generally be made publicly available in redacted form. If a comment has so much confidential business information or personal identifying information that it cannot be effectively redacted, all or part of that comment may not be made publicly available. Comments posted to http://www.regulations.gov may include any personal identifying information (such as name, address, and phone number) included in the text of your electronic submission that is not identified as directed above as confidential. An electronic copy of this document and supplemental information to this proposed rule are available at http://www.regulations.gov for easy reference. Request for Hearing, Notice of Appearance at Hearing, Waiver of an Opportunity for a Hearing or To Participate in a Hearing Pursuant to 21 U.S.C. 811(a), this action is a formal rulemaking ``on the record after opportunity for a hearing.'' Such proceedings are conducted pursuant to the provisions of the Administrative Procedure Act (APA), 5 U.S.C. 551-559. 21 CFR 1308.41-1308.45; 21 CFR part 1316, subpart D. In accordance with 21 CFR 1308.44(a)-(c), requests for hearing, notices of appearance, and waivers of an opportunity for a hearing or to participate in a hearing may be submitted only by interested persons, defined 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).'' 21 CFR 1300.01. Such requests or notices must conform to the requirements of 21 CFR 1308.44(a) or (b), and 1316.47 or 1316.48, as applicable, and include a [[Page 48045]] statement of 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 a hearing is restricted to: ``find[ing] that such drug or other substance has a potential for abuse, and * * * 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 * * *.'' All requests for hearing and waivers of participation must be sent to the 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, as amended. 21 U.S.C. 801-971. Titles II and III are referred to as the ``Controlled Substances Act'' and the ``Controlled Substances Import and Export Act,'' respectively, and are collectively referred to as the ``Controlled Substances Act'' or the ``CSA'' for the purpose of this action. The DEA publishes the implementing regulations for these statutes in title 21 of the Code of Federal Regulations (CFR), chapter II. The CSA and its implementing regulations are designed to prevent, detect, and eliminate the diversion of controlled substances and listed chemicals into the illicit market while ensuring an adequate supply is available for the legitimate medical, scientific, research, and industrial needs of the United States. Controlled substances have the potential for abuse and dependence and are controlled to protect the public health and safety. Under the CSA, each controlled substance is classified into one of five schedules based upon its potential for abuse, its currently accepted medical use in treatment in the United States, and the degree of dependence the substance may cause. 21 U.S.C. 812. The initial schedules of controlled substances established by Congress are found at 21 U.S.C. 812(c), and the current list of all scheduled substances is published at 21 CFR part 1308. Pursuant to 21 U.S.C. 811(a)(1), the Attorney General may, by rule, ``add to such a schedule or transfer between such schedules any drug or other substance if he * * * finds that such drug or other substance has a potential for abuse, and * * * 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 * * *.'' The Attorney General has delegated scheduling authority under 21 U.S.C. 811 to the Administrator of the DEA. 28 CFR 0.100. The CSA provides that scheduling of any drug or other substance may be initiated by the Attorney General (1) on her 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). If finalized, this action would impose the regulatory controls and administrative, civil, and criminal sanctions of schedule IV controlled substances for any person who handles eluxadoline. Background Eluxadoline is a new molecular entity with central nervous system opioid properties. It has not been marketed in any country. Eluxadoline has mixed mu opioid receptor (MOR) and kappa opioid receptor (KOR) agonist and delta opioid receptor (DOR) antagonist properties. Recently, the Food and Drug Administration (FDA) approved eluxadoline as a prescription drug for the treatment of irritable bowel syndrome with diarrhea (IBS-d). Eluxadoline will be marketed as 75 and 100 milligrams (mg) oral tablets under the trade name of Viberzi. Proposed Determination To Schedule Eluxadoline Pursuant to 21 U.S.C. 811(a)(1), proceedings to add a drug or substance to those controlled under the CSA may be initiated by request of the Secretary of the HHS.\1\ The HHS provided the DEA with a scientific and medical evaluation document (dated May 5, 2015) prepared by the FDA entitled ``Basis for the Recommendation to Place Eluxadoline and Its Salts into schedule IV of the Controlled Substances Act'' and a scheduling recommendation. Pursuant to 21 U.S.C. 811(b), this document contained an eight-factor analysis of the abuse potential of eluxadoline as a new drug, along with the HHS' recommendation to control eluxadoline under schedule IV of the CSA. --------------------------------------------------------------------------- \1\ As set forth in a memorandum of understanding entered into by the HHS, the Food and Drug Administration (FDA), and the National Institute on Drug Abuse (NIDA), the FDA acts as the lead agency within the HHS in carrying out the Secretary's scheduling responsibilities under the CSA, with the concurrence of the NIDA. 50 FR 9518, Mar. 8, 1985. In addition, because the Secretary of the HHS has delegated to the Assistant Secretary for Health of the HHS the authority to make domestic drug scheduling recommendations, for purposes of this document, all subsequent references to ``Secretary'' have been replaced with ``Assistant Secretary.'' --------------------------------------------------------------------------- In response, the DEA reviewed the scientific and medical evaluation and scheduling recommendation provided by the HHS, and all other relevant data, and completed its own eight-factor review document pursuant to 21 U.S.C. 811(c). Included below is a brief summary of each factor as analyzed by the HHS and the DEA, and as considered by the DEA in its proposed scheduling decision. Please note that both the DEA and the HHS analyses are available in their entirety under ``Supporting and Related Material'' in the public docket for this proposed rule at http://www.regulations.gov, under Docket Number ``DEA-419N''. Full analysis of, and citations to, the information referenced in the summary may also be found in the supporting and related material. 1. The Drug's Actual or Relative Potential for Abuse: Eluxadoline is a new chemical entity that has not been marketed in the U.S. or in any other country. As such, there is no information available which details actual abuse of eluxadoline. However, the legislative history of the CSA suggests that the DEA consider the following criteria in determining whether a particular drug or substance has a potential for abuse: \2\ --------------------------------------------------------------------------- \2\ 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. (1) There is evidence that individuals are taking the drug or drugs containing such a substance in amounts sufficient to create a hazard to their health or to the safety of other individuals or to the community; (2) There is significant diversion of the drug or substance from legitimate drug channels; (3) Individuals are taking the substance on their own initiative rather than on the basis of medical advice from a practitioner licensed by law to administer such drugs in the course of his professional practice; or (4) 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 they will have the same potentiality for abuse as such substance, 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. Both the HHS and the DEA note that three of the above mentioned four criteria (1, 2, and 3) do not apply to eluxadoline for the following reasons. Eluxadoline is a new molecular entity [[Page 48046]] and has not been marketed in any country. Accordingly, it has not been diverted from legitimate sources, and individuals have not taken this substance in amounts sufficient to create a hazard to public health or safety. Therefore, criterion 4 is the only one that applies to eluxadoline. Eluxadoline acts as a high affinity agonist at MORs and KORs and as an antagonist at DORs. Eluxadoline produced opioid agonistic effects such as centrally mediated analgesia, sedation, motor impairment, respiratory depression, and death in some animals. Eluxadoline generalized to morphine in a drug discrimination study in monkeys suggesting its MOR agonist properties. Monkeys self-administered eluxadoline indicating its rewarding properties. Receptor binding and functional profile studies demonstrate that eluxadoline has KOR agonistic activity. Pentazocine (schedule IV opioid analgesic) and butorphanol (schedule IV opioid analgesic) are the two currently marketed opioid drugs with KOR agonist activity. Pentazocine and butorphanol were initially approved for market as non-controlled drugs. However, subsequent reports of their actual abuse supported control as schedule IV drugs under the CSA. Clinical studies indicated that pentazocine and butorphanol have been shown to cause greater dysphoria and to be less abusable than the schedule II opioids. In human abuse potential studies, eluxadoline produced both positive and negative responses. The maximal effects of eluxadoline on Drug Liking are greater than that of placebo, but less than that of oxycodone (schedule II). Eluxadoline produced small statistically significant increases in several positive subjective responses such as visual analog scale (VAS) scores for Take Drug Again, Subjective Drug Value, Good Drug Effects, High, and the Addiction Research Center Inventory-Morphine Benzedrine Group (ARCI-MBG, Euphoria). The positive subjective responses to eluxadoline were most often statistically significantly less than those produced by oxycodone. Eluxadoline produced a high rate of euphoria in human abuse potential studies. However, these euphoric effects of eluxadoline are less than that of oxycodone. Eluxadoline at all doses elicited a small but significant increase in the VAS score for Drug Disliking. Eluxadoline also produced a statistically significant increase in VAS Bad Drug Effects, ARCI Lysergic Acid Diethylamide (ARCI-LSD, Dysphoria), but did not cause a significant increase in Drowsiness and Sedation. These results are also similar to those produced by pentazocine in a published study which reported a statistically significant increase in the VAS score for Bad Drug Effects and the score for ARCI-LSD (Dysphoria). Eluxadoline produced dysphoric effects consistent with kappa agonist activity related effects produced by pentazocine and butorphanol. In summary, eluxadoline appears to be so related in its action to substances already listed as having potential for abuse, and which have been controlled in schedule IV of the CSA, to make it likely that eluxadoline will have the same potential for abuse as those substances. 2. Scientific Evidence of Its Pharmacological Effects, If Known: The HHS, in its scientific and medical evaluation document, reviewed data from pre-clinical and clinical studies on eluxadoline. The HHS' findings are summarized below. Pre-Clinical In Vitro Pharmacological Studies Eluxadoline has high affinity at the MOR, KOR, and DOR. Eluxadoline lacked significant affinity for other binding sites including those associated with abuse potential. Similar to butorphanol (schedule IV), eluxadoline acted as an agonist at both MOR and KOR, but acted as an antagonist at DOR. Pentazocine (schedule IV) also has agonist activity at KOR. Pre-Clinical In Vivo Studies In the Irwin test (a test of general behavioral responses), there were no noticeable behavioral changes produced by eluxadoline at three subcutaneous doses of 500, 1000, or 2000 mg/kg in mice. Similarly, there were no changes in motor activity, reflexes, excitation, body tone, righting reflex, and rotorod tests or in body temperature in rats following oral administration of eluxadoline (30 or 300 mg/kg). However, intravenous administration of eluxadoline HCl (5, 10 and 20 mg/kg/day) in rats for 14 days followed by a 14-day recovery period produced classic opioid-related behaviors including general arousal, handling reactivity, stereotypy, tail pinch response, touch response, changes in posture, gait, mobility, righting reflex, respiration, and hindlimb splay. In a toxicity study in Cynomolgus monkeys, animals treated with eluxadoline (50, 100, and 200 mg/kg/day) or vehicle via oral gavage for nine months, followed by a four-week recovery period (for the vehicle and 200 mg/kg groups), exhibited no changes in behavior during the 39-week treatment period. In a dose-finding study, daily intravenous administration of 20 mg/kg eluxadoline for seven days produced opioid-associated behaviors (decreased respiration and periods of unconsciousness). These effects were severely pronounced following 40 mg/kg dose. All animals in the highest dose group (40 mg/kg reduced to 30 mg/kg on the second day of the dosing after one animal died) exhibited opioid overdose symptoms such as decreased activity, unresponsiveness, decreased body temperature and respiration rates. Opioid antagonist naloxone (0.1 mg/kg) was administered either subcutaneously or intravenously to more or less severely affected animals, respectively. Upon reducing the eluxadoline dose from 40 mg/kg to 30 mg/kg, all animals continued to respond with opioid overdose symptoms. In a hot-plate test for studying anti-nociceptive effects in mice, oral administration of eluxadoline up to doses of 1000 mg/kg showed no significant analgesic responses. However, subcutaneous administration of both 10 and 50 mg/kg eluxadoline caused significant increases in hot plate latencies and produced concurrent opioid-associated behaviors such as Straub tail and increased limb tone. As mentioned in the HHS scientific and medical evaluation and scheduling recommendation, drug discrimination tests in animals serve as an important experimental method for predicting whether the effects of a given test drug will be similar to that of a standard training drug used in the study. In drug discrimination studies conducted in Rhesus monkeys trained to discriminate between subcutaneously administered morphine (1 mg/kg) and vehicle using shock stimulus termination procedure, intravenous administration of 17.8 mg/kg dose of eluxadoline HCl produced full generalization to morphine (1 mg/kg) in the only monkey tested. When this same monkey was tested at 10 mg/kg, there was no generalization. However, the 10 mg/kg dose of eluxadoline produced full generalization in a different monkey. The lowest doses of eluxadoline at 1.0 (n = 1) and 3.2 mg/kg (n = 2) produced no generalization (<20%) to morphine. Eluxadoline, as a mu and kappa opioid agonist, produces an interoceptive cue similar to that of mu opioid agonist, morphine (schedule II). These data are similar to those from several published human studies in which butorphanol (schedule IV, mu and kappa opioid agonist), pentazocine (schedule IV, kappa opioid agonist) and tramadol (schedule IV, mu opioid agonist [[Page 48047]] prodrug) generalized to hydromorphone (schedule II, mu opioid agonist). Thus, these drug discrimination data demonstrate that mu opioid agonists will be recognized by animals and humans as having similar pharmacological properties to each other. Drug self-administration tests in animals are used to evaluate the rewarding effects of drugs. There is a good correlation between those drugs that are self-administered by animals and those that are abused by humans. The data from self-administration studies provide a measure for abuse potential. In a self-administration study with monkeys (n = 5) trained to self-administer heroin (0.032 mg/kg/infusion in two monkeys or 0.01 mg/kg/infusion in three monkeys), the 0.32 and 1.0 mg/ kg/infusion doses of eluxadoline HCl did not produce self- administration in one monkey trained to self-administer the higher 0.032 mg/kg/infusion dose of heroin, or in three other monkeys trained to self-administer the lower 0.001 mg/kg/infusion dose of heroin. When the highest dose of eluxadoline HCI (3.2 mg/kg/infusion) was tested first in the two monkeys trained at the 0.032 mg/kg/infusion dose of heroin, the self-administration rate of eluxadoline HCl (10-19 infusions/session) was less than that of heroin, but more than that of saline (2-4 infusions/session). The self-administration of eluxadoline in animals seems similar to that of the mu and kappa opioid agonist, butorphanol (schedule IV), a kappa opioid agonist, pentazocine (schedule IV) and another mu opioid agonist prodrug, tramadol (schedule IV). Human Behavioral Studies In a clinical study, the abuse potential, safety, tolerability, and pharmacokinetics of orally administered eluxadoline (100, 300 and 1000 mg) were compared with positive control drug, oxycodone (30 and 60 mg) in healthy non-dependent recreational opioid users. Of the subjects who received any study treatment, a total of 33 subjects completed the study. On the primary subjective measure of VAS Drug Liking, eluxadoline at the two supratherapeutic doses (300 and 1000 mg) produced statistically significant higher maximum (Emax) scores on Drug Liking compared to placebo. When compared to that of either dose of oxycodone on Drug Liking, all three tested doses of eluxadoline (100, 300 and 1000 mg) showed statistically significant lower Emax scores. Eighteen of the 36 subjects who received eluxadoline showed a statistically significant positive response on Drug Liking with at least one of the eluxadoline doses tested. Data from the secondary subjective measures showed that oxycodone (30 and 60 mg) statistically significantly increased scores on other positive subjective responses such as the VAS for Overall Drug Liking, Take Drug Again, Subjective Drug Value, Good Drug Effects, High, and ARCI-MBG (Euphoria). At supratherapeutic oral doses (300 and/or 1000 mg), eluxadoline elicited statistically significant increases as compared to the placebo in positive subjective responses such as VAS for Take Drug Again, Subjective Drug Value, Good Drug Effects, High, and ARCI-MBG (Euphoria). The positive subjective responses to eluxadoline were most often statistically significantly less than those produced by either dose of oxycodone (30 and 60 mg). The HHS states that these results are similar to those produced by a kappa opioid agonist, pentazocine (schedule IV). Eluxadoline at all doses elicited a small but significant increase in the VAS score for Drug Disliking, but it happened one to two hours before the peak Drug Liking response. Furthermore, there were no statistically significant differences in Drug Disliking between eluxadoline and oxycodone (60 mg). Eluxadoline also produced a statistically significant increase in VAS Bad Drug Effects, and ARCI-LSD (Dysphoria), but did not cause a significant increase in Drowsiness and Sedation. These results are also similar to those produced by pentazocine in a published study which reported a statistically significant increase in the VAS score for Bad Drug Effects and the score for ARCI-LSD (Dysphoria). Oral administration of eluxadoline produced an increase in several classical opioid-like adverse events (AEs) associated with mu opioid agonists. Eluxadoline (ranging from 14-28%) produced euphoria in a dose-dependent manner and it was greater than that after placebo (5%) but less than that of oxycodone (ranging from 73-76%). Eluxadoline induced centrally-mediated responses such as somnolence (ranging from 19-42%), and it overlaps with the rate reported for oxycodone (38-41%) and placebo (19%). Peripheral opioid-associated AEs such as dry mouth were also mentioned (11-19% for eluxadoline and 11-13% for oxycodone). Pruritus was also reported with a range of 8-11% for eluxadoline and 54-70% for oxycodone. The above AEs support that eluxadoline produced typical opioid-like effects, although these are less frequent than reported for oxycodone. Another clinical study evaluated the abuse potential and safety of intranasal administration of crushed eluxadoline (100 and 200 mg) in comparison to crushed oxycodone HCl (crushed, 15 and 30 mg) in 31 healthy adult, non-dependent recreational opioid users. On the primary subjective measure of Drug Liking VAS, eluxadoline (100 and 200 mg) failed to produce Emax scores on Drug Liking that were statistically different from that of placebo while oxycodone at both tested doses (15 and 30 mg) produced statistically significant higher maximum (Emax) scores compared to placebo. Results for the secondary subjective measures show oxycodone (15 and 30 mg) significantly increased scores on positive subjective responses including the VAS for Overall Drug Liking, Take Drug Again, Subjective Drug Value, Good Drug Effects, High, and ARCI-MBG (Euphoria). Eluxadoline (100 and 200 mg) produced significant increases compared to placebo in these positive subjective responses. The positive subjective responses to eluxadoline were most often significantly less than those produced by either dose of oxycodone. Intranasal eluxadoline produced a small but statistically significant increase in the VAS for Drug Disliking while oxycodone did not. Eluxadoline also produced a significant increase in VAS Bad Drug Effects, ARCI-LSD (Dysphoria), Drowsiness, and Sedation. Oxycodone at both doses increased each of these negative subjective measurements, to a degree significantly greater than that of placebo but similar to the high dose of eluxadoline. Subjects identified eluxadoline as an opioid to a degree that was less than that of oxycodone. Intranasal administration of eluxadoline caused adverse events such as euphoria after the 100 mg (22%) and the 200 mg doses (19%). Rate of euphoria following eluxadoline was less than that of oxycodone at 15 mg (44%) and 30 mg (67%), and greater than placebo (0%). All incidences of euphoria produced by eluxadoline were mild in intensity. The clinical efficacy studies conducted with oral eluxadoline (75 and 100 mg/BID) reported abuse-related AEs. The AE of euphoric mood was reported by only two IBS-d patients in the pooled Phase 2 and 3 safety trials (0.2% of population). The dose of eluxadoline for both these subjects was 100 mg BID. Similarly, the AE of ``feeling drunk'' was reported by only two subjects (0.1% of subjects in the 75 mg group and 0.1% of subjects in the 100 mg group). Other than euphoria, anxiety (1.7%) and somnolence (0.7%) [[Page 48048]] were the most commonly reported abuse-related AEs. There were a few other central nervous system-associated AEs observed in clinical trials. These included headache (4.0-4.5%), dizziness (2.2-3.2%), and fatigue (1.9-2.6%). Thus there was a very low incidence of euphoria- related AEs in these clinical studies. It is not uncommon for patients participating in clinical studies to exhibit a low rate of euphoria- related AEs compared to participants in Phase I human abuse potential studies. This difference may be due to the underlying disease state of the patient population in clinical studies versus the healthy subject population in human abuse potential studies. 3. The State of Current Scientific Knowledge Regarding Eluxadoline: The chemical name of eluxadoline is 5-[[[(2S)-2-amino-3-[4- aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H- imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid. The molecular formula of eluxadoline is C 32 H35 N5 O5 and its molecular weight is 569.65. Eluxadoline has two asymmetric carbons, and there are at least four different optical isomers. Because eluxadoline contains a primary amine and a carboxylic acid in its structure, the pH of the solution will determine whether the primary amine will be protonated (positively charged) and the carboxylic acid will be deprotonated (negatively charged). The synthesis of eluxadoline requires a high level of expertise and knowledge in organic chemistry. The tablets could be cracked and easily crushed by users with a tablet crusher or a mortar and pestle. However, the unique physicochemical properties of eluxadoline may present a challenge to isolate eluxadoline for purposes of abuse. The half-life of eluxadoline is approximately five hours, with high inter-subject variability. Eluxadoline has a low oral bioavailability due to poor GI permeability and moderate hepatic first-pass extraction involving OATP1B1-mediated hepatic uptake of eluxadoline. Co- administration with food lowered systemic exposures. Biliary excretion accounted for over 80% of overall elimination, while there is a minimal elimination by renal excretion. 4. History and Current Pattern of Abuse: Because eluxadoline is a new molecular entity and has not been marketed in any country, information as to the history and current pattern of its abuse is not available. Data from pre-clinical and clinical studies indicated that eluxadoline shares pharmacological similarities with schedule IV drugs such as pentazocine and butorphanol and has similar abuse potential (see factors 1 and 2). Pentazocine and butorphanol were initially approved for market as non-controlled drugs. However, subsequent reports of actual abuse of pentazocine and butorphanol supported control as schedule IV drugs under the CSA. It is likely that eluxadoline, upon approval for marketing, will be abused for its rewarding effects. Eluxadoline generalized to the stimulus effects of morphine (schedule II) in animal drug discrimination studies. These discriminative stimulus effects are similar to that for butorphanol, a schedule IV mu and kappa opioid receptor agonist and for pentazocine, a schedule IV kappa opioid receptor agonist. In two human abuse potential studies, eluxadoline produced both positive and negative subjective responses. The maximal effects of eluxadoline on Drug Liking are greater than that of placebo, but less than that of oxycodone (schedule II). Eluxadoline at all doses elicited a small but significant increase in the VAS score for Drug Disliking. The negative subjective responses of eluxadoline may be reflective of its kappa opioid receptor agonist properties and these are similar to those of schedule IV opioids, butorphanol and pentazocine. These dysphoric effects may indicate a lower abuse potential of a substance. In human abuse potential studies oral or intranasal administration of eluxadoline produced euphoria with a degree less than that of oxycodone. As of May 20, 2015, no reports for eluxadoline were identified in either the National Forensic Laboratory Information System (NFLIS),\3\ or System to Retrieve Information on Drug Evidence (STRIDE).\4\ --------------------------------------------------------------------------- \3\ NFLIS is a program of the DEA that collects drug identification results from drug cases analyzed by other Federal, State, and local forensic laboratories. \4\ STRIDE collected the results of drug evidence analyzed at DEA laboratories and reflects evidence submitted by the DEA, other Federal law enforcement agencies, and some local law enforcement agencies. On October 1, 2014, STARLiMS replaced STRIDE as the DEA laboratory drug evidence data system of record. --------------------------------------------------------------------------- 5. The Scope, Duration, and Significance of Abuse: Because eluxadoline is a new molecular entity and has not been marketed in any country, information as to the scope, duration and significance of its abuse is not available. Both pre-clinical and clinical studies indicate that eluxadoline shares pharmacological similarities with schedule IV drugs such as butorphanol and pentazocine and has similar abuse potential. Pentazocine and butorphanol were initially marketed as uncontrolled drugs. However subsequent reports of abuse of butorphanol and pentazocine led to their control as schedule IV drugs under the CSA. Thus, if eluxadoline were to be marketed as a non-controlled drug, it is likely to be abused for its rewarding properties. If uncontrolled, it is also likely that individuals seeking opioids will abuse eluxadoline as a substitute for other opioids that are controlled under the CSA. In human abuse potential studies, eluxadoline produced both positive and negative subjective responses. The maximal effects of eluxadoline on Drug Liking are greater than that of placebo, but less than that of oxycodone (schedule II). Eluxadoline at all doses elicited a small but significant increase in the VAS score for Drug Disliking. The negative subjective responses of eluxadoline may be reflective of its kappa opioid receptor agonist properties and these are similar to those of schedule IV opioids, butorphanol and pentazocine. These dysphoric effects may indicate a lower abuse potential of eluxadoline. 6. What, If Any, Risk There Is To the Public Health: Data from pre- clinical and clinical studies indicate that eluxadoline has abuse potential similar to schedule IV opioids such as butorphanol and pentazocine. Abuse potential of a drug is considered a risk to the public health. Available information suggests that if eluxadoline were to be marketed as a non-controlled drug, it would be abused for its rewarding properties. The major concern regarding eluxadoline's risk to public health is based on animal studies in monkeys treated with eluxadoline, where the animals exhibited opioid overdose symptoms such as decreased activity, unresponsiveness, decreased body temperature, and decreased respiration rates. Severe sedation and slumping were also observed in monkeys following self-administration with eluxadoline. Furthermore, opioid-like effects of eluxadoline may not be reversible unless adequate or repeated administration of opioid antagonists such as naloxone or naltrexone is performed. 7. Its Psychic or Physiological Dependence Liability: Several pre- clinical studies both on Cynomolgus monkeys and rats treated with different doses of eluxadoline followed by various recovery or drug discontinuation periods showed no behavioral changes during the treatment period. There were also no behaviors suggestive of withdrawal during the observed recovery periods. Thus, chronic administration of eluxadoline [[Page 48049]] did not result in withdrawal signs in laboratory monkeys and rats. However, monkeys self-administered eluxadoline. This suggests that eluxadoline has sufficient rewarding effects to induce reinforcement. In human subjects, the abuse-related AEs reported in clinical studies found that eluxadoline produced a low incidence of euphoria, ``feeling drunk,'' anxiety, somnolence, headache, abdominal pain, dizziness, and fatigue, which are suggestive of its ability to produce psychic dependence. 8. Whether the Substance is an Immediate Precursor of a Substance Already Controlled Under the CSA: Eluxadoline is not an immediate precursor of any substance controlled under the CSA. Conclusion: Based on consideration of the scientific and medical evaluation conducted by the HHS and its recommendation, and after considering its own eight-factor analysis, the DEA has determined that these facts and all relevant data constitute substantial evidence of potential for abuse of eluxadoline. As such, the DEA hereby proposes to schedule eluxadoline as a controlled substance under the CSA. Findings for Schedule Placement The CSA establishes five schedules of controlled substances known as schedules I, II, III, IV, and V. The statute outlines the findings required in placing a drug or other substance in any schedule. 21 U.S.C. 812(b). After consideration of the analysis and recommendation of the Assistant Secretary for Health of the HHS and review of all available data, the Administrator of the DEA, pursuant to 21 U.S.C. 812(b), finds that: (1) The drug or other substance has a low potential for abuse relative to the drugs or other substances in schedule III. Eluxadoline has a low potential for abuse relative to the drugs or other substances in schedule III. The overall abuse potential of eluxadoline is comparable to the schedule IV substances such as pentazocine and butorphanol. (2) The drug or other substance has a currently accepted medical use in treatment in the United States. Recently, the FDA approved eluxadoline as a prescription drug for the treatment of irritable bowel syndrome with diarrhea (IBS-d). Therefore, eluxadoline has a currently accepted medical use in treatment in the United States. (3) 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. Abuse of eluxadoline may lead to limited psychological dependence similar to that of schedule IV drugs, but less than that of schedule III drugs. Based on these findings, the Administrator of the DEA concludes that eluxadoline, 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 Eluxadoline If this rule is finalized as proposed, eluxadoline would be subject to the CSA's schedule IV regulatory controls and administrative, civil, and criminal sanctions applicable to the manufacture, distribution, dispensing, importing, exporting, research, and conduct of instructional activities involving schedule IV substances, including the following: 1. Registration. Any person who handles (manufactures, distributes, dispenses, imports, exports, engages in research, or conducts instructional activities with) eluxadoline, or who desires to handle eluxadoline, would be required to be registered with the DEA to conduct such activities pursuant to 21 U.S.C. 822, 823, 957, and 958 and in accordance with 21 CFR parts 1301 and 1312. Any person who currently handles eluxadoline, and is not registered with the DEA, would need to submit an application for registration and may not continue to handle eluxadoline as of the effective date of the final rule, unless the DEA has approved that application for registration, pursuant to 21 U.S.C. 822, 823, 957, 958, and in accordance with 21 CFR parts 1301 and 1312. 2. Security. Eluxadoline would be subject to schedule III-V security requirements and would need to be handled and stored pursuant to 21 U.S.C. 821, 823, 871(b) and in accordance with 21 CFR 1301.71- 1301.93. 3. Labeling and Packaging. All labels and labeling for commercial containers of eluxadoline on or after finalization of this proposed rule would need to comply with 21 U.S.C. 825 and 958(e), and be in accordance with 21 CFR part 1302. 4. Inventory. Every DEA registrant who possesses any quantity of eluxadoline on the effective date of the final rule would be required to take an inventory of all stocks of eluxadoline on hand as of the effective date of the rule, pursuant to 21 U.S.C. 827 and 958, and in accordance with 21 CFR 1304.03, 1304.04, and 1304.11(a) and (d). Any person who becomes registered with the DEA after the effective date of the final rule must take an initial inventory of all stocks of controlled substances (including eluxadoline) on hand on the date the registrant first engages in the handling of controlled substances, pursuant to 21 U.S.C. 827 and 958 and in accordance with 21 CFR 1304.03, 1304.04, and 1304.11(a) and (b). After the initial inventory, every DEA registrant would be required to take an inventory of all controlled substances (including eluxadoline) on hand, on a biennial basis, pursuant to 21 U.S.C. 827 and 958, and in accordance with 21 CFR 1304.03, 1304.04, and 1304.11. 5. Records. All DEA registrants would be required to maintain records with respect to eluxadoline pursuant to 21 U.S.C. 827 and 958, and in accordance with 21 CFR parts 1304, 1307, and 1312. 6. Prescriptions. All prescriptions for eluxadoline or products containing eluxadoline would need to comply with 21 U.S.C. 829, and be issued in accordance with 21 CFR parts 1306 and 1311, subpart C. 7. Importation and Exportation. All importation and exportation of eluxadoline would need to be in compliance with 21 U.S.C. 952, 953, 957, and 958, and in accordance with 21 CFR part 1312. 8. Criminal Liability. Any activity involving eluxadoline not authorized by, or in violation of, the CSA, occurring on or after finalization of this proposed rule, would be unlawful, and may subject the person to administrative, civil, and/or criminal sanctions. 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 performed ``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 procedures and criteria for scheduling a drug or other substance. Such actions are exempt from review by the Office of Management and Budget (OMB) 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 to eliminate drafting errors and ambiguity, minimize litigation, provide a clear legal standard for affected conduct, and promote simplification and burden reduction. Executive Order 13132 This proposed rulemaking does not have federalism implications warranting the application of Executive Order [[Page 48050]] 13132. The proposed rule does not have substantial direct effects on the States, on the relationship between the national government and the States, or the distribution of power and responsibilities among the various levels of government. Executive Order 13175 This proposed rule will not have tribal implications warranting the application of Executive Order 13175. It does not have substantial direct effects on one or more Indian tribes, on the relationship between the Federal government and Indian tribes, or on the distribution of power and responsibilities between the Federal government and Indian tribes. Regulatory Flexibility Act The Administrator, in accordance with the Regulatory Flexibility Act (RFA), 5 U.S.C. 601-612, has reviewed this proposed rule and by approving it certifies that it will not have a significant economic impact on a substantial number of small entities. The purpose of this proposed rule is to place eluxadoline, including its salts, isomers, and salts of isomers, into schedule IV of the CSA. No less restrictive measures (i.e., non-control, or control in schedule V) enable the DEA to meet its statutory obligations under the CSA. In preparing this certification, the DEA has assessed economic impact by size category and has considered costs with respect to the various DEA registrant business activity classes. Eluxadoline is a new molecular entity which has not yet been marketed in the United States or any other country. Although the manufacturer is expected to enjoy market exclusivity for many years, the DEA has no basis to determine the level of contracted or outsourced manufacturing activities or the breadth of the distribution network. Furthermore, due to the wide variety of unidentifiable and unquantifiable variables that could potentially influence the dispensing and distribution rates of new pharmaceutical drugs, the DEA is unable to determine the number of potential small entities that might handle eluxadoline. However, the DEA estimates that all persons who would handle, or propose to handle, eluxadoline are currently registered with the DEA to handle schedule IV controlled substances, because it is a pharmaceutical controlled substance intended for medical treatment. Accordingly, the number of DEA registrations authorized to handle schedule IV controlled substances is a reasonable estimate for the maximum number of eluxadoline handlers. Therefore, the DEA estimates that 1.6 million (1,554,254 as of June 2015) controlled substance registrations, representing approximately 427,584 entities, would be the maximum number of entities affected by this rule. The DEA estimates that 418,141 (97.8%) of 427,584 affected entities are ``small entities'' in accordance with the RFA and SBA size standards. The DEA anticipates that prospective eluxadoline handlers already handle other schedule IV controlled substances and that the cost impact as a result of placing eluxadoline in schedule IV would be nominal. As the anticipated eluxadoline handlers already handle other scheduled IV controlled substances, they already have DEA registrations and the required security and recordkeeping processes, equipment, and facilities in place, and would only require a nominal increase in security, inventory, recordkeeping and labeling costs. As discussed above, while the DEA does not have a basis to estimate the number of affected entities, the DEA estimates that the maximum number of affected entities is 427,584 of which 418,141 are estimated to be small entities. Since the affected entities are expected to handle other schedule IV controlled substances and maintain security and recordkeeping facilities and processes consistent with schedule IV controlled substances, the DEA estimates any economic impact will be nominal. Because of these facts, this proposed rule will not result in a significant economic impact on a substantial number of small entities. Unfunded Mandates Reform Act of 1995 In accordance with the Unfunded Mandates Reform Act (UMRA) of 1995, 2 U.S.C. 1501 et seq., the DEA has determined and certifies that this action would not result in any Federal mandate that may result ``in the expenditure by State, local, and tribal governments, in the aggregate, or by the private sector, of $100,000,000 or more (adjusted for inflation) in any one year.'' Therefore, neither a Small Government Agency Plan nor any other action is required under UMRA of 1995. Paperwork Reduction Act of 1995 This action does not impose a new collection of information requirement under the Paperwork Reduction Act of 1995, 44 U.S.C. 3501- 3521. This action would not impose recordkeeping or reporting requirements on State or local governments, individuals, businesses, or organizations. An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB control number. 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, the DEA proposes to amend 21 CFR part 1308 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. Amend Sec. 1308.14 by adding paragraph (g)(3) to read as follows: Sec. 1308.14 Schedule IV. * * * * * (g) * * * (3) Eluxadoline (5-[[[(2S)-2-amino-3-[4-aminocarbonyl)- (9725) 2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H- imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid) (including its optical isomers) and its salts, isomers, and salts of isomers.......................... [[Page 48051]] Dated: August 5, 2015. Chuck Rosenberg, Acting Administrator. [FR Doc. 2015-19655 Filed 8-10-15; 8:45 am] BILLING CODE 4410-09-P
![48044 Federal Register / Vol. 80, No. 154 / Tuesday, August 11, 2015 / Proposed Rules
DEPARTMENT OF JUSTICE • Electronic comments: The Drug (such as your name, address, etc.) as
Enforcement Administration encourages part of your comment, but do not want
Drug Enforcement Administration that all comments be submitted it to be made publicly available, you
electronically through the Federal must include the phrase ‘‘PERSONAL
21 CFR Part 1308 eRulemaking Portal, which provides the IDENTIFYING INFORMATION’’ in the
[Docket No. DEA–419N] ability to type short comments directly first paragraph of your comment. You
into the comment field on the Web page must also place the personal identifying
Schedules of Controlled Substances: or to attach a file for lengthier information you do not want made
Placement of Eluxadoline Into comments. Please go to http:// publicly available in the first paragraph
Schedule IV www.regulations.gov and follow the of your comment and identify what
online instructions at that site for information you want redacted.
AGENCY: Drug Enforcement submitting comments. Upon completion If you want to submit confidential
Administration, Department of Justice. of your submission you will receive a business information as part of your
ACTION: Notice of proposed rulemaking. Comment Tracking Number for your comment, but do not want it to be made
comment. Please be aware that publicly available, you must include the
SUMMARY: The Drug Enforcement
submitted comments are not phrase ‘‘CONFIDENTIAL BUSINESS
Administration proposes to place the
instantaneously available for public INFORMATION’’ in the first paragraph
substance eluxadoline (5-[[[(2S)-2-
view on Regulations.gov. If you have of your comment. You must also
amino-3-[4-aminocarbonyl)-2,6-
received a Comment Tracking Number, prominently identify confidential
dimethylphenyl]-1-oxopropyl][(1S)-1-(4-
your comment has been successfully business information to be redacted
phenyl-1H-imidazol-2-
submitted and there is no need to within the comment.
yl)ethyl]amino]methyl]-2- Comments containing personal
methoxybenzoic acid), including its resubmit the same comment.
• Paper comments: Paper comments identifying information and confidential
salts, isomers, and salts of isomers, into business information identified as
schedule IV of the Controlled that duplicate the electronic submission
are not necessary and are discouraged. directed above will generally be made
Substances Act (CSA). This proposed publicly available in redacted form. If a
scheduling action is pursuant to the Should you wish to mail a paper
comment in lieu of an electronic comment has so much confidential
CSA which requires that such actions be business information or personal
made on the record after opportunity for comment, it should be sent via regular
or express mail to: Drug Enforcement identifying information that it cannot be
a hearing through formal rulemaking. If effectively redacted, all or part of that
finalized, this action would impose the Administration, Attn: DEA Federal
Register Representative/ODL, 8701 comment may not be made publicly
regulatory controls and administrative, available. Comments posted to http://
civil, and criminal sanctions applicable Morrissette Drive, Springfield, Virginia
22152. www.regulations.gov may include any
to schedule IV controlled substances on personal identifying information (such
persons who handle (manufacture, • Hearing requests: All requests for
hearing and waivers of participation as name, address, and phone number)
distribute, dispense, import, export, included in the text of your electronic
engage in research, conduct must be sent to: Drug Enforcement
submission that is not identified as
instructional activities, or possess), or Administration, Attn: Federal Register
directed above as confidential.
propose to handle eluxadoline. Representative/ODL, 8701 Morrissette
An electronic copy of this document
DATES: Interested persons may file Drive, Springfield, Virginia 22152. All and supplemental information to this
written comments on this proposal in requests for hearing and waivers of proposed rule are available at http://
accordance with 21 CFR 1308.43(g). participation should also be sent to: www.regulations.gov for easy reference.
Electronic comments must be Drug Enforcement Administration, Attn:
submitted, and written comments must Hearing Clerk/LJ, 8701 Morrissette Request for Hearing, Notice of
be postmarked, on or before September Drive, Springfield, Virginia 22152. Appearance at Hearing, Waiver of an
10, 2015. Commenters should be aware FOR FURTHER INFORMATION CONTACT: John Opportunity for a Hearing or To
that the electronic Federal Docket R. Scherbenske, Office of Diversion Participate in a Hearing
Management System will not accept Control, Drug Enforcement Pursuant to 21 U.S.C. 811(a), this
comments after 11:59 p.m. Eastern Time Administration; Mailing Address: 8701 action is a formal rulemaking ‘‘on the
on the last day of the comment period. Morrissette Drive, Springfield, Virginia record after opportunity for a hearing.’’
Interested persons, defined at 21 CFR 22152; Telephone: (202) 598–6812. Such proceedings are conducted
1300.01 as those ‘‘adversely affected or SUPPLEMENTARY INFORMATION: pursuant to the provisions of the
aggrieved by any rule or proposed rule Administrative Procedure Act (APA), 5
issuable pursuant to section 201 of the Posting of Public Comments U.S.C. 551–559. 21 CFR 1308.41–
Act (21 U.S.C. 811),’’ may file a request Please note that all comments 1308.45; 21 CFR part 1316, subpart D.
for hearing, notice of appearance, or received in response to this docket are In accordance with 21 CFR 1308.44(a)–
waiver of hearing pursuant to 21 CFR considered part of the public record. (c), requests for hearing, notices of
1308.44 and in accordance with 21 CFR They will, unless reasonable cause is appearance, and waivers of an
1316.45, 1316.47, 1316.48, or 1316.49, given, be made available by the Drug opportunity for a hearing or to
as applicable. Requests for hearing, Enforcement Administration (DEA) for participate in a hearing may be
notices of appearance, and waivers of an public inspection online at http:// submitted only by interested persons,
rmajette on DSK2TPTVN1PROD with PROPOSALS
opportunity for a hearing or to www.regulations.gov. Such information defined as those ‘‘adversely affected or
participate in a hearing must be includes personal identifying aggrieved by any rule or proposed rule
received on or before September 10, information (such as your name, issuable pursuant to section 201 of the
2015. address, etc.) voluntarily submitted by Act (21 U.S.C. 811).’’ 21 CFR 1300.01.
ADDRESSES: To ensure proper handling the commenter. The Freedom of Such requests or notices must conform
of comments, please reference ‘‘Docket Information Act (FOIA) applies to all to the requirements of 21 CFR
No. DEA–419N’’ on all correspondence, comments received. If you want to 1308.44(a) or (b), and 1316.47 or
including any attachments. submit personal identifying information 1316.48, as applicable, and include a
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![Federal Register / Vol. 80, No. 154 / Tuesday, August 11, 2015 / Proposed Rules 48045
statement of interest of the person in the for abuse, and * * * makes with respect the HHS’ recommendation to control
proceeding and the objections or issues, to such drug or other substance the eluxadoline under schedule IV of the
if any, concerning which the person findings prescribed by subsection (b) of CSA.
desires to be heard. Any waiver must section 812 of this title for the schedule In response, the DEA reviewed the
conform to the requirements of 21 CFR in which such drug is to be placed scientific and medical evaluation and
1308.44(c) and 1316.49, including a * * *.’’ The Attorney General has scheduling recommendation provided
written statement regarding the delegated scheduling authority under 21 by the HHS, and all other relevant data,
interested person’s position on the U.S.C. 811 to the Administrator of the and completed its own eight-factor
matters of fact and law involved in any DEA. 28 CFR 0.100. review document pursuant to 21 U.S.C.
hearing. The CSA provides that scheduling of 811(c). Included below is a brief
Please note that pursuant to 21 U.S.C. any drug or other substance may be summary of each factor as analyzed by
811(a), the purpose and subject matter initiated by the Attorney General (1) on the HHS and the DEA, and as
of a hearing is restricted to: ‘‘find[ing] her own motion; (2) at the request of the considered by the DEA in its proposed
that such drug or other substance has a Secretary of Health and Human Services scheduling decision. Please note that
potential for abuse, and * * * mak[ing] (HHS); or (3) on the petition of any both the DEA and the HHS analyses are
with respect to such drug or other interested party. 21 U.S.C. 811(a). If available in their entirety under
substance the findings prescribed by finalized, this action would impose the ‘‘Supporting and Related Material’’ in
subsection (b) of section 812 of this title regulatory controls and administrative, the public docket for this proposed rule
for the schedule in which such drug is civil, and criminal sanctions of schedule at http://www.regulations.gov, under
to be placed * * *.’’ All requests for IV controlled substances for any person Docket Number ‘‘DEA–419N’’. Full
hearing and waivers of participation who handles eluxadoline. analysis of, and citations to, the
must be sent to the DEA using the information referenced in the summary
address information provided above. Background
may also be found in the supporting and
Legal Authority Eluxadoline is a new molecular entity related material.
with central nervous system opioid 1. The Drug’s Actual or Relative
The DEA implements and enforces properties. It has not been marketed in Potential for Abuse: Eluxadoline is a
titles II and III of the Comprehensive any country. Eluxadoline has mixed mu new chemical entity that has not been
Drug Abuse Prevention and Control Act opioid receptor (MOR) and kappa marketed in the U.S. or in any other
of 1970, as amended. 21 U.S.C. 801–971. opioid receptor (KOR) agonist and delta country. As such, there is no
Titles II and III are referred to as the opioid receptor (DOR) antagonist information available which details
‘‘Controlled Substances Act’’ and the properties. Recently, the Food and Drug actual abuse of eluxadoline. However,
‘‘Controlled Substances Import and Administration (FDA) approved the legislative history of the CSA
Export Act,’’ respectively, and are eluxadoline as a prescription drug for suggests that the DEA consider the
collectively referred to as the the treatment of irritable bowel following criteria in determining
‘‘Controlled Substances Act’’ or the syndrome with diarrhea (IBS-d). whether a particular drug or substance
‘‘CSA’’ for the purpose of this action. Eluxadoline will be marketed as 75 and has a potential for abuse: 2
The DEA publishes the implementing 100 milligrams (mg) oral tablets under
regulations for these statutes in title 21 (1) There is evidence that individuals are
the trade name of Viberzi. taking the drug or drugs containing such a
of the Code of Federal Regulations
substance in amounts sufficient to create a
(CFR), chapter II. The CSA and its Proposed Determination To Schedule
hazard to their health or to the safety of other
implementing regulations are designed Eluxadoline individuals or to the community;
to prevent, detect, and eliminate the Pursuant to 21 U.S.C. 811(a)(1), (2) There is significant diversion of the
diversion of controlled substances and proceedings to add a drug or substance drug or substance from legitimate drug
listed chemicals into the illicit market to those controlled under the CSA may channels;
while ensuring an adequate supply is (3) Individuals are taking the substance on
be initiated by request of the Secretary their own initiative rather than on the basis
available for the legitimate medical, of the HHS.1 The HHS provided the
scientific, research, and industrial needs of medical advice from a practitioner
DEA with a scientific and medical licensed by law to administer such drugs in
of the United States. Controlled evaluation document (dated May 5, the course of his professional practice; or
substances have the potential for abuse 2015) prepared by the FDA entitled (4) The drug or drugs containing such a
and dependence and are controlled to ‘‘Basis for the Recommendation to Place substance are new drugs so related in their
protect the public health and safety. Eluxadoline and Its Salts into schedule action to a drug or drugs already listed as
Under the CSA, each controlled IV of the Controlled Substances Act’’ having a potential for abuse to make it likely
substance is classified into one of five and a scheduling recommendation. that they will have the same potentiality for
schedules based upon its potential for abuse as such substance, thus making it
Pursuant to 21 U.S.C. 811(b), this reasonable to assume that there may be
abuse, its currently accepted medical document contained an eight-factor significant diversions from legitimate
use in treatment in the United States, analysis of the abuse potential of channels, significant use contrary to or
and the degree of dependence the eluxadoline as a new drug, along with without medical advice, or that it has a
substance may cause. 21 U.S.C. 812. The substantial capability of creating hazards to
initial schedules of controlled 1 As set forth in a memorandum of understanding the health of the user or to the safety of the
substances established by Congress are entered into by the HHS, the Food and Drug community.
found at 21 U.S.C. 812(c), and the Administration (FDA), and the National Institute on
Both the HHS and the DEA note that
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current list of all scheduled substances Drug Abuse (NIDA), the FDA acts as the lead agency
within the HHS in carrying out the Secretary’s three of the above mentioned four
is published at 21 CFR part 1308. scheduling responsibilities under the CSA, with the criteria (1, 2, and 3) do not apply to
Pursuant to 21 U.S.C. 811(a)(1), the concurrence of the NIDA. 50 FR 9518, Mar. 8, 1985. eluxadoline for the following reasons.
Attorney General may, by rule, ‘‘add to In addition, because the Secretary of the HHS has
delegated to the Assistant Secretary for Health of Eluxadoline is a new molecular entity
such a schedule or transfer between
the HHS the authority to make domestic drug
such schedules any drug or other scheduling recommendations, for purposes of this 2 Comprehensive Drug Abuse Prevention and
substance if he * * * finds that such document, all subsequent references to ‘‘Secretary’’ Control Act of 1970, H.R. Rep. No. 91–1444, 91st
drug or other substance has a potential have been replaced with ‘‘Assistant Secretary.’’ Cong., Sess. 1 (1970); 1970 U.S.C.C.A.N. 4566, 4601.
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![48048 Federal Register / Vol. 80, No. 154 / Tuesday, August 11, 2015 / Proposed Rules
were the most commonly reported as pentazocine and butorphanol and has uncontrolled drugs. However
abuse-related AEs. There were a few similar abuse potential (see factors 1 subsequent reports of abuse of
other central nervous system-associated and 2). Pentazocine and butorphanol butorphanol and pentazocine led to
AEs observed in clinical trials. These were initially approved for market as their control as schedule IV drugs under
included headache (4.0–4.5%), non-controlled drugs. However, the CSA. Thus, if eluxadoline were to be
dizziness (2.2–3.2%), and fatigue (1.9– subsequent reports of actual abuse of marketed as a non-controlled drug, it is
2.6%). Thus there was a very low pentazocine and butorphanol supported likely to be abused for its rewarding
incidence of euphoria-related AEs in control as schedule IV drugs under the properties. If uncontrolled, it is also
these clinical studies. It is not CSA. It is likely that eluxadoline, upon likely that individuals seeking opioids
uncommon for patients participating in approval for marketing, will be abused will abuse eluxadoline as a substitute
clinical studies to exhibit a low rate of for its rewarding effects. for other opioids that are controlled
euphoria-related AEs compared to Eluxadoline generalized to the under the CSA.
participants in Phase I human abuse stimulus effects of morphine (schedule In human abuse potential studies,
potential studies. This difference may II) in animal drug discrimination eluxadoline produced both positive and
be due to the underlying disease state of studies. These discriminative stimulus negative subjective responses. The
the patient population in clinical effects are similar to that for maximal effects of eluxadoline on Drug
studies versus the healthy subject butorphanol, a schedule IV mu and Liking are greater than that of placebo,
population in human abuse potential kappa opioid receptor agonist and for but less than that of oxycodone
studies. pentazocine, a schedule IV kappa opioid (schedule II). Eluxadoline at all doses
3. The State of Current Scientific receptor agonist. In two human abuse elicited a small but significant increase
Knowledge Regarding Eluxadoline: The potential studies, eluxadoline produced in the VAS score for Drug Disliking. The
chemical name of eluxadoline is 5- both positive and negative subjective negative subjective responses of
[[[(2S)-2-amino-3-[4-aminocarbonyl)-2,6- responses. The maximal effects of eluxadoline may be reflective of its
dimethylphenyl]-1-oxopropyl][(1S)-1-(4- eluxadoline on Drug Liking are greater kappa opioid receptor agonist properties
phenyl-1H-imidazol-2- than that of placebo, but less than that and these are similar to those of
yl)ethyl]amino]methyl]-2- of oxycodone (schedule II). Eluxadoline schedule IV opioids, butorphanol and
methoxybenzoic acid. The molecular at all doses elicited a small but pentazocine. These dysphoric effects
formula of eluxadoline is C32H35N5O5 significant increase in the VAS score for may indicate a lower abuse potential of
and its molecular weight is 569.65. Drug Disliking. The negative subjective eluxadoline.
Eluxadoline has two asymmetric responses of eluxadoline may be 6. What, If Any, Risk There Is To the
carbons, and there are at least four reflective of its kappa opioid receptor Public Health: Data from pre-clinical
different optical isomers. Because agonist properties and these are similar and clinical studies indicate that
eluxadoline contains a primary amine eluxadoline has abuse potential similar
to those of schedule IV opioids,
and a carboxylic acid in its structure, to schedule IV opioids such as
butorphanol and pentazocine. These
the pH of the solution will determine butorphanol and pentazocine. Abuse
dysphoric effects may indicate a lower
whether the primary amine will be potential of a drug is considered a risk
abuse potential of a substance. In
protonated (positively charged) and the to the public health. Available
human abuse potential studies oral or
carboxylic acid will be deprotonated information suggests that if eluxadoline
intranasal administration of eluxadoline
(negatively charged). The synthesis of were to be marketed as a non-controlled
produced euphoria with a degree less
eluxadoline requires a high level of drug, it would be abused for its
than that of oxycodone.
expertise and knowledge in organic rewarding properties. The major
As of May 20, 2015, no reports for
chemistry. The tablets could be cracked concern regarding eluxadoline’s risk to
eluxadoline were identified in either the public health is based on animal studies
and easily crushed by users with a tablet
National Forensic Laboratory in monkeys treated with eluxadoline,
crusher or a mortar and pestle.
Information System (NFLIS),3 or System where the animals exhibited opioid
However, the unique physicochemical
to Retrieve Information on Drug overdose symptoms such as decreased
properties of eluxadoline may present a
Evidence (STRIDE).4 activity, unresponsiveness, decreased
challenge to isolate eluxadoline for
5. The Scope, Duration, and body temperature, and decreased
purposes of abuse.
The half-life of eluxadoline is Significance of Abuse: Because respiration rates. Severe sedation and
approximately five hours, with high eluxadoline is a new molecular entity slumping were also observed in
inter-subject variability. Eluxadoline has and has not been marketed in any monkeys following self-administration
a low oral bioavailability due to poor GI country, information as to the scope, with eluxadoline. Furthermore, opioid-
permeability and moderate hepatic first- duration and significance of its abuse is like effects of eluxadoline may not be
pass extraction involving OATP1B1- not available. Both pre-clinical and reversible unless adequate or repeated
mediated hepatic uptake of eluxadoline. clinical studies indicate that administration of opioid antagonists
Co-administration with food lowered eluxadoline shares pharmacological such as naloxone or naltrexone is
systemic exposures. Biliary excretion similarities with schedule IV drugs such performed.
accounted for over 80% of overall as butorphanol and pentazocine and has 7. Its Psychic or Physiological
elimination, while there is a minimal similar abuse potential. Pentazocine and Dependence Liability: Several pre-
elimination by renal excretion. butorphanol were initially marketed as clinical studies both on Cynomolgus
4. History and Current Pattern of monkeys and rats treated with different
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3 NFLIS is a program of the DEA that collects drug
Abuse: Because eluxadoline is a new doses of eluxadoline followed by
identification results from drug cases analyzed by
molecular entity and has not been other Federal, State, and local forensic laboratories. various recovery or drug
marketed in any country, information as 4 STRIDE collected the results of drug evidence discontinuation periods showed no
to the history and current pattern of its analyzed at DEA laboratories and reflects evidence behavioral changes during the treatment
abuse is not available. Data from pre- submitted by the DEA, other Federal law period. There were also no behaviors
enforcement agencies, and some local law
clinical and clinical studies indicated enforcement agencies. On October 1, 2014,
suggestive of withdrawal during the
that eluxadoline shares pharmacological STARLiMS replaced STRIDE as the DEA laboratory observed recovery periods. Thus,
similarities with schedule IV drugs such drug evidence data system of record. chronic administration of eluxadoline
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![48050 Federal Register / Vol. 80, No. 154 / Tuesday, August 11, 2015 / Proposed Rules
13132. The proposed rule does not have the number of potential small entities significant economic impact on a
substantial direct effects on the States, that might handle eluxadoline. substantial number of small entities.
on the relationship between the national However, the DEA estimates that all
Unfunded Mandates Reform Act of 1995
government and the States, or the persons who would handle, or propose
distribution of power and to handle, eluxadoline are currently In accordance with the Unfunded
responsibilities among the various registered with the DEA to handle Mandates Reform Act (UMRA) of 1995,
levels of government. schedule IV controlled substances, 2 U.S.C. 1501 et seq., the DEA has
because it is a pharmaceutical determined and certifies that this action
Executive Order 13175
controlled substance intended for would not result in any Federal
This proposed rule will not have medical treatment. Accordingly, the mandate that may result ‘‘in the
tribal implications warranting the number of DEA registrations authorized expenditure by State, local, and tribal
application of Executive Order 13175. It to handle schedule IV controlled governments, in the aggregate, or by the
does not have substantial direct effects substances is a reasonable estimate for private sector, of $100,000,000 or more
on one or more Indian tribes, on the the maximum number of eluxadoline (adjusted for inflation) in any one year.’’
relationship between the Federal handlers. Therefore, the DEA estimates Therefore, neither a Small Government
government and Indian tribes, or on the that 1.6 million (1,554,254 as of June Agency Plan nor any other action is
distribution of power and 2015) controlled substance registrations, required under UMRA of 1995.
responsibilities between the Federal representing approximately 427,584
government and Indian tribes. Paperwork Reduction Act of 1995
entities, would be the maximum
Regulatory Flexibility Act number of entities affected by this rule. This action does not impose a new
The DEA estimates that 418,141 (97.8%) collection of information requirement
The Administrator, in accordance of 427,584 affected entities are ‘‘small under the Paperwork Reduction Act of
with the Regulatory Flexibility Act entities’’ in accordance with the RFA 1995, 44 U.S.C. 3501–3521. This action
(RFA), 5 U.S.C. 601–612, has reviewed and SBA size standards. would not impose recordkeeping or
this proposed rule and by approving it reporting requirements on State or local
certifies that it will not have a The DEA anticipates that prospective
eluxadoline handlers already handle governments, individuals, businesses, or
significant economic impact on a organizations. An agency may not
substantial number of small entities. other schedule IV controlled substances
and that the cost impact as a result of conduct or sponsor, and a person is not
The purpose of this proposed rule is to required to respond to, a collection of
place eluxadoline, including its salts, placing eluxadoline in schedule IV
would be nominal. As the anticipated information unless it displays a
isomers, and salts of isomers, into currently valid OMB control number.
schedule IV of the CSA. No less eluxadoline handlers already handle
restrictive measures (i.e., non-control, or other scheduled IV controlled List of Subjects in 21 CFR Part 1308
control in schedule V) enable the DEA substances, they already have DEA
registrations and the required security Administrative practice and
to meet its statutory obligations under procedure, Drug traffic control,
the CSA. In preparing this certification, and recordkeeping processes,
equipment, and facilities in place, and Reporting and recordkeeping
the DEA has assessed economic impact requirements.
by size category and has considered would only require a nominal increase
costs with respect to the various DEA in security, inventory, recordkeeping For the reasons set out above, the DEA
registrant business activity classes. and labeling costs. proposes to amend 21 CFR part 1308 as
Eluxadoline is a new molecular entity As discussed above, while the DEA follows:
which has not yet been marketed in the does not have a basis to estimate the
PART 1308—SCHEDULES OF
United States or any other country. number of affected entities, the DEA
CONTROLLED SUBSTANCES
Although the manufacturer is expected estimates that the maximum number of
to enjoy market exclusivity for many affected entities is 427,584 of which ■ 1. The authority citation for 21 CFR
years, the DEA has no basis to 418,141 are estimated to be small part 1308 continues to read as follows:
determine the level of contracted or entities. Since the affected entities are
outsourced manufacturing activities or expected to handle other schedule IV Authority: 21 U.S.C. 811, 812, 871(b),
the breadth of the distribution network. controlled substances and maintain unless otherwise noted.
Furthermore, due to the wide variety of security and recordkeeping facilities ■ 2. Amend § 1308.14 by adding
unidentifiable and unquantifiable and processes consistent with schedule paragraph (g)(3) to read as follows:
variables that could potentially IV controlled substances, the DEA
influence the dispensing and estimates any economic impact will be § 1308.14 Schedule IV.
distribution rates of new pharmaceutical nominal. Because of these facts, this * * * * *
drugs, the DEA is unable to determine proposed rule will not result in a (g) * * *
(3) Eluxadoline (5-[[[(2S)-2-amino-3-[4-aminocarbonyl)-2,6-dimethylphenyl]-1-oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-
yl)ethyl]amino]methyl]-2-methoxybenzoic acid) (including its optical isomers) and its salts, isomers, and salts of isomers (9725)
rmajette on DSK2TPTVN1PROD with PROPOSALS
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![Federal Register / Vol. 80, No. 154 / Tuesday, August 11, 2015 / Proposed Rules 48051
Dated: August 5, 2015. ADDRESSES: Submit your comments, Dated: July 30, 2015.
Chuck Rosenberg, identified by Docket ID No. EPA–R04– Heather McTeer Toney,
Acting Administrator. OAR–2015–0248 by one of the following Regional Administrator, Region 4.
[FR Doc. 2015–19655 Filed 8–10–15; 8:45 am] methods: [FR Doc. 2015–19727 Filed 8–10–15; 8:45 am]
BILLING CODE 4410–09–P 1. www.regulations.gov: Follow the BILLING CODE 6560–50–P
on-line instructions for submitting
comments.
ENVIRONMENTAL PROTECTION 2. Email: R4-ARMS@epa.gov. ENVIRONMENTAL PROTECTION
AGENCY 3. Fax: (404) 562–9019. AGENCY
4. Mail: ‘‘EPA–R04–OAR–2015–
40 CFR Part 52 0248,’’ Air Regulatory Management 40 CFR Part 52
[EPA–R04–OAR–2015–0248; FRL–9932–19– Section (formerly the Regulatory [EPA–R04–OAR–2015–0384; FRL–9932–22–
Region 4] Development Section), Air Planning and Region 4]
Implementation Branch (formerly the
Approval and Promulgation of Air Planning Branch), Air, Pesticides Approval and Promulgation of
Implementation Plans; Georgia; and Toxics Management Division, U.S. Implementation Plans; Kentucky: New
Atlanta; Requirements for the 2008 Environmental Protection Agency, Sources in or Impacting Nonattainment
8-Hour Ozone Standard Region 4, 61 Forsyth Street SW., Areas
AGENCY: Environmental Protection Atlanta, Georgia 30303–8960. AGENCY: Environmental Protection
Agency. 5. Hand Delivery or Courier: Lynorae Agency
ACTION: Proposed rule. Benjamin, Chief, Air Regulatory ACTION: Proposed rule.
Management Section, Air Planning and
SUMMARY: The Environmental Protection Implementation Branch, Air, Pesticides SUMMARY: The Environmental Protection
Agency (EPA) is proposing to approve a and Toxics Management Division, U.S. Agency (EPA) is proposing to approve
state implementation plan revision Environmental Protection Agency, the Commonwealth of Kentucky’s
submitted by the State of Georgia, Region 4, 61 Forsyth Street SW., September 23, 2011, State
through Georgia Environmental Atlanta, Georgia 30303–8960. Such Implementation Plan (SIP) revision,
Protection Division on February 6, 2015, deliveries are only accepted during the submitted through the Kentucky
to address the base year emissions Regional Office’s normal hours of Division for Air Quality (KY DAQ),
inventory and emissions statements operation. The Regional Office’s official which modifies the SIP by making
requirements for the 2008 8-hour ozone hours of business are Monday through changes to Kentucky regulation,
national ambient air quality standards Friday, 8:30 a.m. to 4:30 p.m., excluding ‘‘Review of new sources in or impacting
for the Atlanta, Georgia 2008 8-hour Federal holidays. Please see the direct upon nonattainment areas.’’ EPA has
ozone nonattainment area (hereinafter final rule which is located in the Rules preliminarily determined that
referred to as the ‘‘Atlanta Area’’). These section of this Federal Register for Kentucky’s requested SIP revision meets
requirements apply to all ozone detailed instructions on how to submit the applicable provisions of the Clean
nonattainment areas. The Atlanta Area comments. Air Act (CAA or Act) and EPA
is comprised of 15 counties in Atlanta regulations regarding Nonattainment
FOR FURTHER INFORMATION CONTACT:
(Bartow, Cherokee, Clayton, Cobb, New Source Review (NNSR) permitting.
Tiereny Bell, Air Regulatory
Coweta, DeKalb, Douglas, Fayette,
Management Section, Air Planning and DATES: Written comments must be
Forsyth, Fulton, Gwinnett, Henry,
Implementation Branch, Air, Pesticides received on or before September 10,
Newton, Paulding, and Rockdale). This
and Toxics Management Division, U.S. 2015.
proposed action is being taken pursuant
Environmental Protection Agency,
to the Clean Air Act and its ADDRESSES: Submit your comments,
Region 4, 61 Forsyth Street SW.,
implementing regulations. identified by Docket ID Number EPA–
In the Final Rules Section of this Atlanta, Georgia 30303–8960. Ms. Bell
R04–OAR–2015–0384 by one of the
Federal Register, EPA is approving the can be reached at (404) 562–9088 and
following methods:
State’s SIP revision as a direct final rule via electronic mail at bell.tiereny@
1. www.regulations.gov: Follow the
without prior proposal because the epa.gov.
on-line instructions for submitting
Agency views this as a noncontroversial SUPPLEMENTARY INFORMATION: For comments.
submittal and anticipates no adverse additional information see the direct 2. Email: R4-ARMS@epa.gov.
comments. A detailed rationale for the final rule which is published in the 3. Fax: (404) 562–9019.
approval is set forth in the direct final Rules Section of this Federal Register. 4. Mail: ‘‘EPA–R04–OAR–2015–
rule. If no adverse comments are A detailed rationale for the approval is 0384’’, Air Regulatory Management
received in response to this rule, no set forth in the direct final rule and Section, Air Planning and
further activity is contemplated. If EPA incorporated herein by reference. If no Implementation Branch, Air, Pesticides
receives adverse comments, the direct adverse comments are received in and Toxics Management Division, U.S.
final rule will be withdrawn and all response to this rule, no further activity Environmental Protection Agency,
public comments received will be is contemplated. If EPA receives adverse Region 4, 61 Forsyth Street SW.,
addressed in a subsequent final rule comments, the direct final rule will be Atlanta, Georgia 30303–8960.
rmajette on DSK2TPTVN1PROD with PROPOSALS
based on this proposed rule. EPA will withdrawn and all public comments 5. Hand Delivery or Courier: Ms.
not institute a second comment period received will be addressed in a Lynorae Benjamin, Chief, Air Regulatory
on this document. Any parties subsequent final rule based on this Management Section, Air Planning and
interested in commenting on this proposed rule. EPA will not institute a Implementation Branch, Air, Pesticides
document should do so at this time. second comment period on this and Toxics Management Division, U.S.
DATES: Written comments must be document. Any parties interested in Environmental Protection Agency,
received on or before September 10, commenting on this document should Region 4, 61 Forsyth Street SW.,
2015. do so at this time. Atlanta, Georgia 30303–8960. Such
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Document Created: 2016-09-27 22:25:15
Document Modified: 2016-09-27 22:25:15
| Category | Regulatory Information | |
| Collection | Federal Register | |
| sudoc Class | AE 2.7: GS 4.107: AE 2.106: | |
| Publisher | Office of the Federal Register, National Archives and Records Administration | |
| Section | Proposed Rules | |
| Action | Notice of proposed rulemaking. | |
| Dates | Interested persons may file written comments on this proposal in accordance with 21 CFR 1308.43(g). Electronic comments must be submitted, and written comments must be postmarked, on or before September 10, 2015. Commenters should be aware that the electronic Federal Docket Management System will not accept comments after 11:59 p.m. Eastern Time on the last day of the comment period. | |
| Contact | John R. Scherbenske, Office of | |
| FR Citation | 80 FR 48044 | |
| CFR Associated | Administrative Practice and Procedure; Drug Traffic Control and Reporting and Recordkeeping Requirements |
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