Schedules of Controlled Substances: Removal of Naldemedine From Control, 32153-32157 [2017-14482]

Download as PDF Federal Register / Vol. 82, No. 132 / Wednesday, July 12, 2017 / Proposed Rules Paragraph 6005 Class E Airspace Areas Extending Upward From 700 Feet or More Above the Surface of the Earth. * * * * * AGL WI E5 Stevens Point, WI [Amended] Stevens Point Municipal Airport, WI (Lat. 44°32′43″ N., long. 89°31′49″ W.) That airspace extending upward from 700 feet above the surface within a 6.6-mile radius of Stevens Point Municipal Airport. Issued in Fort Worth, Texas, on June 30, 2017. Walter Tweedy, Acting Manager, Operations Support Group, ATO Central Service Center. [FR Doc. 2017–14527 Filed 7–11–17; 8:45 am] BILLING CODE 4910–13–P DEPARTMENT OF JUSTICE Drug Enforcement Administration 21 CFR Part 1308 [Docket No. DEA–468] Schedules of Controlled Substances: Removal of Naldemedine From Control Drug Enforcement Administration, Department of Justice. ACTION: Notice of proposed rulemaking. AGENCY: The Drug Enforcement Administration (DEA) proposes to remove naldemedine (4R,4aS,7aR,12bS)3-(cyclopropylmethyl)-4a,7,9trihydroxy-N-(2-(3-phenyl-1,2,4oxadiazol-5-yl)propan-2-yl)2,3,4,4a,5,7a-hexahydro-1H-4,12methanobenzofuro[3,2-e]isoquinoline-6carboxamide) including its salts from the schedules of the Controlled Substances Act (CSA). This action is pursuant to the CSA which requires that such actions be made on the record after opportunity for a hearing through formal rulemaking. Naldemedine is currently a schedule II controlled substance because it can be derived from opium alkaloids. This action would remove the regulatory controls and administrative, civil, and criminal sanctions applicable to controlled substances, including those specific to schedule II controlled substances, on persons who handle (manufacture, distribute, reverse distribute, dispense, conduct research, import, export, or conduct chemical analysis) or propose to handle naldemedine. DATES: Interested persons may file written comments on this proposal in accordance with 21 CFR 1308.43(g). Comments must be submitted electronically or postmarked on or before August 11, 2017. Commenters should be aware that the electronic nlaroche on DSK30NT082PROD with PROPOSALS SUMMARY: VerDate Sep<11>2014 14:04 Jul 11, 2017 Jkt 241001 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, may file a request for hearing or waiver of hearing pursuant to 21 CFR 1308.44 and in accordance with 21 CFR 1316.45, 1316.47, 1316.48, and/or 1316.49, as applicable. Requests for hearing and waivers of an opportunity for a hearing or to participate in a hearing must be received on or before August 11, 2017. ADDRESSES: To ensure proper handling of comments, please reference ‘‘Docket No. DEA–468’’ on all electronic and written 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 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. 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/DRW, 8701 Morrissette Drive, Springfield, Virginia 22152. • Hearing requests: All requests for a hearing and waivers of participation must be sent to: Drug Enforcement Administration, Attn: Administrator, 8701 Morrissette Drive, Springfield, Virginia 22152. All requests for hearing and waivers of participation should be sent to: (1) Drug Enforcement Administration, Attn: Hearing Clerk/LJ, 8701 Morrissette Drive, Springfield, Virginia 22152; and (2) Drug Enforcement Administration, Attn: DEA Federal Register Representative/DRW, 8701 Morrissette Drive, Springfield, Virginia 22152. FOR FURTHER INFORMATION CONTACT: Michael J. Lewis, Diversion Control Division, Drug Enforcement Administration; Mailing Address: 8701 PO 00000 Frm 00005 Fmt 4702 Sfmt 4702 32153 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 all of 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 the confidential business information to be redacted within the comment. Comments containing personal identifying information or confidential business information identified as directed above will be made publicly available in redacted form. If a comment has so much confidential business 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, or Waiver of Participation in 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 E:\FR\FM\12JYP1.SGM 12JYP1 32154 Federal Register / Vol. 82, No. 132 / Wednesday, July 12, 2017 / Proposed Rules nlaroche on DSK30NT082PROD with PROPOSALS 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 in accordance with 21 CFR 1316.45, 1316.47, 1316.48, and/or 1316. 49 as applicable, and include a 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 may include 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 held in relation to this rulemaking is restricted to: ‘‘(A) find[ing] that such drug or other substance has a potential for abuse, and (B) mak[ing] with respect to such drug or other substance the findings prescribed by subsection (b) of section 812 of this title for the schedule in which such drug is to be placed * * *.’’ All requests for hearing and waivers of participation must be sent to the DEA using the address information provided above. Legal Authority Pursuant to 21 U.S.C. 811(a)(2), the Attorney General may, by rule, ‘‘remove any drug or other substance from the schedules if he finds that the drug or other substance does not meet the requirements for inclusion in any schedule.’’ 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 proceedings for the issuance, amendment, or repeal of the scheduling of any drug or other substance may be initiated by the Attorney General (1) on his own motion, (2) at the request of the Secretary of the Department of Health and Human Services (HHS),1 or (3) on the petition 1 As set forth in a memorandum of understanding entered into by the HHS, the 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 VerDate Sep<11>2014 14:04 Jul 11, 2017 Jkt 241001 of any interested party. 21 U.S.C. 811(a). This action was initiated at the request of the Acting Assistant Secretary for Health of the HHS and by a petition by the sponsor to DEA to remove naldemedine from the list of scheduled controlled substances of the CSA, and is supported by, inter alia, a recommendation from the Assistant Secretary of the HHS and an evaluation of all relevant data by the DEA. This action would remove the regulatory controls and administrative, civil, and criminal sanctions applicable to controlled substances, including those specific to schedule II controlled substances, on persons who handle or propose to handle naldemedine. Background Naldemedine, known chemically as (4R,4aS,7aR,12bS)-3(cyclopropylmethyl)-4a,7,9-trihydroxyN-(2-(3-phenyl-1,2,4-oxadiazol-5yl)propan-2-yl)-2,3,4,4a,5,7a-hexahydro1H-4,12-methanobenzofuro[3,2e]isoquinoline-6-carboxamide, is an opium alkaloid derivative. Naldemedine is a high-affinity antagonist at the mu, kappa, and delta opioid receptors. On March 23, 2016, a new drug application (NDA) was submitted by Shionogi (Sponsor) to the Food and Drug Administration (FDA) for approval of naldemedine for the treatment of opioid induced constipation in patients with chronic non-cancer pain. On June 8, 2016, the DEA received a petition from the drug sponsor (Shionogi, Inc.), requesting that the DEA amend 21 CFR 1308.12(b)(1) to exclude naldemedine as a schedule II substance from the Controlled Substances Act (CSA). The petitioner stated that naldemedine is a potent peripherally acting mu-opioid receptor antagonist. In accordance with 21 CFR 1308.43(c), the DEA accepted the petition for filing on August 5, 2016. On March 23, 2017, the FDA approved naldemedine for marketing under the trade name Symproic® (0.2 mg tablets).2 Naldemedine is indicated for the treatment of opioid-induced constipation (OIC) in adults with chronic non-cancer pain. Opioidinduced constipation is caused by an activation of mu-opioid receptors in the gastrointestinal tract. Naldemedine, a 9518, Mar. 8, 1985. The Secretary of the HHS has delegated to the Assistant Secretary for Health of the HHS the authority to make domestic drug scheduling recommendations. 58 FR 35460, July 1, 1993. 2 http://www.accessdata.fda.gov/drugsatfda_ docs/appletter/2017/208854Orig1s000ltr.pdf (last accessed 04/13/2017). PO 00000 Frm 00006 Fmt 4702 Sfmt 4702 peripheral acting mu-opioid antagonist, can prevent OIC. Naldemedine is a schedule II controlled substance under 21 U.S.C. 812(a)(1) and 21 CFR 1308.12(b)(I), as a derivative of opium alkaloids and opiates. Proposed Determination To Decontrol Naldemedine According to the HHS, the sponsor submitted a New Drug Application (NDA) for naldemedine on March 23, 2016. In the NDA submission, the sponsor requested that naldemedine and its salts be removed from all schedules for control under the CSA. Based on the NDA, the HHS mentioned that naldemedine is an antagonist of peripheral opioid receptors. On March 22, 2017, the HHS provided the DEA with a scientific and medical evaluation document prepared by the FDA entitled ‘‘Basis for the Recommendation to Decontrol Naldemedine and its Salts from the Controlled Substances Act.’’ Pursuant to 21 U.S.C. 811(b), this document contained an eight-factor analysis of the abuse potential of naldemedine as a new drug, along with the HHS’ recommendation to decontrol naldemedine from the schedules of the CSA. In response, the DEA reviewed the scientific and medical evaluations and scheduling recommendation provided by the HHS, and all other relevant data, and completed its own eight-factor review document on naldemedine pursuant to 21 U.S.C. 811(c). Included below is a brief summary of each factor as analyzed by the HHS and DEA, and as considered by the DEA in this proposal to remove naldemedine from the schedules of the CSA. Please note that both the DEA and HHS analyses are available in their entirety under ‘‘Supporting and Related Material’’ of the public docket for this rule at http:// www.regulations.gov under docket number DEA–468. 1. The Drug’s Actual or Relative Potential for Abuse Naldemedine is a high affinity peripherally acting mu-opioid receptor antagonist. According to HHS, naldemedine is not available or marketed in any country, so there is a lack of evidence of diversion, illicit manufacturing, or deliberate ingestion (HHS review, 2017). Data obtained from scientific behavioral studies (drug discrimination and self-administration) show that naldemedine does not demonstrate a potential for abuse (HHS review, 2017). In clinical studies, naldemedine did not produce euphoria E:\FR\FM\12JYP1.SGM 12JYP1 Federal Register / Vol. 82, No. 132 / Wednesday, July 12, 2017 / Proposed Rules or abuse potential related adverse events (AEs) (HHS review, 2017). These data demonstrate that naldemedine lacks a potential for abuse. nlaroche on DSK30NT082PROD with PROPOSALS 2. Scientific Evidence of the Drug’s Pharmacological Effects, if Known Data submitted by HHS demonstrate that naldemedine binds strongly to all three opioid receptor sites: Mu, kappa and delta, and acts as an antagonist at all three opioid receptor sites. Under both acute and chronic administration of naldemedine, penetration into the blood-brain barrier was non-significant, thereby suggesting that naldemedine is unlikely to have abuse potential (HHS review, 2017). Data obtained from in vivo studies conducted by Kanemasa (2015) 3 demonstrate that naldemedine potently inhibits constipating effects produced by opioids and that pretreatment with naldemedine (up to 30 mg/kg) had no influence on morphine’s analgesic effect in rats. According to the HHS, results obtained from Phase 1 study conducted in a single-dose pooled population (n = 224) showed that naldemedine was well tolerated in healthy subjects not taking opioid medications (HHS review, 2017). HHS also presented adverse events (AEs) from three pooled phase 3 repeated dose studies with naldemedine (n = 1,163 vs placebo, n = 1,165). It was noted by HHS that naldemedine was well tolerated in individuals taking opioid drugs. AEs reported at a rate ≥2% for naldemedine included nasopharyngitis, upper respiratory tract infection, urinary tract infection, diarrhea, abdominal distention, abdominal pain, flatulence, nausea, vomiting, hyperhidrosis, arthralgia, and back pain. Headache was the only centrally-mediated AE reported (2%) for individuals taking naldemedine, but it should be noted that individuals in the placebo group also reported headaches at the same percentage (2%). There were no reports of euphoria, hallucination or other abuse-related adverse events in either the naldemedine or placebotreated groups. 3. The State of Current Scientific Knowledge Regarding the Drug or Other Substance Naldemedine tosylate (active ingredient in naldemedine drug product) is known chemically as (4R,4aS,7aR,12bS)-3(cyclopropylmethyl)-4a,7,9-trihydroxy3 Kanemasa T, Koike K, Arai T, Horita N, Chiba H, Tsuyoshi K, Hasegawa M. 2015. Effects of Naldemedine: A Peripherally Acting Mu-Opioid Receptor Antagonist in Rat Models of OpioidInduced Constipation. American Journal of Gastroentrology. S110: 1322. VerDate Sep<11>2014 14:04 Jul 11, 2017 Jkt 241001 N-(2-(3-phenyl-1,2,4-oxadiazol-5yl)propan-2-yl)-2,3,4,4a,5,7a-hexahydro1H-4,12-methanobenzofuro[3,2e]isoquinoline-6-carboxamide 4methylbenzenesulfonate. According to HHS, naldemedine tosylate is slightly soluble in water and ethanol, soluble in methanol, and freely soluble in dimethylsulfoxide. Naldemedine tosylate is synthesized in a two-step/ four-reaction derivation process from naltrexone hydrochloride, an opioid antagonist. The HHS further notes that the side chain addition makes naldemedine’s lipid solubility low and thereby reduces its ability to cross the blood-brain barrier. HHS reported that the Sponsor studied the pharmacokinetic profile of naldemedine in humans. Study participants were administered a single oral dose of naldemedine (0.1—100 mg). Data endpoints that were studied included time to peak plasma concentrations (Tmax), peak plasma concentrations (Cmax), area under the curve (AUC), and drug half-life (t 1⁄2). Over the tested doses (0.1—100 mg naldemedine), the pharmacokinetic parameter ranges were as follows: Tmax—0.5 to 1.0 hours; Cmax—2 ng/ml to 2,560 ng/ml; AUC—11 ng.h/ml to 3,980 ng.h/ml; t 1⁄2 ¥ ∼9 hours for all doses. 4. Its History and Current Pattern of Abuse Naldemedine is not marketed in the United States or in other countries. Based on its pharmacological similarities to other opioid receptor antagonists, naltrexone, naloxone and naloxegol, it is unlikely that naldemedine possesses abuse related indications. According to the HHS, there has been no evidence of abuserelated symptoms associated with naldemedine from the preclinical and clinical studies. 5. The Scope, Duration, and Significance of Abuse The DEA searched the National Forensic Laboratory Information System (NFLIS) 4 and STARLiMS (a web-based, commercial laboratory information management system) 5 databases; there 4 NFLIS is a national drug forensic laboratory reporting system that systematically collects results from drug chemistry analyses conducted by participating Federal, State and local forensic laboratories across the country. 5 STRIDE was a database of drug exhibits sent to DEA laboratories for analysis. 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. PO 00000 Frm 00007 Fmt 4702 Sfmt 4702 32155 have been no reports of naldemedine seizures in the United States. As mentioned in Factors 1 and 2, there were no abuse or euphoria-related adverse events reported from naldemedine use in clinical trials submitted by the Sponsor in the NDA submission. 6. What, if any, Risk There Is to the Public Health According to the HHS, there are no signs or symptoms that show that naldemedine has abuse potential; hence, the possibility of abuse and public health risk is very unlikely. Naldemedine at a dose up to 5-times the recommended dose did result in cardiotoxicity (Migoya et al 2017).6 Naldemedine’s mechanism of action as a mu-opioid receptor antagonist and lack of cardiotoxicity underscores its minimal potential to be associated with public health risk and public health risk as related to abuse. 7. Its Psychic or Physiological Dependence Liability In in vivo physical dependence studies, both during the drug administration period and 7 days following drug discontinuation, no symptoms of physical dependence were observed for naldemedine (HHS review, 2017). The HHS also mentioned that the lack of naldemedine self-administration by animals is consistent with a lack of psychic dependence liability. Hence, naldemedine does not have psychological or physical dependence liability. 8. Whether the Substance Is an Immediate Precursor of a Substance Already Controlled Under the CSA Naldemedine is not considered an immediate precursor of any controlled substance. Conclusion Based on the recommendation of the Assistant Secretary for Health, received in accordance with section 201(b) of the Act (21 U.S.C. 811(b)), and the independent review of the available data by DEA, the Acting Administrator of DEA, pursuant to sections 201(a) and 201(b) of the Act (21 U.S.C. 811(a) and 811(c)), finds that: (1) Naldemedine has no potential for abuse and does not meet the finding for control under any CSA schedule. Naldemedine is a high-affinity DEA laboratory data submitted after September 30, 2014 are reposited in STARLiMS. 6 Migoya E, Fukumura K, Yamada T, Arjona Ferreira J. 2017. Effect of naldemedine, a peripherally acting mu-opioidreceptor antagonist, on QT interval. The Journal of Pain S81:426. E:\FR\FM\12JYP1.SGM 12JYP1 32156 Federal Register / Vol. 82, No. 132 / Wednesday, July 12, 2017 / Proposed Rules antagonist at the three opioid receptors, mu, delta, and kappa. It is not related in action to a drug or other substance already listed as having potential for abuse and has no abuse potential. (2) Naldemedine has a currently accepted medical use in the United States; Naldemedine was approved for marketing on March 23, 2017 under the brand name Symproic® for the treatment of opioid-induced constipation in adults with chronic noncancer pain. (3) Naldemedine does not have physical or psychological dependence potential; Naldemedine does not produce physical dependence in animals. In animal self-administration studies, naldemedine did not produce significant self-administration infusions. Hence, naldemedine does not have psychological dependence liability. Based on these findings, the Acting Administrator of DEA concludes that naldemedine does not meet the requirements for inclusion in any schedule, and should be removed from control under the CSA. Regulatory Analyses Executive Orders 12866 and 15363 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 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. nlaroche on DSK30NT082PROD with PROPOSALS Executive Order 13132 This proposed rulemaking does not have federalism implications warranting the application of Executive Order 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. VerDate Sep<11>2014 14:04 Jul 11, 2017 Jkt 241001 Executive Order 13175 This proposed rule does 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 (5 U.S.C. 601–612) (RFA), has reviewed this proposed rule and by approving it certifies that it will not, if promulgated, have a significant economic impact on a substantial number of small entities. The purpose of this rule is to remove naldemedine from the list of schedules of the CSA. This action will remove regulatory controls and administrative, civil, and criminal sanctions applicable to controlled substances for handlers and proposed handlers of naldemedine. Accordingly, it has the potential for some economic impact in the form of cost savings. If finalized, the proposed rule will affect all persons who would handle, or propose to handle, naldemedine. Due to the wide variety of unidentifiable and unquantifiable variables that potentially could influence handling of naldemedine, the DEA is unable to determine the number of entities and small entities which would handle naldemedine. However, the DEA estimates that all persons who would handle, or propose to handle naldemedine, are currently registered with the DEA to handle controlled substances. Therefore, the 1.7 million (1,683,023 as of April 2016) controlled substance registrations, representing approximately 436,761 entities, would be the maximum number of entities affected by this rule. The DEA estimates that 425,856 (97.5%) of 436,761 affected entities are ‘‘small entities’’ in accordance with the RFA and Small Business Administration size standards. The DEA estimates all controlled substances registrants handle both controlled and non-controlled substances and these registrants are expected to continue to handle naldemedine if the proposed rule were finalized. Additionally, since prospective naldemedine handlers are likely to handle other controlled substances, the cost benefits they would receive as a result of the de-control of naldemedine is minimal. As naldemedine handlers continue to handle other controlled substances, they PO 00000 Frm 00008 Fmt 4702 Sfmt 4702 will need to maintain their DEA registration and keep the same security and recordkeeping processes, equipment, and facilities in place and would experience only minimal reduction in security, inventory, recordkeeping, and labeling costs. Physical security control requirements are the same for controlled substances listed in schedules II, III, IV, and V for the vast majority of registrants (practitioners). 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 436,761 of which 425,856 are estimated to be small entities. Since the affected entities are expected to handle other controlled substances and maintain security and recordkeeping facilities and processes consistent with controlled substances, the DEA estimates any economic impact will be minimal. Because of these facts, this rule will not, if promulgated, have 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 This action does not impose a new collection of information requirement under the Paperwork Reduction Act, 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: E:\FR\FM\12JYP1.SGM 12JYP1 Federal Register / Vol. 82, No. 132 / Wednesday, July 12, 2017 / Proposed Rules PART 1308—SCHEDULES OF CONTROLLED SUBSTANCES 1. The authority citation for 21 CFR part 1308 continues to read as follows: ■ Authority: 21 U.S.C. 811, 812, 871(b), unless otherwise noted. 2. In § 1308.12, amend the introductory text of paragraph (b)(1) to read as follows: ■ § 1308.12 Schedule II. * * * * * (b) * * * (1) Opium and opiate, and any salt, compound, derivative, or preparation of opium or opiate excluding apomorphine, thebaine-derived butorphanol, dextrorphan, nalbuphine, naldemedine, nalmefene, naloxegol, naloxone, and naltrexone, and their respective salts, but including the following: * * * * * Dated: July 5, 2017. Chuck Rosenburg, Acting Administrator. BILLING CODE 4410–09–P DEPARTMENT OF HOMELAND SECURITY Coast Guard 33 CFR Part 117 [Docket No. USCG–2017–0108] RIN 1625–AA09 Drawbridge Operation Regulation; Tombigbee River, Near Jackson, Alabama Coast Guard, DHS. Notice of proposed rulemaking. AGENCY: The Coast Guard proposes to change the operating schedule that governs the Norfolk Southern Railroad (NSRR) Vertical Lift Span Bridge across Tombigbee River, mile 44.90, near Jackson, between Washington and Clarke Counties, Alabama. This rule proposes to move the current on-site bridge tender control station to a geographically remote centralized control point located in Decatur, Alabama. nlaroche on DSK30NT082PROD with PROPOSALS SUMMARY: Comments and related material must reach the Coast Guard on or before September 11, 2017. ADDRESSES: You may submit comments identified by docket number USCG– 2017–0108 using Federal eRulemaking Portal at http://www.regulations.gov. DATES: VerDate Sep<11>2014 14:04 Jul 11, 2017 Jkt 241001 I. Table of Abbreviations CFR Code of Federal Regulations DHS Department of Homeland Security E.O. Executive Order FR Federal Register NPRM Notice of proposed rulemaking U.S.C. United States Code NSRR Norfolk Southern Railroad Pub. L. Public Law § Section U.S.C. United States Code II. Background, Purpose and Legal Basis In accordance with 33 CFR 117.42, the District Commander may authorize a drawbridge to operate under an automated system or from a remote location. The purpose of this rule is to allow the draw of this bridge to operate from a remote location. The draw will continue to be maintained in the open to navigation position except during the passage of trains. Mariners should not experience any changes in the level of service. [FR Doc. 2017–14482 Filed 7–11–17; 8:45 am] ACTION: See the ‘‘Public Participation and Request for Comments’’ portion of the SUPPLEMENTARY INFORMATION section below for instruction on submitting comments. FOR FURTHER INFORMATION CONTACT: If you have questions on this proposed rule, call or email Ms. Donna Gagliano; Bridge Administration Branch, Eighth Coast Guard District; telephone 504– 671–2128, email Donna.Gagliano@ uscg.mil. SUPPLEMENTARY INFORMATION: III. Discussion of the Proposed Rule The Coast Guard, at the request of NSRR, is changing the method of operation for the NSRR Vertical Lift Bridge across Tombigbee River, mile 44.90, near Jackson, Alabama. Due to the need for increased efficiency in railroad operations, NSRR requested a change to the method of operating the draw from on-site to a draw tender operating the bridge remotely. Presently, the draw is maintained in the open-to-navigation position and closed only for the passage of trains or maintenance. The bridge owner would like to operate the draw remotely using a drawtender at a centralized railroad operation in Decatur, Alabama, rather than maintaining the current on-site operation and drawtender. The implementation of this rule, in effect, removes the requirement that a drawtender be present on site at all times. Under the new remote operation procedure, the draw will continue to be maintained in the open-to-navigation position and lowered only for the PO 00000 Frm 00009 Fmt 4702 Sfmt 4702 32157 passage of trains or for maintenance. There will be no modifications to the operation of the bridge as it relates to the passage of vessels. Instead, this change will allow the bridge owner to increase efficiency by coordinating bridge operations and vessel transits with train dispatch operations in Decatur, AL. IV. Regulatory Analyses We developed this proposed rule after considering numerous statutes and Executive Orders related to rulemaking. Below we summarize our analyses based on these statues and Executive Orders and we discuss First Amendment rights of protesters. A. Regulatory Planning and Review E.O.s 12866 and 13563 direct agencies to assess the costs and benefits of available regulatory alternatives and, if regulation is necessary, to select regulatory approaches that maximize net benefits. E.O. 13563 emphasizes the importance of quantifying both costs and benefits, of reducing costs, of harmonizing rules, and of promoting flexibility. This NPRM has not been designated a ‘‘significant regulatory action,’’ under E.O. 12866. Accordingly, NPRM it has not been reviewed by the Office of Management and Budget. This interim rule is not a significant regulatory action because the draw will be maintained in the open-to-navigation position. Therefore, mariners will experience no changes in transiting through the bridge site. No new restrictions on or actions from the mariner are required by this rule. The intent of the proposed rule is to improve safety and efficiency of bridge operations as it relates to vessel and railroad traffic. Centralizing the bridge tender would have no impact on the existing regulations regarding hours or methods of bridge operations. B. Impact on Small Entities The Regulatory Flexibility Act of 1980 (RFA), 5 U.S.C. 601–612, as amended, requires federal agencies to consider the potential impact of regulations on small entities during rulemaking. The term ‘‘small entities’’ comprises small businesses, not-for-profit organizations that are independently owned and operated and are not dominant in their fields, and governmental jurisdictions with populations of less than 50,000. The Coast Guard certifies under 5 U.S.C. 605(b) that this proposed rule will not have a significant economic impact on a substantial number of small entities. ‘‘While some owners or operators of vessels intending to transit the bridge E:\FR\FM\12JYP1.SGM 12JYP1

Agencies

[Federal Register Volume 82, Number 132 (Wednesday, July 12, 2017)]
[Proposed Rules]
[Pages 32153-32157]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2017-14482]


=======================================================================
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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Part 1308

[Docket No. DEA-468]


Schedules of Controlled Substances: Removal of Naldemedine From 
Control

AGENCY: Drug Enforcement Administration, Department of Justice.

ACTION: Notice of proposed rulemaking.

-----------------------------------------------------------------------

SUMMARY: The Drug Enforcement Administration (DEA) proposes to remove 
naldemedine (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,7,9-trihydroxy-
N-(2-(3-phenyl-1,2,4-oxadiazol-5-yl)propan-2-yl)-2,3,4,4a,5,7a-
hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-6-carboxamide) 
including its salts from the schedules of the Controlled Substances Act 
(CSA). This action is pursuant to the CSA which requires that such 
actions be made on the record after opportunity for a hearing through 
formal rulemaking. Naldemedine is currently a schedule II controlled 
substance because it can be derived from opium alkaloids. This action 
would remove the regulatory controls and administrative, civil, and 
criminal sanctions applicable to controlled substances, including those 
specific to schedule II controlled substances, on persons who handle 
(manufacture, distribute, reverse distribute, dispense, conduct 
research, import, export, or conduct chemical analysis) or propose to 
handle naldemedine.

DATES: Interested persons may file written comments on this proposal in 
accordance with 21 CFR 1308.43(g). Comments must be submitted 
electronically or postmarked on or before August 11, 2017. 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, may file a request for hearing or waiver of 
hearing pursuant to 21 CFR 1308.44 and in accordance with 21 CFR 
1316.45, 1316.47, 1316.48, and/or 1316.49, as applicable. Requests for 
hearing and waivers of an opportunity for a hearing or to participate 
in a hearing must be received on or before August 11, 2017.

ADDRESSES: To ensure proper handling of comments, please reference 
``Docket No. DEA-468'' on all electronic and written 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 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. 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/DRW, 8701 Morrissette Drive, 
Springfield, Virginia 22152.
     Hearing requests: All requests for a hearing and waivers 
of participation must be sent to: Drug Enforcement Administration, 
Attn: Administrator, 8701 Morrissette Drive, Springfield, Virginia 
22152. All requests for hearing and waivers of participation should be 
sent to: (1) Drug Enforcement Administration, Attn: Hearing Clerk/LJ, 
8701 Morrissette Drive, Springfield, Virginia 22152; and (2) Drug 
Enforcement Administration, Attn: DEA Federal Register Representative/
DRW, 8701 Morrissette Drive, Springfield, Virginia 22152.

FOR FURTHER INFORMATION CONTACT: Michael J. Lewis, Diversion Control 
Division, 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 all of 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 the 
confidential business information to be redacted within the comment.
    Comments containing personal identifying information or 
confidential business information identified as directed above will be 
made publicly available in redacted form. If a comment has so much 
confidential business 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, or Waiver of Participation in 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

[[Page 32154]]

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 in accordance with 21 CFR 1316.45, 1316.47, 
1316.48, and/or 1316. 49 as applicable, and include a 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 may include 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 held in relation to this rulemaking is 
restricted to: ``(A) find[ing] that such drug or other substance has a 
potential for abuse, and (B) mak[ing] with respect to such drug or 
other substance the findings prescribed by subsection (b) of section 
812 of this title for the schedule in which such drug is to be placed * 
* *.'' All requests for hearing and waivers of participation must be 
sent to the DEA using the address information provided above.

Legal Authority

    Pursuant to 21 U.S.C. 811(a)(2), the Attorney General may, by rule, 
``remove any drug or other substance from the schedules if he finds 
that the drug or other substance does not meet the requirements for 
inclusion in any schedule.'' 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 proceedings for the issuance, amendment, or 
repeal of the scheduling of any drug or other substance may be 
initiated by the Attorney General (1) on his own motion, (2) at the 
request of the Secretary of the Department of Health and Human Services 
(HHS),\1\ or (3) on the petition of any interested party. 21 U.S.C. 
811(a). This action was initiated at the request of the Acting 
Assistant Secretary for Health of the HHS and by a petition by the 
sponsor to DEA to remove naldemedine from the list of scheduled 
controlled substances of the CSA, and is supported by, inter alia, a 
recommendation from the Assistant Secretary of the HHS and an 
evaluation of all relevant data by the DEA. This action would remove 
the regulatory controls and administrative, civil, and criminal 
sanctions applicable to controlled substances, including those specific 
to schedule II controlled substances, on persons who handle or propose 
to handle naldemedine.
---------------------------------------------------------------------------

    \1\ As set forth in a memorandum of understanding entered into 
by the HHS, the 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. The Secretary 
of the HHS has delegated to the Assistant Secretary for Health of 
the HHS the authority to make domestic drug scheduling 
recommendations. 58 FR 35460, July 1, 1993.
---------------------------------------------------------------------------

Background

    Naldemedine, known chemically as (4R,4aS,7aR,12bS)-3-
(cyclopropylmethyl)-4a,7,9-trihydroxy-N-(2-(3-phenyl-1,2,4-oxadiazol-5-
yl)propan-2-yl)-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-
e]isoquinoline-6-carboxamide, is an opium alkaloid derivative. 
Naldemedine is a high-affinity antagonist at the mu, kappa, and delta 
opioid receptors. On March 23, 2016, a new drug application (NDA) was 
submitted by Shionogi (Sponsor) to the Food and Drug Administration 
(FDA) for approval of naldemedine for the treatment of opioid induced 
constipation in patients with chronic non-cancer pain.
    On June 8, 2016, the DEA received a petition from the drug sponsor 
(Shionogi, Inc.), requesting that the DEA amend 21 CFR 1308.12(b)(1) to 
exclude naldemedine as a schedule II substance from the Controlled 
Substances Act (CSA). The petitioner stated that naldemedine is a 
potent peripherally acting mu-opioid receptor antagonist. In accordance 
with 21 CFR 1308.43(c), the DEA accepted the petition for filing on 
August 5, 2016.
    On March 23, 2017, the FDA approved naldemedine for marketing under 
the trade name Symproic[supreg] (0.2 mg tablets).\2\ Naldemedine is 
indicated for the treatment of opioid-induced constipation (OIC) in 
adults with chronic non-cancer pain. Opioid-induced constipation is 
caused by an activation of mu-opioid receptors in the gastrointestinal 
tract. Naldemedine, a peripheral acting mu-opioid antagonist, can 
prevent OIC.
---------------------------------------------------------------------------

    \2\ http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/208854Orig1s000ltr.pdf (last accessed 04/13/2017).
---------------------------------------------------------------------------

    Naldemedine is a schedule II controlled substance under 21 U.S.C. 
812(a)(1) and 21 CFR 1308.12(b)(I), as a derivative of opium alkaloids 
and opiates.

Proposed Determination To Decontrol Naldemedine

    According to the HHS, the sponsor submitted a New Drug Application 
(NDA) for naldemedine on March 23, 2016. In the NDA submission, the 
sponsor requested that naldemedine and its salts be removed from all 
schedules for control under the CSA. Based on the NDA, the HHS 
mentioned that naldemedine is an antagonist of peripheral opioid 
receptors.
    On March 22, 2017, the HHS provided the DEA with a scientific and 
medical evaluation document prepared by the FDA entitled ``Basis for 
the Recommendation to Decontrol Naldemedine and its Salts from the 
Controlled Substances Act.'' Pursuant to 21 U.S.C. 811(b), this 
document contained an eight-factor analysis of the abuse potential of 
naldemedine as a new drug, along with the HHS' recommendation to 
decontrol naldemedine from the schedules of the CSA.
    In response, the DEA reviewed the scientific and medical 
evaluations and scheduling recommendation provided by the HHS, and all 
other relevant data, and completed its own eight-factor review document 
on naldemedine pursuant to 21 U.S.C. 811(c). Included below is a brief 
summary of each factor as analyzed by the HHS and DEA, and as 
considered by the DEA in this proposal to remove naldemedine from the 
schedules of the CSA. Please note that both the DEA and HHS analyses 
are available in their entirety under ``Supporting and Related 
Material'' of the public docket for this rule at http://www.regulations.gov under docket number DEA-468.

1. The Drug's Actual or Relative Potential for Abuse

    Naldemedine is a high affinity peripherally acting mu-opioid 
receptor antagonist. According to HHS, naldemedine is not available or 
marketed in any country, so there is a lack of evidence of diversion, 
illicit manufacturing, or deliberate ingestion (HHS review, 2017). Data 
obtained from scientific behavioral studies (drug discrimination and 
self-administration) show that naldemedine does not demonstrate a 
potential for abuse (HHS review, 2017). In clinical studies, 
naldemedine did not produce euphoria

[[Page 32155]]

or abuse potential related adverse events (AEs) (HHS review, 2017). 
These data demonstrate that naldemedine lacks a potential for abuse.

2. Scientific Evidence of the Drug's Pharmacological Effects, if Known

    Data submitted by HHS demonstrate that naldemedine binds strongly 
to all three opioid receptor sites: Mu, kappa and delta, and acts as an 
antagonist at all three opioid receptor sites. Under both acute and 
chronic administration of naldemedine, penetration into the blood-brain 
barrier was non-significant, thereby suggesting that naldemedine is 
unlikely to have abuse potential (HHS review, 2017). Data obtained from 
in vivo studies conducted by Kanemasa (2015) \3\ demonstrate that 
naldemedine potently inhibits constipating effects produced by opioids 
and that pretreatment with naldemedine (up to 30 mg/kg) had no 
influence on morphine's analgesic effect in rats.
---------------------------------------------------------------------------

    \3\ Kanemasa T, Koike K, Arai T, Horita N, Chiba H, Tsuyoshi K, 
Hasegawa M. 2015. Effects of Naldemedine: A Peripherally Acting Mu-
Opioid Receptor Antagonist in Rat Models of Opioid-Induced 
Constipation. American Journal of Gastroentrology. S110: 1322.
---------------------------------------------------------------------------

    According to the HHS, results obtained from Phase 1 study conducted 
in a single-dose pooled population (n = 224) showed that naldemedine 
was well tolerated in healthy subjects not taking opioid medications 
(HHS review, 2017). HHS also presented adverse events (AEs) from three 
pooled phase 3 repeated dose studies with naldemedine (n = 1,163 vs 
placebo, n = 1,165). It was noted by HHS that naldemedine was well 
tolerated in individuals taking opioid drugs. AEs reported at a rate 
>=2% for naldemedine included nasopharyngitis, upper respiratory tract 
infection, urinary tract infection, diarrhea, abdominal distention, 
abdominal pain, flatulence, nausea, vomiting, hyperhidrosis, 
arthralgia, and back pain. Headache was the only centrally-mediated AE 
reported (2%) for individuals taking naldemedine, but it should be 
noted that individuals in the placebo group also reported headaches at 
the same percentage (2%). There were no reports of euphoria, 
hallucination or other abuse-related adverse events in either the 
naldemedine or placebo-treated groups.

3. The State of Current Scientific Knowledge Regarding the Drug or 
Other Substance

    Naldemedine tosylate (active ingredient in naldemedine drug 
product) is known chemically as (4R,4aS,7aR,12bS)-3-
(cyclopropylmethyl)-4a,7,9-trihydroxy-N-(2-(3-phenyl-1,2,4-oxadiazol-5-
yl)propan-2-yl)-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-
e]isoquinoline-6-carboxamide 4-methylbenzenesulfonate. According to 
HHS, naldemedine tosylate is slightly soluble in water and ethanol, 
soluble in methanol, and freely soluble in dimethylsulfoxide. 
Naldemedine tosylate is synthesized in a two-step/four-reaction 
derivation process from naltrexone hydrochloride, an opioid antagonist. 
The HHS further notes that the side chain addition makes naldemedine's 
lipid solubility low and thereby reduces its ability to cross the 
blood-brain barrier.
    HHS reported that the Sponsor studied the pharmacokinetic profile 
of naldemedine in humans. Study participants were administered a single 
oral dose of naldemedine (0.1--100 mg). Data endpoints that were 
studied included time to peak plasma concentrations (Tmax), peak plasma 
concentrations (Cmax), area under the curve (AUC), and drug half-life 
(t \1/2\). Over the tested doses (0.1--100 mg naldemedine), 
the pharmacokinetic parameter ranges were as follows: Tmax--0.5 to 1.0 
hours; Cmax--2 ng/ml to 2,560 ng/ml; AUC--11 ng.h/ml to 3,980 ng.h/ml; 
t \1/2\ - ~9 hours for all doses.

4. Its History and Current Pattern of Abuse

    Naldemedine is not marketed in the United States or in other 
countries. Based on its pharmacological similarities to other opioid 
receptor antagonists, naltrexone, naloxone and naloxegol, it is 
unlikely that naldemedine possesses abuse related indications. 
According to the HHS, there has been no evidence of abuse-related 
symptoms associated with naldemedine from the preclinical and clinical 
studies.

5. The Scope, Duration, and Significance of Abuse

    The DEA searched the National Forensic Laboratory Information 
System (NFLIS) \4\ and STARLiMS (a web-based, commercial laboratory 
information management system) \5\ databases; there have been no 
reports of naldemedine seizures in the United States. As mentioned in 
Factors 1 and 2, there were no abuse or euphoria-related adverse events 
reported from naldemedine use in clinical trials submitted by the 
Sponsor in the NDA submission.
---------------------------------------------------------------------------

    \4\ NFLIS is a national drug forensic laboratory reporting 
system that systematically collects results from drug chemistry 
analyses conducted by participating Federal, State and local 
forensic laboratories across the country.
    \5\ STRIDE was a database of drug exhibits sent to DEA 
laboratories for analysis. 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. DEA laboratory data submitted after September 30, 2014 are 
reposited in STARLiMS.
---------------------------------------------------------------------------

6. What, if any, Risk There Is to the Public Health

    According to the HHS, there are no signs or symptoms that show that 
naldemedine has abuse potential; hence, the possibility of abuse and 
public health risk is very unlikely. Naldemedine at a dose up to 5-
times the recommended dose did result in cardiotoxicity (Migoya et al 
2017).\6\ Naldemedine's mechanism of action as a mu-opioid receptor 
antagonist and lack of cardiotoxicity underscores its minimal potential 
to be associated with public health risk and public health risk as 
related to abuse.
---------------------------------------------------------------------------

    \6\ Migoya E, Fukumura K, Yamada T, Arjona Ferreira J. 2017. 
Effect of naldemedine, a peripherally acting mu-opioidreceptor 
antagonist, on QT interval. The Journal of Pain S81:426.
---------------------------------------------------------------------------

7. Its Psychic or Physiological Dependence Liability

    In in vivo physical dependence studies, both during the drug 
administration period and 7 days following drug discontinuation, no 
symptoms of physical dependence were observed for naldemedine (HHS 
review, 2017). The HHS also mentioned that the lack of naldemedine 
self-administration by animals is consistent with a lack of psychic 
dependence liability. Hence, naldemedine does not have psychological or 
physical dependence liability.

8. Whether the Substance Is an Immediate Precursor of a Substance 
Already Controlled Under the CSA

    Naldemedine is not considered an immediate precursor of any 
controlled substance.

Conclusion

    Based on the recommendation of the Assistant Secretary for Health, 
received in accordance with section 201(b) of the Act (21 U.S.C. 
811(b)), and the independent review of the available data by DEA, the 
Acting Administrator of DEA, pursuant to sections 201(a) and 201(b) of 
the Act (21 U.S.C. 811(a) and 811(c)), finds that:
    (1) Naldemedine has no potential for abuse and does not meet the 
finding for control under any CSA schedule. Naldemedine is a high-
affinity

[[Page 32156]]

antagonist at the three opioid receptors, mu, delta, and kappa. It is 
not related in action to a drug or other substance already listed as 
having potential for abuse and has no abuse potential.
    (2) Naldemedine has a currently accepted medical use in the United 
States; Naldemedine was approved for marketing on March 23, 2017 under 
the brand name Symproic[supreg] for the treatment of opioid-induced 
constipation in adults with chronic non-cancer pain.
    (3) Naldemedine does not have physical or psychological dependence 
potential; Naldemedine does not produce physical dependence in animals. 
In animal self-administration studies, naldemedine did not produce 
significant self-administration infusions. Hence, naldemedine does not 
have psychological dependence liability.
    Based on these findings, the Acting Administrator of DEA concludes 
that naldemedine does not meet the requirements for inclusion in any 
schedule, and should be removed from control under the CSA.

Regulatory Analyses

Executive Orders 12866 and 15363

    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 
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 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 does 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 (5 U.S.C. 601-612) (RFA), has reviewed this proposed rule and by 
approving it certifies that it will not, if promulgated, have a 
significant economic impact on a substantial number of small entities. 
The purpose of this rule is to remove naldemedine from the list of 
schedules of the CSA. This action will remove regulatory controls and 
administrative, civil, and criminal sanctions applicable to controlled 
substances for handlers and proposed handlers of naldemedine. 
Accordingly, it has the potential for some economic impact in the form 
of cost savings.
    If finalized, the proposed rule will affect all persons who would 
handle, or propose to handle, naldemedine. Due to the wide variety of 
unidentifiable and unquantifiable variables that potentially could 
influence handling of naldemedine, the DEA is unable to determine the 
number of entities and small entities which would handle naldemedine. 
However, the DEA estimates that all persons who would handle, or 
propose to handle naldemedine, are currently registered with the DEA to 
handle controlled substances. Therefore, the 1.7 million (1,683,023 as 
of April 2016) controlled substance registrations, representing 
approximately 436,761 entities, would be the maximum number of entities 
affected by this rule. The DEA estimates that 425,856 (97.5%) of 
436,761 affected entities are ``small entities'' in accordance with the 
RFA and Small Business Administration size standards.
    The DEA estimates all controlled substances registrants handle both 
controlled and non-controlled substances and these registrants are 
expected to continue to handle naldemedine if the proposed rule were 
finalized. Additionally, since prospective naldemedine handlers are 
likely to handle other controlled substances, the cost benefits they 
would receive as a result of the de-control of naldemedine is minimal. 
As naldemedine handlers continue to handle other controlled substances, 
they will need to maintain their DEA registration and keep the same 
security and recordkeeping processes, equipment, and facilities in 
place and would experience only minimal reduction in security, 
inventory, recordkeeping, and labeling costs. Physical security control 
requirements are the same for controlled substances listed in schedules 
II, III, IV, and V for the vast majority of registrants 
(practitioners).
    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 436,761 of which 425,856 are estimated to be small 
entities. Since the affected entities are expected to handle other 
controlled substances and maintain security and recordkeeping 
facilities and processes consistent with controlled substances, the DEA 
estimates any economic impact will be minimal. Because of these facts, 
this rule will not, if promulgated, have 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

    This action does not impose a new collection of information 
requirement under the Paperwork Reduction Act, 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:

[[Page 32157]]

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. In Sec.  1308.12, amend the introductory text of paragraph (b)(1) to 
read as follows:


Sec.  1308.12  Schedule II.

* * * * *
    (b) * * *
    (1) Opium and opiate, and any salt, compound, derivative, or 
preparation of opium or opiate excluding apomorphine, thebaine-derived 
butorphanol, dextrorphan, nalbuphine, naldemedine, nalmefene, 
naloxegol, naloxone, and naltrexone, and their respective salts, but 
including the following:
* * * * *

    Dated: July 5, 2017.
Chuck Rosenburg,
Acting Administrator.
[FR Doc. 2017-14482 Filed 7-11-17; 8:45 am]
 BILLING CODE 4410-09-P