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Federal Register / Vol. 86, No. 40 / Wednesday, March 3, 2021 / Rules and Regulations
Enforcement Administration maintains lemborexant, including its salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible, in schedule IV of the CSA.
DATES: The effective date of this final rulemaking is March 3, 2021.
FOR FURTHER INFORMATION CONTACT: Dr.
Terrence L. Boos, Drug and Chemical Evaluation Section, Diversion Control Division, Drug Enforcement Administration; Mailing Address: 8701
Morrissette Drive, Springfield, Virginia 22152; Telephone: 5713623249.
SUPPLEMENTARY INFORMATION:
Background and Legal Authority Under the Controlled Substances Act CSA, as amended in 2015 by the Improving Regulatory Transparency for New Medical Therapies Act Pub. L.
11489, when the Drug Enforcement Administration DEA receives notification from the Department of Health and Human Services HHS that the Secretary has approved a certain new drug and HHS recommends control in the CSA schedule IIV, DEA is required to issue an interim final rule, with opportunity for public comment and to request a hearing, controlling the drug within a specified 90-day timeframe and to subsequently issue a final rule. 21 U.S.C. 811j. When controlling a drug pursuant to subsection j, DEA must apply the scheduling criteria of 21 U.S.C. 811 b through d and 812b. 21 U.S.C.
811j3.
On April 7, 2020, DEA published an interim final rule to make lemborexant including its salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible a schedule IV controlled substance. 85 FR 19387. The interim final rule provided an opportunity for interested persons to submit comments as well as file a request for hearing or waiver of hearing, on or before May 7, 2020. DEA did not receive any requests for hearing or waiver of hearing.

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Comments Received DEA received five comments in response to the interim final rule for the placement of lemborexant into schedule IV of the CSA. The submissions were from individual or anonymous commenters. Two commenters provided support for the interim final rule, one commenter opposed the rule, one commenter solely included a link to potential malware, and one commenter expressed views on a subject not related to the rule. As these final two comments were outside the scope of this
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rulemaking, DEA did not summarize or respond to them below.
Support of the Interim Final Rule A commenter supported controlling lemborexant as a schedule IV controlled substance, if such control helped to prevent abuse of, or the addiction to, this substance. Another commenter noted HHS, in its analysis, found that lemborexant had similar abuse potential to other schedule IV sedatives such as suvorexant and zolpidem, and therefore, agreed with HHSs recommendation of schedule IV control for lemborexant. In addition, this commenter referenced a study, conducted by Eisai, Inc. the Sponsor of the new drug application for Dayvigo lemborexant, and recommended that DEA add this particular study analysis regarding abuse and dependency potential to DEAs final rule, under the Determination to Schedule Lemborexant section, to further support DEAs placing lemborexant in schedule IV.
DEA Response: DEA appreciates the support for this rulemaking. DEA
determined in the interim final rule, and re-affirms in this final rule, that there is substantial evidence of a potential for abuse of lemborexant, and lemborexant warrants control in schedule IV.
Regarding the commenters request that DEA include the study analysis in this final rule, DEA assumes that the commenter is referring to the human abuse potential HAP study conducted by Eisai, Inc. In the event the commenter is referencing this study, DEA asserts that the HAP study conducted by the Sponsor was included in both the DEA and HHS lemborexant eight-factor reviews and in the interim final rule located in the Determination to Schedule Lemborexant section in Factor 2 and in the Determination of Appropriate Schedule in section 3 of the interim final rule.
Opposition to the Interim Final Rule A commenter claimed that DEA did not rely on the pharmacological data for lemborexant or follow any of the other factors required to be considered under 21 U.S.C. 811c to determine the placement of lemborexant in schedule IV. Instead, the commenter stated that DEA relied on a small and unrepeated sample group and its subjective responses, which matched responses to the schedule IV sedative suvorexant.
The commenter also contended that there is a disparity in DEAs scheduling treatment for lemborexant schedule IV
and Rozarem non-controlled, as these both are sedativeswith the same Food and Drug Administration FDA-

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approved indicationthat exert pharmacological activity by other means than binding to gamma-aminobutyric acid GABA receptors. As such, the commenter considered DEAs decision to schedule lemborexant arbitrary and capricious. This commenter further stated that the placement of lemborexant in schedule IV of the CSA
would increase the regulatory restrictions on a drug intended to treat insomnia, thereby causing many to resort to more dangerous and addictive substances such as benzodiazepines and other drugs that bind to the GABA
receptor. Lastly, the commenter stated lemborexant is a new molecular entity thus evidence of actual abuse or potential for abuse liability does not exist. Therefore, the commenter asserted that DEA should either not place lemborexant in the same schedule as drugs with proven abuse potential, such as Xanax and Ambien, or delay scheduling lemborexant until evidence of actual abuse data can be produced using the eight-factors stipulated in 21
U.S.C. 811c.
DEA Response: Regarding the commenters point concerning the lack of appropriate pharmacological data in support of the abuse potential of lemborexant, DEA asserts that pharmacological data serves as only one portion of the data used to determine abuse potential and abuse liability. As stated in the interim final rule, while lemborexant is highly selective for both the orexin 1 and orexin 2 receptors and has little to no affinity to other central nervous system receptor sites associated with abuse potential, in a clinical HAP
study of lemborexant, lemborexant produced statistically significant increases in positive subjective measures in the bipolar visual analog scale i.e., Drug Liking, Overall Drug Liking, Good Effects, High, Stoned, and Take Drug Again that were greater than placebo and statistically similar to other sedatives in the same drug class. Thus, in this HAP study, lemborexant showed potential for abuse. Following comprehensive evaluation of all available data, including both preclinical and clinical data as related to the eight-factor analysis pursuant to 21 U.S.C. 811c, HHS recommended schedule IV for lemborexant. Upon careful consideration of all available data, DEA concurred with HHS
recommendation that lemborexant possesses abuse potential comparable to other schedule IV depressants.
Regarding the commenters concerns that the control of lemborexant as a schedule IV drug would negatively impact treatment choices and increase addiction risks, DEA contends that there
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