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Federal Register / Vol. 86, No. 104 / Wednesday, June 2, 2021 / Rules and Regulations
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isomers, and salts of isomers is possible, in schedule IV of the Controlled Substances Act.
DATES: The effective date of this rulemaking is July 2, 2021.
FOR FURTHER INFORMATION CONTACT:
Terrence L. Boos, Drug and Chemical Evaluation Section, Diversion Control Division, Drug Enforcement Administration; Telephone: 571776
2265.
SUPPLEMENTARY INFORMATION:
Background and Legal Authority On October 6, 2020, the Drug Enforcement Administration DEA, pursuant to 21 U.S.C. 811j, published an interim final rule IFR 85 FR 63014
to make remimazolam 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 substances. See 21 CFR 1308.14c51
DEA Controlled Substance Code 2846.
Over time, alternative chemical names have been used to describe this same specific substance. In the preamble to the IFR, DEA provided 4Himidazol1,2-a1,4benzodiazepine-4propionic acid, 8-bromo-1-methyl-6-2pyridinyl-4S-methyl ester, benzenesulfonate 1:1 and also, methyl 3-4S-8-bromo-1-methyl-6-pyridin-2yl-4H-imidazo1,2-a1,4benzodiazepin4ylpropanoate benzenesulfonic acid 1
as the chemical names of remimazolam, which refer to the benzenesulfonic acid salt of remimazolam. Since DEA
controlled remimazolam and its salts, isomers, and salts of isomers in schedule IV by publication of the IFR, DEA believes it is more appropriate to include chemical names consistent with the free base of this substance, namely 4H-imidazol1,2a1,4benzodiazepine-4-propionic acid, 8-bromo-1-methyl-6-2-pyridinyl-4Smethyl ester and methyl 3-4S-8bromo-1-methyl-6-pyridin-2-yl-4Himidazo1,2-a1,4benzodiazepin4ylpropanoate in the preamble of this final rule. It bears emphasis that the chemical that is the subject of this final rule is the same substance that was the subject of the IFR. DEA simply is using alternative chemical descriptions to refer to that same substance in this preamble.
Remimazolam is a new molecular entity with central nervous system depressant properties, and the Food and Drug Administration FDA, in July 2020, approved the use of BYFAVO
1 The
Department of Health and Human Services also referred to the substance by these chemical names in its April 2020 scientific and medical evaluation and scheduling recommendation.

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Remimazolam as an intravenous medication for the induction and maintenance of procedural sedation in adults undergoing procedures lasting 30
minutes or less. The IFR to schedule remimazolam provided opportunity for interested persons to submit comments, as well as file a request for hearing or waiver of hearing, on or before November 5, 2020. DEA did not receive any requests for hearing or waiver of hearing.
Comments Received In response to the IFR, DEA received three comments, from one individual and two anonymous sources. One commenter supported schedule IV
placement; the second commenter suggested placement in schedule III
instead; and the third commenter expressed views on a non-DEA
rulemaking. DEA will not summarize or respond to this last comment as it was outside the scope of this rulemaking.
Schedule IV Placement An anonymous commenter briefly expressed that schedule IV was the appropriate schedule for remimazolam based on the data from clinical trials conducted, limited side effects, and its better performance as compared to similar substances such as midazolam.
DEA Response: DEA determined in the IFR, and re-affirms in this final rule, that remimazolam meets the criteria under 21 U.S.C. 812b4 for schedule IV control. As described by the Department of Health and Human Services HHS,2 and in DEAs August 2020 eight-factor analysis, remimazolam demonstrated abuse potential similar to midazolam, a schedule IV depressant.
DEA appreciates the support for this rulemaking.
Schedule III Placement One individual commenter expressed concerns with DEAs placement of remimazolam in schedule IV and instead suggested placing remimazolam in schedule III. The commenter briefly discussed the pharmacology of remimazolam and noted that both HHS
and DEA stated the abuse potential and public health risk of remimazolam is similar to schedule IV benzodiazepines.
However, the commenter stated that remimazolam induced positive euphoria related responses in a human abuse potential study leading to dependence to relative drugs in schedule III and recommended 2 Basis for the Recommendation to Control Remimazolam and Its Salts in Schedule IV of the Controlled Substances Act. Department of Health and Human Services. April 15, 2020. Received by DEA on July 10, 2020.

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classifying remimazolam as schedule III
due to FDA placing a black box warning label on benzodiazepines and the numerous studies illustrating the abuse and misuse of benzodiazepines within the public communities. The commenter noted that schedule III
provided more restrictions and could protect the public from harm. The individual summarized four reference articles related to the historic medical use and abuse of prescription benzodiazepines, diversion and trafficking of licit and illicit benzodiazepines, and the serious adverse effects that may occur with misuse and abuse of benzodiazepines, including an increase in benzodiazepine-related deaths. Further, the commenter believed that the opioid epidemic has overshadowed the benzodiazepines misuse and abuse, but suggested that benzodiazepines and opioids are working in tandem wreaking havoc in the lives of many and that creating a strong foundation through classification of drugs can place precedent in ensuring the health and safety of American citizens.
DEA Response: DEA considered the commenters position; however, does find placement in schedule IV to be appropriate for remimazolam. As discussed briefly in the background and legal authority section above, and in more detail in the IFR 85 FR 63014, 6301563016, FDA approved the New Drug Application NDA for BYFAVO
remimazolam, and HHS provided DEA
with a scientific and medical evaluation and a scheduling recommendation for control of remimazolam in schedule IV.
Pursuant to 21 U.S.C. 811j, the scheduling recommendation by HHS
and FDA approval of the NDA
necessitated DEAs review and its own determination for the scheduling action to first issue the IFR and subsequently to issue this final rule in accordance with 21 U.S.C. 811b. DEA considered HHS scientific and medical evaluation and scheduling recommendation, and all other relevant data and concurred with HHS recommendation that remimazolam has low potential of abuse relative to substances in schedule III
and therefore supportedand continues to support through this final rule placement of remimazolam in schedule IV. DEA notes that under 21 U.S.C.
811b, HHSs recommendation shall be binding on the Administrator of DEA as delegated by the Attorney General as to any scientific or medical considerations involved in three of the eight factors specified in 21 U.S.C. 811c i.e., factors pertaining to the substances actual or relative potential for abuse, its history
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