[Federal Register Volume 86, Number 98 (Monday, May 24, 2021)]
[Rules and Regulations]
[Pages 27803-27806]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2021-10827]


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DEPARTMENT OF JUSTICE

Drug Enforcement Administration

21 CFR Part 1308

[Docket No. DEA-558]


Schedules of Controlled Substances: Placement of Lasmiditan in 
Schedule V

AGENCY: Drug Enforcement Administration, Department of Justice.

ACTION: Final rule.

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SUMMARY: This final rule adopts an interim final rule with request for 
comments published in the Federal Register on January 31, 2020, placing 
lasmiditan (2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-
carbonyl)pyridine-2-yl-benzamide), including its salts, in schedule V 
of the Controlled Substances Act without change, apart from a minor 
amendment to the placement ordering of lasmiditan already made by 
intervening rules. With the issuance of this final rule, the Drug 
Enforcement Administration maintains lasmiditan, including its salts, 
in schedule V of the Controlled Substances Act.

DATES: The effective date of this final rulemaking is May 24, 2021.

FOR FURTHER INFORMATION CONTACT: Terrence L. Boos, Drug and Chemical 
Evaluation Section, Drug Enforcement Administration; Telephone: (571) 
362-3249.

SUPPLEMENTARY INFORMATION: 

Background and Legal Authority

    On January 31, 2020, the Drug Enforcement Administration (DEA), 
pursuant to 21 U.S.C. 811(j), published an interim final rule placing 
lasmiditan, a recently Food and Drug Administration (FDA)-approved 
medication for the acute treatment of patients with migraine, in 
schedule V of

[[Page 27804]]

the Controlled Substances Act (CSA).\1\ 85 FR 5557. Specifically, this 
interim final rule placed lasmiditan in 21 CFR 1308.15(e)(4). As 
provided in paragraph (e), the placement of a substance in this 
depressant's category includes its salts. However, DEA incorrectly 
stated in the preamble of the interim final rule that lasmiditan 
(including its salts, isomers, and salts of isomers whenever the 
existence of such salts, isomers, and salts of isomers is possible) was 
placed in schedule V. The preamble of this final rule now correctly 
refers solely to lasmiditan and its salts. It bears emphasis that the 
regulatory text used in this final rule remains unchanged from that 
used in the interim final rule, apart from the change in placement 
ordering of lasmiditan due to intervening rules. DEA's issuance of the 
interim and final rules for placement of cenobamate in schedule V 
changed the placement order of lasmiditan from Sec.  1308.15(e)(4) to 
1308.15(e)(5). 85 FR 13741, March 10, 2020; and 85 FR 51340, August 20, 
2020.
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    \1\ The interim final rule stated that FDA, in October 2019, 
approved the new drug application for Reyvow (lasmiditan) 50 and 100 
mg oral tablets for the acute treatment of migraine with or without 
aura in adults.
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    The interim final rule referenced two supporting documents and 
stated they were available for viewing on the electronic docket. 
Specifically, the two documents cited are as follows: (1) The 
Department of Health and Human Services (HHS) October 2019 scientific 
and medical evaluation and scheduling recommendation (HHS Eight-Factor 
analysis), and (2) DEA's January 2020 Eight-Factor analysis. DEA has 
discovered that these documents were not posted to the electronic 
docket. However, they were available for viewing at DEA headquarters. 
Upon publication of this final rule, DEA will post to the docket the 
DEA January 2020 and HHS Eight-Factor analyses that should have 
accompanied the interim final rule, as well as DEA's August 2020 Eight-
Factor analysis.
    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 March 2, 2020. DEA did not receive any 
requests for hearing or waiver of hearing.

Comments Received

    In response to the interim final rule, DEA received five comments, 
four from individuals and one from a pharmaceutical manufacturer (the 
Sponsor of the new drug application (NDA) for Reyvow (lasmiditan)). One 
individual supported schedule V placement; two other individuals 
instead suggested schedule IV placement with the option to reclassify 
to schedule V after a provisional period; the manufacturer did not 
provide a position on the scheduling action but requested that the 
half-life information for lasmiditan be corrected; and the remaining 
individual 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 V Placement

    An individual commenter briefly discussed the background and abuse 
liability of lasmiditan, and stated that lasmiditan at doses greater 
than 200 mg has shown potential for abuse. In light of the current 
opioid epidemic, the commenter believes it is important that DEA 
appropriately regulate prescription medications with abuse potential. 
The commenter agreed that the schedule V classification for lasmiditan 
provides adequate oversight, without being overly regulatory, and will 
ensure the safety of the public.
    DEA Response: DEA determined in the interim final rule, and re-
affirms in this final rule, that lasmiditan meets the criteria under 21 
U.S.C. 812(b)(5) for schedule V control. As described by HHS, testing 
of lasmiditan at supratherapeutic dosages (400 mg) did show that it has 
abuse potential, however these effects of all doses of lasmiditan (100, 
200 and 400 mg) were significantly lower than alprazolam (see Factor 2 
of 8 factor analysis). DEA appreciates the support for this rulemaking.

Schedule IV Placement With Option To Reclassify After Provisional 
Period

    Two individual commenters expressed concerns with DEA's placing 
lasmiditan in schedule V due to the overall lack of data for the drug's 
abuse and dependence risks. One of these commenters cited a 2019 Phase 
1 randomized, placebo- and alprazolam-controlled crossover study, which 
provided both therapeutic (100 and 200 mg) and supratherapeutic (400 
mg) dosages of lasmiditan to the study subjects.\2\ This commenter 
stated that the researchers, after characterizing the subjective-liking 
drug effects, considered lasmiditan to have a low potential for abuse 
(compared to schedule IV alprazolam). However, the study authors listed 
the common adverse events occurring for lasmiditan at the three doses--
100 mg, 200 mg, and 400 mg--and specifically noted that higher doses 
produced greater events for somnolence (32.7%, 40.0%, and 54.5%, 
respectively) and euphoric mood (25.5%, 49.1%, and 45.5%, 
respectively). This same commenter stated that this was the only study 
of this type conducted, and its small study size of 58 participants 
could have a large margin for error.
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    \2\ Wilbraham, D., Berg, P.H., Tsai, M., Liffick, E., Loo, L.S., 
Doty, E.G., & Sellers, E. (2020). Abuse Potential of Lasmiditan: A 
Phase 1 Randomized, Placebo- and Alprazolam-Controlled Crossover 
Study. Journal of clinical pharmacology, 60(4), 495-504.
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    The other commenter also stated, very generally without referring 
to any specific study findings, that lasmiditan has lower potential for 
abuse and dependence than alprazolam. This commenter noted though the 
similar therapeutic effects for lasmiditan at higher doses, and stated 
this could be problematic for patients with chronic migraine taking 
lasmiditan. This commenter referenced a 2015 journal article 
(Weatherall, 2015),\3\ and stated ``[s]tudies have shown that those who 
suffer from chronic migraines also have medication overuse.'' In the 
commenter's opinion, such medication overuse could lead to heightened 
abuse and dependence risks.
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    \3\ Weatherall, M. W. (2015). The diagnosis and treatment of 
chronic migraine. Therapeutic Advances in Chronic Disease, 6(3), 
115-123.
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    As a result, this commenter believed schedule IV was more 
appropriate for this nascent drug, as a schedule IV classification 
provides more oversight by physicians for prescribing this drug to 
patients. Specifically, this commenter referenced a 2019 publication, 
updated in 2020, that indicated schedule IV drugs are drugs utilized 
for pain control as long as the provider deems the drug medically 
necessary and beneficial to the patient. Both commenters urged DEA to 
consider placing lasmiditan in schedule IV for a probationary or 
provisional time period with the option to reclassify lasmiditan as a 
schedule V substance. This option could be implemented once more 
rigorous clinical studies are conducted, and the analyzed results 
accurately demonstrate potential for abuse and dependency, justifying 
schedule V placement.
    DEA Response: DEA notes that FDA approved an NDA for Reyvow 
(lasmiditan), and HHS provided DEA with an evaluation and a scheduling 
recommendation for control of lasmiditan in schedule V. As provided in 
21 U.S.C. 811(j), the scheduling recommendation by HHS and the FDA 
approval of the NDA necessitated DEA review and its own determination 
for the scheduling action (to first issue the interim final rule and 
subsequently to

[[Page 27805]]

issue this final rule) pursuant to 21 U.S.C. 811(a) and (b) and 812. As 
discussed in the interim final rule, DEA's scheduling determination was 
based on consideration of the eight factors listed in 21 U.S.C. 811(c), 
HHS' scientific and medical evaluation and scheduling recommendation, 
and all other relevant data. DEA concurred with HHS' recommendation 
that lasmiditan has low potential for abuse relative to substances in 
schedule IV and therefore supported--and continues to support through 
this final rule--placement of lasmiditan in schedule V. DEA notes that 
under 21 U.S.C. 811(b), HHS' recommendations 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. 811(c) (i.e., factors 1, 4, and 5). 
Regarding the commenters' issues with lasmiditan's placement in 
schedule V, there is still significant oversight for schedule V drugs. 
For both the interim final rule and this final rule, DEA made the 
findings required under 21 U.S.C. 812(b)(5) for the placement of 
lasmiditan in schedule V. None of the commenters requested a hearing on 
the scheduling of lasmiditan.
    DEA would like to further clarify that the commenter who cited 
Weatherall, 2015 over-generalized the author's statements on the 
studies' findings pertaining to chronic migraine patients and 
medication overuse. In actuality, Weatherall (2015) stated that 
``[m]any patients with chronic migraine also have medication overuse,'' 
suggesting that while medication overuse does occur in migraine 
patients, it does not occur in all patients as stated by the commenter.

Half-Life Information for Lasmiditan

    The manufacturer commenter (the Sponsor of the NDA for Reyvow 
(lasmiditan)) stated that the interim final rule, in the factor 3 
discussion, inaccurately listed the half-life for lasmiditan as 
``approximately 31 hours,'' based on a general reference to rat 
studies. The commenter contended that DEA used findings from one 
specific rat study, which was included in the NDA for lasmiditan, to 
set this long half-life for lasmiditan. The commenter noted that this 
study determined the half-life by measuring circulating levels of 
radioactivity, and the reported findings were actually 27-32 hours. In 
addition, the commenter stated that, similarly to half-life findings 
for lasmiditan in clinical studies, this rat study's findings of a 
longer half-life is not a reflection of lasmiditan alone. Rather, this 
half-life reflects ``all drug-related analytes (i.e., pharmacologically 
inactive metabolites), some of which have longer half-lives than the 
parent drug, lasmiditan.'' This commenter provided findings from 
another rat study included in the NDA for lasmiditan, which used a non-
radiolabeled dose of lasmiditan. The commenter stated that this rat 
study used measures to detect only the half-life of the parent (intact) 
drug, lasmiditan; the study reported the mean lasmiditan half-life in 
plasma as 2-3 hours. Therefore, the commenter requested that DEA 
correct the factor 3 discussion regarding the lasmiditan half-life data 
to state: ``Rat studies demonstrate that lasmiditan has a half-life of 
2-3 hours.''
    DEA Response: The eight-factor analysis described in the interim 
final rule is an abridged version of DEA's eight-factor analysis. 
Regarding the commenter's request that factor 3 discussion provide 
half-life findings from an additional rat study, both the DEA (January 
2020) and HHS eight-factor analyses conducted as part of the interim 
final rule process noted the half-life in their respective tables. In 
DEA's August 2020 eight-factor analysis, information was added in 
Factor 3 to describe this additional study and show a shorter half-life 
(2-3 hours) of lasmiditan as compared to the long half-life obtained 
from the study measuring radioactivity (see Table 5 and 6 of DEA 8-
factor analysis). DEA agrees with the commenter that longer half-lives 
of pharmacologically inactive metabolites can occur.
    Based on the rationale set forth in the interim final rule, DEA 
adopts the interim final rule without change.

Requirements for Handling Lasmiditan

    As indicated above, lasmiditan has been a schedule V controlled 
substance by virtue of the interim final rule issued by DEA in January 
2020. Thus, this final rule does not alter the regulatory requirements 
applicable to handlers of lasmiditan that have been in place since that 
time. Nonetheless, for informational purposes, we restate here those 
requirements. Lasmiditan is subject to the CSA's schedule V regulatory 
controls and administrative, civil, and criminal sanctions applicable 
to the manufacture, distribution, reverse distribution, dispensing, 
importing, exporting, research, and conduct of instructional activities 
and chemical analysis with, and possession involving schedule V 
substances, including, but not limited to, the following:
    1. Registration. Any person who handles (manufactures, distributes, 
reverse distributes, dispenses, imports, exports, engages in research, 
or conducts instructional activities or chemical analysis with, or 
possesses) lasmiditan, or who desires to handle lasmiditan, must be 
registered with 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 or intends to handle lasmiditan, 
and is not registered with DEA, must submit an application for 
registration and may not continue to handle lasmiditan unless DEA has 
approved that application for registration, pursuant to 21 U.S.C. 822, 
823, 957, and 958, and in accordance with 21 CFR parts 1301 and 1312. 
These registration requirements, however, are not applicable to 
patients (end users) who possess lasmiditan pursuant to a lawful 
prescription.
    2. Disposal of stocks. Any person who obtains a schedule V 
registration to handle lasmiditan but who subsequently does not desire, 
or is not able to maintain such registration must surrender all 
quantities of lasmiditan, or may transfer all quantities of lasmiditan 
to a person registered with DEA in accordance with 21 CFR part 1317, in 
addition to all other applicable federal, state, local, and tribal 
laws.
    3. Security. Lasmiditan is subject to schedule III-V security 
requirements for DEA registrants, and it must be handled and stored in 
accordance with 21 CFR 1301.71-1301.93. Non-practitioners handling 
lasmiditan must also comply with the employee screening requirements of 
21 CFR 1301.90-1301.93.
    4. Labeling and Packaging. All labels, labeling, and packaging for 
commercial containers of lasmiditan must comply with 21 U.S.C. 825 and 
958(e), and be in accordance with 21 CFR part 1302.
    5. Inventory. Every DEA registrant who possesses any quantity of 
lasmiditan was required to keep an inventory of lasmiditan on hand, as 
of January 31, 2020, pursuant to 21 U.S.C. 827 and 958(e), and in 
accordance with 21 CFR 1304.03, 1304.04, and 1304.11.
    6. Records and Reports. DEA registrants must maintain records and 
submit reports for lasmiditan, or products containing lasmiditan, 
pursuant to 21 U.S.C. 827 and 958(e), and in accordance with 21 CFR 
1301.74(b) and (c) and parts 1304, 1312, and 1317.
    7. Prescriptions. All prescriptions for lasmiditan, or products 
containing lasmiditan, must comply with 21 U.S.C. 829, and be issued in 
accordance with 21 CFR parts 1306 and 1311, subpart C.
    8. Manufacturing and Distributing. In addition to the general 
requirements of

[[Page 27806]]

the CSA and DEA regulations that are applicable to manufacturers and 
distributors of schedule V controlled substances, such registrants 
should be advised that (consistent with the foregoing considerations) 
any manufacturing or distribution of lasmiditan may only be for the 
legitimate purposes consistent with the drug's labeling, or for 
research activities authorized by the Federal Food, Drug, and Cosmetic 
Act and the CSA.
    9. Importation and Exportation. All importation and exportation of 
lasmiditan must be in compliance with 21 U.S.C. 952, 953, 957, and 958, 
and in accordance with 21 CFR part 1312.
    10. Liability. Any activity involving lasmiditan not authorized by, 
or in violation of, the CSA or its implementing regulations is 
unlawful, and may subject the person to administrative, civil, and/or 
criminal sanctions.

Regulatory Analyses

Administrative Procedure Act

    This final rule affirms the amendment made by the interim final 
rule that is already in effect with a minor change in placement 
ordering of lasmiditan as discussed above. Section 553 of the 
Administrative Procedure Act (APA) (5 U.S.C. 553) generally requires 
notice and comment for rulemakings. However, 21 U.S.C. 811(j) provides 
that in cases where a certain new drug is: (1) Approved by HHS and (2) 
HHS recommends control in CSA schedule II-V, DEA shall issue an interim 
final rule scheduling the drug within 90 days. Additionally, subsection 
(j) specifies that the rulemaking shall become immediately effective as 
an interim final rule without requiring DEA to demonstrate good cause. 
DEA issued an interim final rule on January 31, 2020, which provided 
notice and an opportunity for a hearing on the record and solicited 
public comments on that rule. Subsection (j) further states that after 
giving interested persons the opportunity to comment and to request a 
hearing, the Attorney General, as delegated to the Administrator of 
DEA, shall issue a final rule in accordance with the scheduling 
criteria of 21 U.S.C. 811 (b) through (d) and 812(b). DEA is now 
responding to the comments submitted by the public and issuing the 
final rule in accordance with subsection (j).

Executive Orders 12866 (Regulatory Planning and Review) and 13563 
(Improving Regulation and Regulatory Review)

    In accordance with 21 U.S.C. 811(a) and (j), this 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 (E.O.) 12866 and the 
principles reaffirmed in E.O. 13563.

Executive Order 12988, Civil Justice Reform

    This regulation meets the applicable standards set forth in 
sections 3(a) and 3(b)(2) of E.O. 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, Federalism

    This rulemaking does not have federalism implications warranting 
the application of E.O. 13132. The rule does not have substantial 
direct effects on the States, on the relationship between the national 
government and the States, or on the distribution of power and 
responsibilities among the various levels of government.

Executive Order 13175, Consultation and Coordination With Indian Tribal 
Governments

    This rule does not have tribal implications warranting the 
application of E.O. 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 Regulatory Flexibility Act (RFA) (5 U.S.C. 601-612) applies to 
rules that are subject to notice and comment under section 553(b) of 
the APA. As noted in the above discussion regarding the applicability 
of the APA, DEA was not required to publish a general notice of 
proposed rulemaking. Consequently, the RFA does not apply.

Unfunded Mandates Reform Act of 1995

    In accordance with the Unfunded Mandates Reform Act (UMRA) of 1995, 
2 U.S.C. 1501 et seq., DEA has determined 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 million or more (adjusted annually for 
inflation) in any 1 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.

Congressional Review Act

    This rule is not a major rule as defined by the Congressional 
Review Act (CRA), 5 U.S.C. 804. However, DEA is submitting the required 
reports to the Government Accountability Office, the House, and the 
Senate under the CRA.

List of Subjects in 21 CFR Part 1308

    Administrative practice and procedure, Drug traffic control, 
Reporting and recordkeeping requirements.


0
Accordingly, the interim final rule amending 21 CFR part 1308, which 
was published at 85 FR 5557 on January 31, 2020, and as subsequently 
amended at 85 FR 13741 and 85 FR 51340, is adopted as a final rule 
without change.

D. Christopher Evans,
Acting Administrator.
[FR Doc. 2021-10827 Filed 5-21-21; 8:45 am]
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