Schedules of Controlled Substances: Placement of Lasmiditan in Schedule V
| Published date | 24 May 2021 |
| Citation | 86 FR 27803 |
| Record Number | 2021-10827 |
| Section | Rules and Regulations |
| Court | Drug Enforcement Administration |
Federal Register, Volume 86 Issue 98 (Monday, May 24, 2021)
[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]
BILLING CODE 4410-09-P
