Proposed Rule2022-15335
Schedules of Controlled Substances: Removal of Fenfluramine From Control
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Published
July 19, 2022
Issuing agencies
Justice DepartmentDrug Enforcement Administration
Abstract
The Drug Enforcement Administration proposes to remove fenfluramine (chemical name: N-ethyl-[alpha]-methyl-3- (trifluoromethyl)phenethylamine), including its salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts is possible, from the schedules of the Controlled Substances Act (CSA). This scheduling action is pursuant to the CSA which requires that such actions be made on the record after opportunity for a hearing through formal rulemaking. Fenfluramine is currently a schedule IV controlled substance. This action would remove the regulatory controls and administrative, civil, and criminal sanctions applicable to controlled substances, including those specific to schedule IV controlled substances, on persons who handle (manufacture, distribute, reverse distribute, import, export, dispense, engage in research, conduct instructional activities or chemical analysis with, or possess), or propose to handle fenfluramine.
Full Text
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<title>Federal Register, Volume 87 Issue 137 (Tuesday, July 19, 2022)</title>
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[Federal Register Volume 87, Number 137 (Tuesday, July 19, 2022)]
[Proposed Rules]
[Pages 42979-42985]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2022-15335]
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DEPARTMENT OF JUSTICE
Drug Enforcement Administration
21 CFR Part 1308
[Docket No. DEA-945]
Schedules of Controlled Substances: Removal of Fenfluramine From
Control
AGENCY: Drug Enforcement Administration, Department of Justice.
ACTION: Notice of proposed rulemaking.
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SUMMARY: The Drug Enforcement Administration proposes to remove
fenfluramine (chemical name: N-ethyl-[alpha]-methyl-3-
(trifluoromethyl)phenethylamine), including its salts, isomers, and
salts of isomers whenever the existence of such salts, isomers, and
salts is possible, from the schedules of the Controlled Substances Act
(CSA). This scheduling action is pursuant to the CSA which
[[Page 42980]]
requires that such actions be made on the record after opportunity for
a hearing through formal rulemaking. Fenfluramine is currently a
schedule IV controlled substance. This action would remove the
regulatory controls and administrative, civil, and criminal sanctions
applicable to controlled substances, including those specific to
schedule IV controlled substances, on persons who handle (manufacture,
distribute, reverse distribute, import, export, dispense, engage in
research, conduct instructional activities or chemical analysis with,
or possess), or propose to handle fenfluramine.
DATES: Comments must be submitted electronically or postmarked, on or
before August 18, 2022. Requests for hearing and waivers of an
opportunity for a hearing or to participate in a hearing must be
received on or before August 18, 2022.
ADDRESSES: Interested persons may file written comments on this
proposal in accordance with 21 CFR 1308.43(g). 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. To ensure proper
handling of comments, please reference ``Docket No. DEA-945'' on all
electronic and written correspondence, including any attachments.
<bullet> Electronic comments: The Drug Enforcement Administration
encourages commenters to submit all comments 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>
and follow the on-line instructions at that site for submitting
comments. Upon completion of your submission, you will receive a
Comment Tracking Number. Submitted comments are not instantaneously
available for public view on <a href="http://Regulations.gov">Regulations.gov</a>. If you have received a
Comment Tracking Number, you have submitted your comment successfully
and there is no need to resubmit the same comment. 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.
<bullet> Paper comments: Paper comments that duplicate electronic
submissions are not necessary and are discouraged. Should you wish to
mail a paper comment in lieu of an electronic format, it should be sent
via regular or express mail to: Drug Enforcement Administration, Attn:
DEA Federal Register Representative/DPW, 8701 Morrissette Drive,
Springfield, Virginia 22152.
<bullet> Hearing requests: All requests for a hearing and waivers
of participation, together with a written statement of position on the
matters of fact and law asserted in the hearing, must be sent to: Drug
Enforcement Administration, Attn: Hearing Clerk/OALJ, 8701 Morrissette
Drive, Springfield, Virginia 22152.
FOR FURTHER INFORMATION CONTACT: Terrence L. Boos, Drug & Chemical
Evaluation Section, Diversion Control Division, Drug Enforcement
Administration; Telephone: (571) 362-3249.
SUPPLEMENTARY INFORMATION:
Posting of Public Comments
All comments received in response to this docket are considered
part of the public record. The Drug Enforcement Administration (DEA)
will make comments available, unless reasonable cause is given, for
public inspection online at <a href="https://www.regulations.gov">https://www.regulations.gov</a>. Such
information includes personal identifying information (such as your
name, address, etc.) voluntarily submitted by the commenter. The
Freedom of Information Act 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 DEA to make it
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 DEA to make it 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.
DEA will generally make available in publicly redacted form
comments containing personal identifying information and confidential
business information identified, as directed above. If a comment has so
much confidential business information or personal identifying
information that DEA cannot effectively redact it, DEA may not make all
or part of that comment publicly available. Comments posted to <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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 confidential as
directed above.
An electronic copy of this document and supplemental information to
this proposed rule are available at <a href="https://www.regulations.gov">https://www.regulations.gov</a> for
easy reference.
Request for Hearing or Appearance; Waiver
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 Administrative Procedure
Act (5 U.S.C. 551-559). 21 CFR 1308.41-1308.45, and 21 CFR part 1316,
subpart D. Interested persons may file requests for a hearing or
notices of intent to participate in a hearing in conformity with the
requirements of 21 CFR 1308.44(a) or (b), and such requests must
include a statement of the interest of the person in the proceeding and
the objections or issues, if any, concerning which the person desires
to be heard. 21 CFR 1316.47(a). Any interested person may file a waiver
of an opportunity for a hearing or to participate in a hearing together
with a written statement regarding the interested person's position on
the matters of fact and law involved in any hearing as set forth in 21
CFR 1308.44(c).
Please note that, pursuant to 21 U.S.C. 811(a)(2), the purpose of a
hearing would be to determine whether fenfluramine should be removed
from the list of controlled substances based on a finding that the drug
does not meet the requirements for inclusion in any schedule. All
requests for hearing and waivers of participation, together with a
written statement of position on the matters of fact and law involved
in such hearing, must be sent to DEA using the address information
above.
Legal Authority
The Controlled Substances Act (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 by a petition to
remove fenfluramine from the list of scheduled controlled substances of
the CSA, and is supported by, inter alia, a
[[Page 42981]]
recommendation from the Assistant Secretary for Health of HHS and an
evaluation of all relevant data by DEA. If finalized, this action would
remove the regulatory controls and administrative, civil, and criminal
sanctions applicable to controlled substances, including those specific
to schedule IV controlled substances, on persons who handle or propose
to handle fenfluramine.
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\1\ The Secretary of HHS has delegated to the Assistant
Secretary for Health the authority to make domestic drug scheduling
recommendations.
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Background
Fenfluramine (chemical name: N-ethyl-[alpha]-methyl-3-
(trifluoromethyl)phenethylamine), including its salts, isomers, and
salts of such isomers, is currently controlled under 21 CFR 1308.14(d)
as a schedule IV substance of the CSA. DEA placed fenfluramine in
schedule IV on June 15, 1973 (38 FR 15719), after the U.S. Food and
Drug Administration's (FDA) approval on June 14, 1973 of Pondimin, a
fenfluramine product manufactured by Wyeth Pharmaceuticals, for the
management of exogenous obesity. As noted in the HHS review of
scientific and medical information, on September 25, 2019, Zogenix,
Inc. (Zogenix; the Sponsor) submitted to FDA a New Drug Application
(NDA) for Fintepla (fenfluramine),\2\ for the treatment of seizures
associated with Dravet syndrome (DS) in patients two years of age and
older. (HHS, 2021) FDA approved the NDA on June 25, 2020, with the
labelling listing fenfluramine as a schedule IV controlled substance.
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\2\ Fintepla is an oral solution that contains 2.2 mg/ml
fenfluramine equivalent to 2.5 mg/ml of the hydrochloride salt.
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On March 18, 1991, Interneuron Pharmaceuticals, Inc., the
manufacturer of a fenfluramine product (dexfenfluramine, brand name
Redux), petitioned DEA to decontrol fenfluramine. In response to DEA's
request, HHS's Assistant Secretary for Health submitted to DEA a
scientific and medical evaluation (HHS review) and a scheduling
recommendation to DEA to decontrol fenfluramine on June 3, 1996. On May
6, 1997, DEA published a notice of proposed rulemaking (NPRM) in the
Federal Register to remove fenfluramine from controls under the CSA. 62
FR 24620. On July 8, 1997, FDA issued a public health advisory
regarding the use of fenfluramine, especially in conjunction with
phentermine (schedule IV controlled substance) commonly known as
``phen-fen,'' citing evidence of significant side effects associated
with fenfluramine. FDA announced a voluntary withdrawal by the
pharmaceutical manufacturers of Pondimin (fenfluramine) and Redux
(dexfenfluramine) from the U.S. market on September 15, 1997. HHS
issued a final rule on March 8, 1999, listing drug products that were
withdrawn or removed from the market because they were found to be
unsafe or not effective, including fenfluramine hydrochloride. 64 FR
10944. On February 27, 2003, Indevus Pharmaceuticals, Inc., formerly
known as Interneuron Pharmaceuticals, Inc., wrote to DEA to withdraw
its petition to decontrol fenfluramine because it no longer markets
fenfluramine products in the U.S. In light of the above-mentioned
developments, on May 15, 2003, DEA withdrew the May 1997 NPRM. 68 FR
26247.
On October 18, 2018, Zogenix submitted to DEA a petition requesting
that fenfluramine be removed from schedule IV of the CSA based on the
data and rationale in DEA's May 1997 NPRM and more recent data
collected, including data specific to Fintepla. The petition complied
with the requirements of 21 CFR 1308.43(b) and DEA accepted the
petition for filing on November 13, 2018.
Proposed Determination To Decontrol Fenfluramine
Pursuant to 21 U.S.C. 811(b), on September 22, 2020, DEA, having
gathered the necessary data on fenfluramine, forwarded that data and
the petition to HHS with a request for scientific and medical
evaluation and scheduling recommendation for fenfluramine. On April 16,
2021, DEA received from HHS a scientific and medical evaluation
conducted by FDA entitled ``Basis for the recommendation to remove
fenfluramine (N-ethyl-[alpha]-methyl-3-(trifluoromethyl)phenethylamine)
and its salts from all schedules of control under the Controlled
Substances Act'' and a scheduling recommendation. The National
Institute on Drug Abuse (NIDA) concurred with the scientific and
medical evaluation conducted by FDA. Based on the totality of the
available scientific data, fenfluramine does not conform with the
findings for schedule IV in 21 U.S.C. 812(b)(4) or in any other
schedule as set forth in 21 U.S.C. 812(b). Based on FDA's scientific
and medical review of the eight factors and findings related to the
substance's abuse potential, legitimate medical use, and dependence
liability, HHS recommended that fenfluramine and its salts be removed
from all schedules of the CSA.
The CSA requires DEA, as delegated by the Attorney General,\3\ to
determine whether HHS's scientific and medical evaluation, scheduling
recommendation, as well as all other relevant data constitute
substantial evidence that a substance should be scheduled. 21 U.S.C.
811(b). DEA reviewed the scientific and medical evaluation and
scheduling recommendation provided by HHS, and all other relevant data,
and completed its own eight-factor review document on fenfluramine
pursuant to 21 U.S.C. 811(c). Included below is a brief summary of each
factor as analyzed by HHS and DEA, and as considered by DEA in this
proposal to remove fenfluramine from the schedules of the CSA. Both DEA
and HHS analyses are available in their entirety under ``Supporting and
Related Material'' of the public docket for this rule at <a href="https://www.regulations.gov">https://www.regulations.gov</a> under docket number DEA-945.
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\3\ 28 CFR 0.100(b).
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1. The Drug's Actual or Relative Potential for Abuse
The first factor DEA must consider is the actual or relative
potential for abuse of fenfluramine. The term ``abuse'' is not defined
in the CSA. However, the legislative history of the CSA suggests the
following points in determining whether a particular drug or substance
has a potential for abuse: \4\
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\4\ Comprehensive Drug Abuse Prevention and Control Act of 1970,
H.R. Rep. No. 91-1444, 91st Cong., Sess. 1 (1970); 1970 U.S.C.C.A.N.
4566, 4603.
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a. Whether there is evidence that individuals are taking the drug
or drugs containing such a substance in amounts sufficient to create a
hazard to their health or to the safety of other individuals or to the
community.
As HHS noted, FDA approved fenfluramine (brand name Pondimin) in
the U.S. on June 14, 1973, but FDA announced on September 15, 1997 that
the pharmaceutical manufacturers of Pondimin and Redux (another FDA-
approved fenfluramine product) voluntarily withdrew their products from
the U.S. markets (see 68 FR 26247; May 15, 2003) after FDA issued a
public health advisory in May 1997. FDA's public health advisory
reported increased rates of cardiac valvulopathy and pulmonary arterial
hypertension (PAH) related to fenfluramine use, particularly when used
in the unapproved combination with phentermine for weight loss. On June
25, 2020, FDA approved Fintepla for the treatment of seizures
associated with DS in patients two years of age and older. HHS noted in
their scientific and
[[Page 42982]]
medical evaluation that FDA reviewed the known hazards of fenfluramine
and found no evidence of cardiac valvulopathy or PAH in pediatric DS
patients treated with fenfluramine in the cardiovascular data the
Petitioner submitted as part of their NDA application. FDA concluded
that there is a reduced risk of cardiac valvulopathy or PAH due to the
lower doses used to treat pediatric DS patients relative to the higher
doses prescribed to obese adult patients. DEA notes that the FDA-
approved labeling for Fintepla indicates that patients must be enrolled
in the Fintepla risk evaluation and mitigation strategy (REMS) program
and undergo cardiac monitoring before, during, and after treatment with
fenfluramine to monitor for serious heart valve changes or high blood
pressure in the arteries of the lungs.
b. Whether there is significant diversion of the drug or drugs
containing such a substance from legitimate drug channels.
Fenfluramine was previously marketed in the U.S. from 1973 to 1997.
According to DEA's forensic laboratory database System to Retrieve
Information from Drug Evidence (STRIDE),\5\ 30 cases of fenfluramine
were recorded between 1973 to 1991. Seven reports occurred in 1988 and
involved seizures of fenfluramine from individuals traveling from
Mexico into the U.S. Twenty-three drug seizure reports occurred after
the manufacturers' voluntary withdrawal, in September 1997, of Pondimin
and Redux from the U.S. market (1999 to 2009) in seven states and the
District of Columbia. According to DEA's National Forensic Laboratory
Information System-Drug (NFLIS-Drug),\6\ 177 seizures were reported
from January 1997 to November 2021 in 30 states and the District of
Columbia, with eight of the encounters reported from January 2017
through November 2021. In 169 of the encounters reported, fenfluramine
was reported alone, with another encountered with only cellulose noted,
a common filler or cutting agent. Fenfluramine was commonly encountered
as a powder, capsule, or tablet.
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\5\ STRIDE reflects the results of drug evidence analyzed at DEA
laboratories through September, 2014. STRIDE was queried on July 3,
2019.
\6\ NFLIS-Drug is a national forensic laboratory reporting
system that systematically collects results from drug chemistry
analyses conducted by local, State, and Federal forensic
laboratories in the United States. NFLIS-Drug is a comprehensive
information system that includes data from forensic laboratories
that handle more than 96% of an estimated 1.0 million distinct
annual State and local drug analysis cases. While NFLIS-Drug data is
not direct evidence of abuse, it can lead to an inference that a
drug has been diverted and abused. See 76 FR 77330, 77332, Dec. 12,
2011. NFLIS-Drug was queried on December 20, 2021. Some 2021 reports
to NFLIS-Drug may still be pending.
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Additionally, DEA's May 1997 NPRM included data on fenfluramine
from the Drug Abuse Warning Network (DAWN).\7\ (62 FR 24620, 24621) The
DAWN data showed very little abuse, trafficking, and diversion of
fenfluramine. In addition, HHS stated that there were no reports of
diversion in clinical trials conducted by the current Petitioner.
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\7\ DAWN is a public health surveillance system that monitors
drug-related visits to hospital emergency departments. DAWN was
discontinued in 2011, but the Substance Abuse and Mental Health
Services Administration's website currently indicates that it is re-
establishing this system.
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c. Whether individuals are taking the drug or drugs containing such
a substance on their own initiative rather than on the basis of medical
advice from a practitioner licensed by law to administer such drugs in
the course of his professional practice.
The available evidence suggests that the prevalence of individuals
taking fenfluramine on their own initiative, without advice from a
licensed medical practitioner, does not occur to a meaningful degree.
d. Whether the drug or drugs containing such a substance are new
drugs so related in their action to a substance already listed as
having a potential for abuse to make it likely that it will have the
same potentiality for abuse as such drugs, thus making it reasonable to
assume that there may be significant diversions from legitimate
channels, significant use contrary to or without medical advice, or
that they have a substantial capability of creating hazards to the
health of the user or to the safety of the community.
According to HHS, fenfluramine is a serotonin (5-HT) releasing
agent. Some drugs with the same mechanism of action are controlled in
the CSA (e.g., 3,4-methylenedioxymethamphetamine or MDMA (also known as
ecstasy, schedule I substance) and some are not. HHS further noted that
in animal drug discrimination studies, which are generally sensitive to
mechanisms of action, fenfluramine fully generalized to the
discriminative stimulus effects of serotonergic substances such as
MDMA, quipazine, and MK-212. The latter two are not controlled
substances.
2. Scientific Evidence of the Drug's Pharmacological Effects, If Known
The binding and activity studies indicate that fenfluramine causes
the release and prevents the reuptake of 5-HT; has antagonist activity
at the beta-2 adrenergic receptor, the muscarinic M1 receptor, and the
sodium ion channel (hNav1.5); and has positive allosteric modulator
activity at the nonspecific sigma-1 receptor.
Additionally, d-fenfluramine is a potent agonist of the 5-
HT<INF>2B</INF> receptor despite its weak binding affinity, has
moderate agonist activity at the 5-HT<INF>2C</INF> receptor, and has
weak activity at the 5-HT<INF>2A</INF> receptor, whereas l-
norfenfluramine demonstrated moderate activity at the 5-HT<INF>2B</INF>
receptor and weak activity at the 5-HT<INF>2C</INF> and 5-
HT<INF>2A</INF> receptors, respectively.
Drug discrimination assays in animals can be used to predict if a
test drug will have abuse potential in humans. Although fenfluramine
was first thought of as a stimulant based on its phenethylamine
structure, fenfluramine does not generalize to stimulants when the
discriminative stimulus effects were tested against a range of
stimulant drugs. When rats were trained to discriminate fenfluramine
from vehicle or other drugs, it became evident that fenfluramine
produced discriminative stimulus effects similar to those of
serotonergic substances such as quipazine and MK-212. HHS noted that
fenfluramine fully generalized to drugs that do not have abuse
potential such as lisuride, quipazine, and 1-(m-trifluoro-
methylphenyl)piperazine (TFMPP), and generalized to some drugs that
have abuse potential such as MDMA, but not to para-methoxyamphetamine
(PMA, schedule I substance) or LSD (schedule I substance), which
generalized to norfenfluramine. HHS concluded the drug discrimination
studies are equivocal and do not provide clear evidence of the
hallucinogenic effects of fenfluramine, a finding consistent with its
clinical effects.
The reinforcing effects of fenfluramine, using various models and
animal species, were also reviewed. HHS determined that the
fenfluramine responded similarly to placebo and does not produce
reinforcing effects. Further, HHS stated that these data are consistent
with 5-HT agonists that are phenethylamines and lack stimulant
activity. Fenfluramine is a phenethylamine that produces serotonergic
agonist activity. Therefore, fenfluramine may be expected to produce
placebo-like responding in these reinforcing assays.
According to HHS, after review of the published literature on the
subjective effects of fenfluramine in humans, data indicate that single
oral doses below 80 mg do not produce significant positive subjective
effects. High doses ranging from 120 to 240 mg can produce positive
subjective effects; however, the predominant effects at high doses were
aversive and included sedation.
[[Page 42983]]
Anecdotal reports of abuse of fenfluramine from doctors exist; however,
the published articles mention the subjects prefer other drugs. HHS
mentioned that these effects are consistent with other measures
indicating that subjects are tired, do not appreciate the psychoactive
effects of fenfluramine, and do not ``Want More'' of the drug when
asked.
HHS noted that Fintepla did not produce a concerning number of
abuse-related adverse effects (AEs) after an analysis of the adverse
effect profiles of all phases of development was completed. FDA
reviewed the cardiovascular data submitted in the NDA for Fintepla and
found no evidence of cardiac valvulopathy or PAH in pediatric DS
patients treated with fenfluramine. The studies conducted for the NDA
for Fintepla concluded that there was a reduced risk of cardiac
valvulopathy or PAH because of the lower doses used to treat pediatric
DS patients compared to the higher doses prescribed to obese adult
patients.
3. The State of Current Scientific Knowledge Regarding the Drug or
Other Substance
According to HHS, fenfluramine, also known by the developmental
code ZX008, is the nonproprietary name of N-ethyl-[alpha]-methyl-3-
(trifluoromethyl)phenethylamine hydrochloride and is structurally
similar to the amphetamine class of stimulants.
Fenfluramine has one asymmetric carbon and therefore may exist in
two forms, which are identified as the (d) and the (l) enantiomers.
Fenfluramine represents a mixture of both enantiomers. The molecular
formula of fenfluramine hydrochloride (salt) is
C<INF>12</INF>H<INF>16</INF>F<INF>3</INF>N HCl and the molecular weight
is 267.72 g/mol. Fenfluramine is a white to off-white powder.
Fenfluramine hydrochloride (salt) is soluble in organic solvents like
ethanol (150 mg/mL) at 25 [deg]C and dichloromethane (30-35 mg/mL) at
25 [deg]C.
According to HHS, the development of fenfluramine (Fintepla)
included a study that assessed the permeability of fenfluramine and
norfenfluramine across Caco-2 cells that express P-glycoprotein (P-gp)
transporters. P-gp transporters are known to actively transport foreign
substances out of cells and the central nervous system (CNS) and can
help determine a drug's permeability into the CNS. Both fenfluramine
and norfenfluramine are highly permeable and the permeability was not
affected by the P-gp antagonist valspodar (10 [mu]M), suggesting
fenfluramine and norfenfluramine will pass easily into the CNS.
Pharmacokinetic data indicate that a single oral dose of
fenfluramine (20 mg/kg, PO) in mice produced a C<INF>max</INF> of 0.26
[micro]g/mL and an area under the curve (AUC) of 1.4 [micro]g/mL*hr,
results similar to that of a 60 mg twice daily (BID) dose in healthy
human adults. The same dose (20 mg/kg, PO) in rats produced a
C<INF>max</INF> of 0.36 [micro]g/mL and an AUC of 5.15 [micro]g/mL*hr,
values higher than those in the mouse studies. The T<INF>max</INF> of
fenfluramine in rats ranged from 30 minutes to 2 hours, and the half-
life was 2.5 hours.
According to HHS, the Sponsor of the Fintepla NDA provided
pharmacokinetic data on norfenfluramine. In rats, a single oral dose of
norfenfluramine is rapidly absorbed similarly to fenfluramine, with a
T<INF>max</INF> of 30 minutes and a half-life of 2.5 hours.
Fenfluramine and norfenfluramine are easily distributed throughout the
body and produced approximately 50 percent protein specific binding in
human and rat plasma, however concentrations of both compounds were
determined to be higher in the brain compared to the plasma, by 15 to
60-fold, depending on the study.
Fenfluramine is metabolized to norfenfluramine and is an active
metabolite. Norfenfluramine and its N-oxygenation product were the only
metabolites detected in liver S9 fractions in both rat and human
samples. Fenfluramine and norfenfluramine are excreted primarily
through the renal system (greater than 80%), with a small amount via
the feces.
4. Its History and Current Pattern of Abuse
HHS noted that sporadic anecdotal reports of fenfluramine abuse
were found when fenfluramine was marketed in the United States and
Europe between 1963 and 1997. However, when compared to the large
number of patients who were treated with and prescribed the drug during
this time frame (approximately 55 million patients total, 50 million
European patients with fenfluramine, and 5 million U.S. patients with
fenfluramine or desfenfluramine), the number of people abusing
fenfluramine is relatively small. According to these reports, HHS noted
that these individuals either did not like fenfluramine because of its
dysphoric effects or preferred another drug. Therefore, the history and
current pattern of abuse of fenfluramine is low.
5. The Scope, Duration, and Significance of Abuse
HHS stated that the scope of abuse of fenfluramine was minimal when
it was marketed and when compared to the number of patients to whom it
was prescribed. According to HHS, fenfluramine, in most cases, was not
the drug of choice to produce a psychoactive effect and was used only
when no other drug was available. In most cases, a high dose
fenfluramine \8\ produced a dysphoric effect leading the individual to
stop taking fenfluramine.
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\8\ The HHS review indicated that in human clinical studies and
case reports, a single oral dose of 80 mg did not produce
significant positive subjective effects; however, high single oral
doses of 120 or 240 mg can produce positive subjective effects.
Single oral doses over 80 mg were reported to be aversive and
produce dysphoric effects.
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DEA conducted a search of Federal, State, and local forensic
laboratory databases such as NFLIS-Drug and STRIDE. The STRIDE database
indicated that in the 18 years between 1973 and 1991, 30 cases of
fenfluramine were entered into the database, and, there were 23 drug
seizure reports during the period of 1999 to 2009 in seven states and
the District of Columbia. According to NFLIS-Drug, there were 177
reports of fenfluramine from 30 states and the District of Columbia
between January 1997 and November 2021. Eight of the 177 encounters
were reported from January 2017 through November 2021 (1 in 2017, 3 in
2019, 3 in 2020, 1 in 2021). In 169 of these encounters, fenfluramine
was reported alone. Another encounter was with only cellulose, a common
filler or cutting agent. Fenfluramine was commonly encountered as a
powder, capsule, or tablet.
HHS noted, as a result, the scope, duration, and significance of
abuse of fenfluramine are minimal compared to the millions of patients
who were prescribed and treated with the drug.
6. What, If Any, Risk There Is to the Public Health
Abuse potential of a drug is considered one indication of its risk
to the public health. According to HHS, based on preclinical and
clinical study data (see Factors 1 and 2), there are no signals that
indicate that fenfluramine has abuse potential or that there is a risk
to the public health from individuals abusing fenfluramine.
An FDA public health advisory, released on July 8, 1997, indicated
increased rates of cardiac valvulopathy and PAH in relation to the use
of fenfluramine, particularly in combination with phentermine. FDA
approved Fintepla (fenfluramine) with a boxed warning on the label to
address
[[Page 42984]]
the potential cardiac issues that have been correlated to the
administration of fenfluramine and included language that patients
would need to undergo cardiac assessments before, during, and after
treatment with the drug.\9\
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\9\ DEA notes that this boxed warning also states that Fintepla
is available only through a restricted program, Fintepla REMS.
<a href="https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm?event=IndvRemsDetails.page&REMS=400">https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm?event=IndvRemsDetails.page&REMS=400</a>.
---------------------------------------------------------------------------
Thus, HHS concluded there is likely to be little risk to the public
health from fenfluramine.
7. Its Psychic or Physiological Dependence Liability
The psychic dependence of fenfluramine was assessed in animal and
clinical studies. HHS reported that fenfluramine failed to produce
reinforcing effects in self-administration studies (Factor 2) and
indicated that fenfluramine does not produce psychic dependence. HHS
also noted there was a lack of psychic dependence in the clinical data
discussed in Factors 2 and 4. These data indicate that fenfluramine
produces dysphoric effects and that it is not the drug of choice among
individuals with a drug use disorder. According to HHS, these data
suggest that fenfluramine has low psychic dependence.
As per the physical dependence potential, there are reports of
withdrawal syndrome upon cessation of fenfluramine use. HHS noted that
a search of the FDA Adverse Event Reporting System (commonly known as
FAERS) covering the years fenfluramine was marketed (1973 to 1997)
produced four cases of ``withdrawal syndrome'' associated with
fenfluramine. Physical dependence was not assessed in humans throughout
the clinical development of fenfluramine (Fintepla). The Phase 1
studies were single dose studies or studies in which treatment was
administered for only six days and not long enough to produce
dependence. Additionally, physical dependence could not be assessed in
the Phase 3 studies because the discontinuation of fenfluramine in
seizure patients could not be done abruptly. The Phase 3 studies
included a taper phase. The FDA-approved label recommends that
fenfluramine be withdrawn gradually.
In conclusion, HHS noted that the psychic and physiologic
dependence potential of fenfluramine is minimal in relation to the
number of patients who have been treated with the drug. As a result,
HHS stated that the number of reports of psychic and physiologic
dependence potential of fenfluramine is low.
8. Whether the Substance Is an Immediate Precursor of a Substance
Already Controlled Under the CSA
Fenfluramine is not an immediate precursor of a substance already
controlled under the CSA as defined by 21 U.S.C. 802(23).
Conclusion
Based on consideration of the scientific and medical evaluation and
accompanying recommendation of HHS, and based on DEA's consideration of
its own eight-factor analysis, the Administrator of DEA
(Administrator), pursuant to 21 U.S.C. 811(a) and (c), finds that these
facts and all relevant data demonstrate that fenfluramine does not meet
the requirements under 21 U.S.C. 812(b) for inclusion in any schedule,
and should be removed from control under the CSA. Specifically, the
Administrator finds the following:
(1) Fenfluramine appears to have no potential for abuse. According
to HHS, the profile of activity for fenfluramine differs from other 5-
HT agonists that are phenethylamines as it does not generalize to a
stimulant. In addition, the in vitro, animal, human, and epidemiology
data indicate that fenfluramine has no potential for abuse.
(2) Fenfluramine has a currently accepted medical use in treatment
in the United States. FDA approved the NDA for Fintepla (fenfluramine)
on June 25, 2020 for the treatment of DS in patients aged two years and
older.
(3) Fenfluramine does not appear to have psychological or physical
dependence liability. According to HHS, the reports of psychic or
physiologic dependence of fenfluramine are minimal when viewed in the
context of large number of patients who were treated with the drug in
the United States and Europe between 1963 and 1997. Thus, the psychic
and physiological dependence liability of fenfluramine is lower than
that of substances in schedules IV and V.
Based on these findings, the Administrator concludes that
fenfluramine does not meet the requirements for inclusion in any
schedule and should be removed from control under the CSA.
Regulatory Analyses
Executive Orders 12866 (Regulatory Planning and Review) and 13563
(Improving Regulation and Regulatory Review)
In accordance with 21 U.S.C. 811(a), this proposed scheduling
action is subject to formal rulemaking procedures done ``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
removing a drug or other substance from the list of controlled
substances. Such actions are exempt from review by the Office of
Management and Budget 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 proposed 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 proposed rulemaking does not have federalism implications
warranting the application of E.O. 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, Consultation and Coordination With Indian Tribal
Governments
This proposed rule does not have tribal implications warranting the
application of E.O. 13175. This proposed rule 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), has reviewed this proposed rule and by
approving it certifies that it will not have a significant economic
impact on a substantial number of small entities. The purpose of this
rule is to remove fenfluramine 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 fenfluramine. Accordingly, it has the
potential for some economic impact in the form of cost savings.
[[Page 42985]]
If finalized, the proposed rule will affect all persons who would
handle, or propose to handle fenfluramine. Fenfluramine as a
pharmaceutical product (Fintepla) is currently available and marketed
in the U.S. Because fenfluramine is currently a schedule IV drug, all
legal handling of fenfluramine is currently done under appropriate DEA
license. In such instances, DEA's knowledge of its registrant
population forms the basis for estimating the number of affected
entities and small entities that are affected by this rulemaking. There
are currently 40 unique registrations authorized to handle fenfluramine
specifically, as well as a number of registered analytical labs that
are authorized to handle schedule IV controlled substances generally.
From review of entity names, DEA estimates these 40 registrations
represent 27 entities. Some of these entities are likely to be small
entities. However, since DEA does not have information of registrant
size and the majority of DEA registrants are small entities or are
employed by small entities, DEA estimates a maximum of 27 entities are
small entities. Therefore, DEA conservatively estimates as many as 27
small entities are affected by this proposed rule. However, because
this rule would remove fenfluramine from regulatory controls of the
CSA, it is likely to result in some cost savings. Any person planning
to handle fenfluramine will realize cost savings in the form of saved
DEA registration fees, and the elimination of physical security,
recordkeeping, and reporting requirements. Because of these factors,
DEA projects that this rule will not result in a significant economic
impact on a substantial number of small entities.
Unfunded Mandates Reform Act of 1995
On the basis of information contained in the ``Regulatory
Flexibility Act'' section above, DEA has determined pursuant to the
Unfunded Mandates Reform Act (UMRA) of 1995, (2 U.S.C. 1501 et seq.),
that this proposed 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 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 proposed action does not impose a new collection of
information requirement under the Paperwork Reduction Act of 1995. (44
U.S.C. 3501-3521).
Signing Authority
This document of the Drug Enforcement Administration was signed on
July 13, 2022, by Administrator Anne Milgram. That document with the
original signature and date is maintained by DEA. For administrative
purposes only, and in compliance with requirements of the Office of the
Federal Register, the undersigned DEA Federal Register Liaison Officer
has been authorized to sign and submit the document in electronic
format for publication, as an official document of DEA. This
administrative process in no way alters the legal effect of this
document upon publication in the Federal Register.
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, DEA proposes to amend 21 CFR part
1308 as follows:
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), 956(b), unless otherwise
noted.
Sec. 1308.14 [Amended]
0
2. In Sec. 1308.14, remove and reserve paragraph (d).
Scott Brinks,
Federal Register Liaison Officer, Drug Enforcement Administration.
[FR Doc. 2022-15335 Filed 7-18-22; 8:45 am]
BILLING CODE 4410-09-P
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</html>Indexed from Federal Register on July 19, 2022.
This is legal information, not legal advice. Laws vary by jurisdiction and change frequently. Always verify current law with official sources and consult a licensed attorney in your jurisdiction for advice on your specific situation.