[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 [www.gpo.gov]
[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 https://www.regulations.gov 
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 Regulations.gov. 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 https://www.regulations.gov. 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 https://www.regulations.gov 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 https://www.regulations.gov 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 https://www.regulations.gov 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. 
https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm?event=IndvRemsDetails.page&REMS=400.
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    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