Federal Register / Vol. 87, No. 137 / Tuesday, July 19, 2022 / Proposed Rules 42979 

The Unfunded Mandates Reform Act 

of 1995 (section 202(a)) requires us to 

prepare a written statement, which 

includes an assessment of anticipated 

costs and benefits, before proposing 

‘‘any rule that includes 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 

one year.’’ The current threshold after 

adjustment for inflation is $165 million, 

using the most current (2021) Implicit 

Price Deflator for the Gross Domestic 

Product. The 2021 Agricultural 

Proposed Rule as amended by this 

supplemental proposed rule would not 

result in an expenditure in any year that 

meets or exceeds this amount. 

We have developed a comprehensive 

Preliminary Economic Analysis of 

Impacts (PRIA) that assesses the impacts 

of the supplemental proposed rule (Ref. 

1). We estimate costs and benefits of the 

2021 agricultural water proposed rule in 

the ‘‘Standards for the Growing, 

Harvesting, Packing and Holding of 

Produce for Human Consumption 

Relating to Agricultural Water; 

Preliminary Regulatory Impact 

Analysis’’ (2021 agricultural water 

PRIA) (Ref. 2). This supplemental 

proposed rule makes no substantive 

changes to the provisions in the 2021 

Agricultural Water Proposed Rule. 

Rather, this supplemental proposed rule 

proposes compliance dates for the preharvest agricultural water provisions for 

covered produce other than sprouts, 

which are not specified in the 2021 

Agricultural Water Proposed Rule. The 

costs of the supplemental proposed rule 

are the costs of reading this rule. 

Annualized at either 3 percent or 7 

percent, our primary estimates of this 

supplemental proposed rule are $0.1 

million. The benefit of this 

supplemental proposed rule is clarity to 

stakeholders about the proposed 

compliance dates for the pre-harvest 

agricultural water provisions for 

covered produce other than sprouts 

described in the 2021 agricultural water 

proposed rule. The full preliminary 

analysis of economic impacts is 

available in the docket for this proposed 

rule and at https://www.fda.gov/aboutfda/reports/economic-impact-analysesfda-regulations. 

VI. Analysis of Environmental Impact 

The Agency has carefully considered 

the potential environmental effects of 

this action. FDA has concluded that the 

action will not have a significant impact 

on the human environment, and that an 

environmental impact statement is not 

required. The Agency’s finding of no 

significant impact, including a 

supplement to the finding of no 

significant impact, and the evidence 

supporting that finding may be seen in 

the Dockets Management Staff (see 

ADDRESSES) between 9 a.m. and 4 p.m., 

Monday through Friday (Refs. 3 to 5). 

Under FDA’s regulations implementing 

the National Environmental Policy Act 

(21 CFR part 25), an action of this type 

would require an EA under 21 CFR 

25.31a(a). 

VII. Paperwork Reduction Act of 1995 

FDA tentatively concludes that this 

supplemental notice of proposed 

rulemaking contains no collection of 

information. Therefore, clearance by the 

Office of Management and Budget under 

the Paperwork Reduction Act of 1995 is 

not required. 

VIII. Federalism 

We have analyzed this proposed rule 

in accordance with the principles set 

forth in Executive Order 13132. FDA 

has determined that the proposed rule 

does not contain policies that 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. Accordingly, we 

conclude that the proposed rule does 

not contain policies that have 

federalism implications as defined in 

the Executive order and, consequently, 

a federalism summary impact statement 

is not required. 

IX. Consultation and Coordination With 

Indian Tribal Governments 

We have analyzed this proposed rule 

in accordance with the principles set 

forth in Executive Order 13175. We 

have tentatively determined that the 

rule does not contain policies that 

would have a substantial direct effect 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. The 

Agency solicits comments from tribal 

officials on any potential impact on 

Indian Tribes from this proposed action. 

X. References 

The following reference is on display 

at the Dockets Management Staff (see 

ADDRESSES) and is available for viewing 

by interested persons between 9 a.m. 

and 4 p.m., Monday through Friday; it 

is also available electronically at https:// 

www.regulations.gov. FDA has verified 

the website address, as of the date this 

document publishes in the Federal 

Register, but websites are subject to 

change over time. 

1. FDA, ‘‘Supplemental Notice of Proposed 

Rulemaking: Standards for the Growing, 

Harvesting, Packing, and Holding of 

Produce for Human Consumption 

Relating to Agricultural Water; 

Preliminary Regulatory Impact 

Analysis,’’ 2022. Available at: https://

www.fda.gov/about-fda/reports/ 

economic-impact-analyses-fdaregulations. 

2. FDA, ‘‘Standards for the Growing, 

Harvesting, Packing, and Holding of 

Produce for Human Consumption 

Relating to Agricultural Water; 

Preliminary Regulatory Impact 

Analysis,’’ 2021. Available at: https://

www.fda.gov/about-fda/reports/ 

economic-impact-analyses-fdaregulations. 

3. FDA, ‘‘Environmental Assessment for the 

Proposed Rule: Standards for the 

Growing, Harvesting, Packing, and 

Holding of Produce for Human 

Consumption Relating to Agricultural 

Water,’’ November 9. 2021. 

4. FDA, ‘‘Standards for the Growing, 

Harvesting, Packing, and Holding of 

Produce for Human Consumption 

Relating to Agricultural Water: Finding 

of No Significant Impact,’’ November 9, 

2021. 

5. FDA, ‘‘Standards for the Growing, 

Harvesting, Packing, and Holding of 

Produce for Human Consumption 

Relating to Agricultural Water: 

Supplement to the Finding of No 

Significant Impact.’’ 

Dated: July 11, 2022. 

Robert M. Califf, 

Commissioner of Food and Drugs. 

[FR Doc. 2022–15134 Filed 7–18–22; 8:45 am] 

BILLING CODE 4164–01–P 

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. 

SUMMARY: The Drug Enforcement 

Administration proposes to remove 

fenfluramine (chemical name: N-ethyla-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 


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1The Secretary of HHS has delegated to the 

Assistant Secretary for Health the authority to make 

domestic drug scheduling recommendations. 

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. 

• 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. 

• 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. 

• 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 


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2Fintepla is an oral solution that contains 2.2 mg/ 

ml fenfluramine equivalent to 2.5 mg/ml of the 

hydrochloride salt. 

3 28 CFR 0.100(b). 

4Comprehensive 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. 

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. 

Background 

Fenfluramine (chemical name: Nethyl-a-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. 

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-amethyl-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. 

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

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 FDAapproved 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 


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5STRIDE reflects the results of drug evidence 

analyzed at DEA laboratories through September, 

2014. STRIDE was queried on July 3, 2019. 

6NFLIS-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. 

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. 

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 FDAapproved 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. 

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. 

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 beta2 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–HT2B receptor 

despite its weak binding affinity, has 

moderate agonist activity at the 5–HT2C

receptor, and has weak activity at the 5– 

HT2A receptor, whereas lnorfenfluramine demonstrated moderate 

activity at the 5–HT2B receptor and 

weak activity at the 5–HT2C and 5–HT2A

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-trifluoromethylphenyl)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. 


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8The 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. 

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 abuserelated 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 Nethyl-a-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 

C12H16F3N 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 °C and 

dichloromethane (30–35 mg/mL) at 

25 °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 Pglycoprotein (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 mM), 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 Cmax of 0.26 

mg/mL and an area under the curve 

(AUC) of 1.4 mg/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 Cmax

of 0.36 mg/mL and an AUC of 5.15 mg/ 

mL*hr, values higher than those in the 

mouse studies. The Tmax 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 Tmax 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 Noxygenation 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. 

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 


jspears on DSKJM1Z7X2PROD with PROPOSALS
42984 Federal Register / Vol. 87, No. 137 / Tuesday, July 19, 2022 / Proposed Rules 

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. 

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

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. 


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Federal Register / Vol. 87, No. 137 / Tuesday, July 19, 2022 / Proposed Rules 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 

■ 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. 

§ 1308.14 [Amended] 

■ 2. In § 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 

DEPARTMENT OF HOMELAND 

SECURITY 

Coast Guard 

33 CFR Part 165 

[Docket Number USCG–2022–0595] 

RIN 1625–AA00 

Safety Zone; Ironman Michigan, 

Frankfort Harbor, MI 

AGENCY: Coast Guard, DHS. 

ACTION: Notice of proposed rulemaking. 

SUMMARY: The Coast Guard is proposing 

to establish a temporary safety zone for 

certain waters of Betsie Lake in 

Frankfort, MI. This action is necessary 

to provide for the safety of life on these 

navigable waters during the swim 

portion of an Ironman event on 

September 11, 2022. This proposed 

rulemaking would restrict usage by 

persons and vessels within the safety 

zone. At no time during the effective 

period may vessels transit the waters of 

Betsie Lake in the vicinity of a 

triangular shaped race course enclosed 

by the following three coordinates: 

44°37.80′ N, ¥086°13.91′ W to 44°37.81′ 

N, ¥086°14.22′ W to 44°37.58′ N, 

¥086°13.75′ W, then back to the 

starting point. The race course will be 

marked by buoys. These restrictions 

would apply to all perons and vessels 

during the effective period unless 

authorized by the Captain of the Port 

Lake Michigan or a designated 

representative. We invite your 

comments on this proposed rulemaking. 

DATES: Comments and related material 

must be received by the Coast Guard on 

or before August 18, 2022. 

ADDRESSES: You may submit comments 

identified by docket number USCG– 

2022–0595 using the Federal 

eRulemaking Portal at https://

www.regulations.gov. See the ‘‘Public 

Participation and Request for 

Comments’’ portion of the 

SUPPLEMENTARY INFORMATION section for 

further instructions on submitting 

comments. 

FOR FURTHER INFORMATION CONTACT: If 

you have questions about this proposed 

rulemaking, call or email Chief Petty 

Officer Jeromy Sherrill, Sector Lake 

Michigan Waterways Management 

Division, U.S. Coast Guard; telephone 

414–747–7148, email 

Jeromy.N.Sherrill@uscg.mil. 

SUPPLEMENTARY INFORMATION: 

I. Table of Abbreviations 

CFR Code of Federal Regulations 

DHS Department of Homeland Security 

FR Federal Register 

NPRM Notice of proposed rulemaking 

§ Section 

U.S.C. United States Code 

On June 23, 2022, the Coast Guard 

was notified by the event sponsor of its 

intent to host Ironman Michigan in 

Frankfort, MI on September 11, 2022 

from 8:00 a.m. to 10:15 a.m. The swim 

will begin near Frankfort Municipal 

Marina in Betsie Lake. The race course 

will be triangular shaped area enclosed 

by the following coordinates: 44°37.80′ 

N, ¥086°13.91′ W to 44°37.81′ N, 

¥086°14.22′ W to 44°37.58′ N, 

¥086°13.75′ W, then back to the 

starting point. The race course will be 

marked by buoys. The COTP has 

determined that potential hazards 

associated with the triathlon would be 


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