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Fenfluramine

PubChem CID
3337
Structure
Fenfluramine_small.png
Fenfluramine_3D_Structure.png
Molecular Formula
Synonyms
  • fenfluramine
  • Obedrex
  • Rotondin
  • Pesos
  • Ponderax PA
Molecular Weight
231.26 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2005-03-25
  • Modify:
    2025-02-01
Description
Fenfluramine is a secondary amino compound that is 1-phenyl-propan-2-amine in which one of the meta-hydrogens is substituted by trifluoromethyl, and one of the hydrogens attached to the nitrogen is substituted by an ethyl group. It binds to the serotonin reuptake pump, causing inhbition of serotonin uptake and release of serotonin. The resulting increased levels of serotonin lead to greater serotonin receptor activation which in turn lead to enhancement of serotoninergic transmission in the centres of feeding behavior located in the hypothalamus. This suppresses the appetite for carbohydrates. Fenfluramine was used as the hydrochloride for treatment of diabetes and obesity. It was withdrawn worldwide after reports of heart valve disease and pulmonary hypertension. It has a role as a serotonin uptake inhibitor, a serotonergic agonist and an appetite depressant. It is a secondary amino compound and a member of (trifluoromethyl)benzenes.
Dravet syndrome is a pediatric encephalopathy that typically manifests within the first year of life following exposure to elevated temperatures. It is characterized by recurrent pharmacoresistant seizures, which increase in frequency and severity with disease progression. Concomitantly with these seizures, patients typically display delayed development and neurocognitive impairment. Fenfluramine is a serotonergic phenethylamine originally used as an appetite suppressant until concerns regarding cardiotoxicity in obese patients lead to its withdrawal from the market in 1997. Through its ability to modulate neurotransmission, fenfluramine has reemerged as an effective therapy against pharmacoresistant seizures, such as those involved in Dravet syndrome. Fenfluramine was granted initial FDA approval in 1973 prior to its withdrawal; it was granted a new FDA approval on June 25, 2020, for treatment of patients with Dravet syndrome and Lennox-Gastaut syndrome through the restricted FINTEPLA REMS program. It is currently sold under the name FINTEPLA® by Zogenix INC.
Fenfluramine is an amphetamine derivative and a sympathomimetic stimulant with appetite-suppressant property. Fenfluramine, which was part of the Fen-Phen anti-obesity medication, stimulates the release of serotonin from vesicular storage, and modulates serotonin transporter function. Since serotonin regulates mood and appetite, among other functions, increased serotonin level results in a feeling of fullness and loss of appetite.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Fenfluramine.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

N-ethyl-1-[3-(trifluoromethyl)phenyl]propan-2-amine
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

InChI=1S/C12H16F3N/c1-3-16-9(2)7-10-5-4-6-11(8-10)12(13,14)15/h4-6,8-9,16H,3,7H2,1-2H3
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

DBGIVFWFUFKIQN-UHFFFAOYSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

CCNC(C)CC1=CC(=CC=C1)C(F)(F)F
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C12H16F3N
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

458-24-2

2.3.3 Deprecated CAS

25990-46-9, 5220-89-3

2.3.4 European Community (EC) Number

2.3.5 UNII

2.3.6 ChEBI ID

2.3.7 ChEMBL ID

2.3.8 DrugBank ID

2.3.9 DSSTox Substance ID

2.3.10 HMDB ID

2.3.11 KEGG ID

2.3.12 Metabolomics Workbench ID

2.3.13 NCI Thesaurus Code

2.3.14 Nikkaji Number

2.3.15 PharmGKB ID

2.3.16 RXCUI

2.3.17 Wikidata

2.3.18 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • Fenfluramine
  • Fenfluramine Hydrochloride
  • Fenfluramine Hydrochloride, (+-)-Isomer
  • Fenfluramine Hydrochloride, R Isomer
  • Fenfluramine Hydrochloride, R-Isomer
  • Fenfluramine, (+-)-Isomer
  • Fenfluramine, R Isomer
  • Fenfluramine, R-Isomer
  • Fintepla
  • Hydrochloride, Fenfluramine
  • Isomeride
  • Pondimin

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
231.26 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3
Property Value
3.4
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
1
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
4
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
4
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
231.12348400 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
231.12348400 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
12 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
16
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
203
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
1
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Boiling Point

108-112
L14632
108-112 °C at 12 mm Hg
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 703

3.2.2 Melting Point

160-170
L14632
Crystals from ethanol and ether; mp: 166 °C /Hydrochloride/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 703
Crystals from ethyl acetate; mp: 160-161 °C /dextro-Fenfluramine hydrochloride/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 703
Crystals from ethyl acetate; mp: 160-161 °C /levo-Fenfluramine hydrochloride/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 703

3.2.3 Solubility

412 mg/L
L14632

3.2.4 LogP

log Kow = 3.36
Sangster J; LOGKOW Databank. Sangster Res. Lab., Montreal Quebec, Canada (1993)

3.2.5 Stability / Shelf Life

Generally stable under ordinary conditions in light, air, & heat /Hydrochloride/
Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 823

3.2.6 Optical Rotation

Specific optical rotation: 9.5 deg at 25 °C/D (concentration by volume= 8 g in 100 ml ethanol) /dextro-Fenfluramine/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 703
Specific optical rotation: -9.6 deg at 25 °C/D (concentration by volume= 8 g in 100 ml ethanol) /levo-Fenfluramine/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 703

3.2.7 Decomposition

When heated to decomp it emits very toxic fumes of fluoride ion and oxides of nitrogen.
Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984., p. 1376

3.2.8 Dissociation Constants

pKa
9.92
L14632
White to off-white amorphous powder; does not exhibit polymorphism; melts with 2 degree range between 165-170 °C; pKa 9.92; characteristic odor; sparingly soluble in water & ethanol /Fenfluramine hydrochloride/
Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 823

3.2.9 Kovats Retention Index

Standard non-polar
1220 , 1220 , 1220 , 1240 , 1226 , 1220 , 1240.8 , 1218.2 , 1222 , 1220 , 1220
Semi-standard non-polar
1240.6 , 1183 , 1183 , 1228.4 , 1227 , 1232.2 , 1233.8 , 1224 , 1239.7 , 1173 , 1177 , 1185
Standard polar
1531 , 1532 , 1555 , 1562 , 1569

3.3 Chemical Classes

3.3.1 Drugs

Pharmaceuticals -> Alimentary tract and metabolism -> Antiobesity preparations, excluding diet products
S92 | FLUOROPHARMA | List of ~340 ATC classified fluoro-pharmaceuticals | DOI:10.5281/zenodo.5979646
Pharmaceuticals -> Synthetic Cannabinoids or Psychoactive Compounds
S58 | PSYCHOCANNAB | Synthetic Cannabinoids and Psychoactive Compounds | DOI:10.5281/zenodo.3247723
3.3.1.1 Human Drugs
Human drug -> Prescription
Human drug -> Prescription; Active ingredient (FENFLURAMINE)
Human drugs -> Orphan -> Antiepileptics -> Human pharmacotherapeutic group -> EMA Drug Category
Pharmaceuticals
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664

4 Spectral Information

4.1 Mass Spectrometry

4.1.1 GC-MS

1 of 9
View All
NIST Number
250583
Library
Main library
Total Peaks
169
m/z Top Peak
72
m/z 2nd Highest
44
m/z 3rd Highest
159
Thumbnail
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2 of 9
View All
NIST Number
125735
Library
Replicate library
Total Peaks
73
m/z Top Peak
72
m/z 2nd Highest
44
m/z 3rd Highest
159
Thumbnail
Thumbnail

4.1.2 MS-MS

1 of 11
View All
Spectra ID
Ionization Mode
Positive
Top 5 Peaks

159.0409 100

160.0442 8.01

147.0344 1.40

Thumbnail
Thumbnail
2 of 11
View All
Spectra ID
Ionization Mode
Positive
Top 5 Peaks

159.0409 100

232.1305 15.49

187.0721 9.82

160.0442 5.13

233.1337 1.34

Thumbnail
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4.1.3 LC-MS

1 of 32
View All
Authors
Nikiforos Alygizakis, Nikolaos Thomaidis, University of Athens
Instrument
Bruker maXis Impact
Instrument Type
LC-ESI-QTOF
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
10 eV
Fragmentation Mode
CID
Column Name
Acclaim RSLC C18 2.2um, 2.1x100mm, Thermo
Retention Time
6.2 min
Precursor m/z
232.1308
Precursor Adduct
[M+H]+
Top 5 Peaks

232.1306 999

233.1337 97

159.0409 44

187.0721 40

234.1364 6

Thumbnail
Thumbnail
License
CC BY-SA
2 of 32
View All
Authors
Nikiforos Alygizakis, Nikolaos Thomaidis, University of Athens
Instrument
Bruker maXis Impact
Instrument Type
LC-ESI-QTOF
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
20 eV
Fragmentation Mode
CID
Column Name
Acclaim RSLC C18 2.2um, 2.1x100mm, Thermo
Retention Time
6.2 min
Precursor m/z
232.1308
Precursor Adduct
[M+H]+
Top 5 Peaks

159.0409 999

232.1305 154

187.0721 98

160.0442 51

233.1337 13

Thumbnail
Thumbnail
License
CC BY-SA

4.2 IR Spectra

4.2.1 ATR-IR Spectra

Instrument Name
Bio-Rad FTS
Technique
ATR-Film (MeCl2) (DuraSamplIR II)
Source of Spectrum
Forensic Spectral Research
Source of Sample
Alltech Associates, Inc., Grace Davison Discovery Sciences
Catalog Number
Free base of 01798
Lot Number
Free base of 27082
Copyright
Copyright © 2012-2024 John Wiley & Sons, Inc. All Rights Reserved.
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4.3 Other Spectra

Intense mass spectral peaks: 72 m/z, 159 m/z, 216 m/z, 230 m/z
Pfleger, K., H. Maurer and A. Weber. Mass Spectral and GC Data of Drugs, Poisons and their Metabolites. Parts I and II. Mass Spectra Indexes. Weinheim, Federal Republic of Germany. 1985., p. 369

6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

Fenfluramine is indicated for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome in patients aged two years and older.
Treatment of seizures associated with Dravet syndrome as an add-on therapy to other antiepileptic medicines for patients 2 years of age and older. Fintepla is indicated for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome as an add-on therapy to other anti-epileptic medicines for patients 2 years of age and older.

7.2 FDA Medication Guides

Drug
Active Ingredient
Form;Route
SOLUTION;ORAL
Company
ZOGENIX INC
Date
12/15/23

7.3 FDA Approved Drugs

7.4 FDA National Drug Code Directory

7.5 Drug Labels

Drug and label
Active ingredient and drug

7.6 Clinical Trials

7.6.1 ClinicalTrials.gov

7.6.2 EU Clinical Trials Register

7.7 EMA Drug Information

Medicine
Category
Human drugs -> Orphan
Therapeutic area
Epilepsies, Myoclonic
INN/Common name
fenfluramine
Pharmacotherapeutic Classes
Antiepileptics
Status
This medicine is authorized for use in the European Union
Company
UCB Pharma S.A.  
Market Date
2020-12-18

7.8 Therapeutic Uses

The Food and Drug Administration, acting on ... evidence about significant side-effects associated with fenfluramine and dexfenfluramine, has asked the manufacturers to voluntarily withdraw both treatments for obesity from the market. ... Both companies have agreed to voluntarily withdraw their drugs. The FDA is not requesting the withdrawal of phentermine, the third widely used medication for obesity. The action is based on ... findings from doctors who have evaluated patients taking these two drugs with echocardiograms, a special procedure that can test the functioning of heart valves. These findings indicate that approximately 30 percent of patients who were evaluated had abnormal echocardiograms, even though they had no symptoms. This is a much higher than expected percentage of abnormal test results.
US FDA; Center for Drug Evaluation and Research; FDA Announces Withdrawal Fenfluramine and Dexfenfluramine. For Immediate Release - September 15, 1997. Washington, DC: Food Drug Admin. Available from, as of October 12, 2005: https://www.fda.gov/cder/news/phen/fenphenpr81597.htm
Appetite Depressants; Serotonin Agents; Serotonin Uptake Inhibitors
National Library of Medicine's Medical Subject Headings online file (MeSH, 1999)
Adjunct to caloric restriction in the short term treatment (a few weeks) of exogenous obesity. /Use is included in the labeling approved by the US Food and Drug Administration. /Fenfluramine hydrochloride/
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 97. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1997 (Plus Supplements)., p. 1770

7.9 Drug Warnings

Temporal association between use of fenfluramine (Pondimin) or dexfenfluramine (Redux) and the development of unusual mitral, aortic, tricuspid, and/or pulmonary valvular (usually multivalvular) and echocardiographic abnormalities (that sometimes occurred concomitantly with pulmonary hypertension, occasionally required open heart surgery, and rarely were fatal) resulted in the withdrawal of /this/ anorexigenic agents from the US market in 1997.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2005. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2005 (Plus Supplements)., p. 2357
Fenfluramine is contraindicated in patients with severe hypertension, glaucoma, or symptomatic cardiovascular disease including arrhythmias, and in those with known hypersensitivity to fenfluramine or other sympathomimetic amines. Fenfluramine is contraindicated during or within 14 days of administration of monoamine oxidase inhibitors. The drug is also contraindicated in patients with a history of drug abuse. Fenfluramine should not be administered to patients with alcoholism, since adverse psychiatric effects (e.g., psychosis) may occur.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 97. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1997 (Plus Supplements)., p. 1770
Although some clinical studies have reported the use of fenfluramine in obese children, its safety and efficacy in pediatric patients have not been established and fenfluramine is not recommended for use in children younger than 12 years of age.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 97. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1997 (Plus Supplements)., p. 1770
General anesthetics should be administered with caution to patients receiving fenfluramine prior to surgery, since the drug may have catecholamine depleting effects following prolonged administration. If general anesthesia cannot be avoided, cardiac monitoring and facilities for cardiac resuscitation are essential during surgery in these patients.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 97. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1997 (Plus Supplements)., p. 1771
For more Drug Warnings (Complete) data for FENFLURAMINE (14 total), please visit the HSDB record page.

7.10 Reported Fatal Dose

The lowest reported fatal dose of fenfluramine hydrochloride was 400 mg in a small child and the highest reported nonfatal dose was 1.8 g in an adult.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 97. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1997 (Plus Supplements)., p. 1771

8 Pharmacology and Biochemistry

8.1 Pharmacodynamics

Fenfluramine increases extracellular serotonin levels, and also acts as both a serotonergic 5-HT2 receptor agonist and σ1 receptor antagonist. These activities, through an incompletely understood mechanism, lead to anti-epileptiform activity and therapeutic benefit. This modulation has other effects such as decreased appetite, weight loss, sedation, lethargy, increased blood pressure, and mood alteration including possible suicidal ideation. There is a risk of glaucoma and potentially fatal serotonin syndrome. Fenfluramine should be gradually withdrawn following treatment alteration or cessation.

8.2 MeSH Pharmacological Classification

Serotonin Agents
Drugs used for their effects on serotonergic systems. Among these are drugs that affect serotonin receptors, the life cycle of serotonin, and the survival of serotonergic neurons. (See all compounds classified as Serotonin Agents.)
Selective Serotonin Reuptake Inhibitors
Compounds that specifically inhibit the reuptake of serotonin in the brain. (See all compounds classified as Selective Serotonin Reuptake Inhibitors.)

8.3 ATC Code

N03

N - Nervous system

N03 - Antiepileptics

N03A - Antiepileptics

N03AX - Other antiepileptics

N03AX26 - Fenfluramine

A - Alimentary tract and metabolism

A08 - Antiobesity preparations, excl. diet products

A08A - Antiobesity preparations, excl. diet products

A08AA - Centrally acting antiobesity products

A08AA02 - Fenfluramine

8.4 Absorption, Distribution and Excretion

Absorption
Fenfluramine has a steady-state Tmax of between four and five hours and an absolute bioavailability of approximately 68-74%. Fenfluramine administered to pediatric patients at 0.7 mg/kg/day up to 26 mg resulted in a mean Cmax of 68.0 ng/mL with a coefficient of variation of 41%; similarly the AUC0-24 was 1390 (44%) ng\*h/mL.
Route of Elimination
Over 90% of fenfluramine is excreted in urine and less than 5% in feces; unchanged fenfluramine and the major active metabolite norfenfluramine account for less than 25% of the recovered amount.
Volume of Distribution
Fenfluramine has an apparent volume of distribution of 11.9 L/kg with a coefficient of variation of 16.5% following oral administration in healthy subjects.
Clearance
Fenfluramine has a mean clearance of 24.8 L/h with a coefficient of variation of 29% in healthy subjects.
Postmortem blood concentrations in one adult and three children ranged from 6.5 to 16 mg/L. A fenfluramine hair level of 14.1 ng/mg was demonstrated in an overdose fatality.
Dart, R.C. (ed). Medical Toxicology. Third Edition, Lippincott Williams & Wilkins. Philadelphia, PA. 2004., p. 875
Fenfluramine is widely distributed into tissues with a Vd of 12 to 16 L/kg. ... Excretion of the parent compound is enhanced in acidic urine.
Dart, R.C. (ed). Medical Toxicology. Third Edition, Lippincott Williams & Wilkins. Philadelphia, PA. 2004., p. 874
Fenfluramine is widely distributed in almost all body tissues. Autoradiographic studies in rats showed highest concentrations of the drug in stomach and intestine; lower concentrations were found in lungs, liver, brain and spinal cord, and bone marrow. In monkeys, fenfluramine and its de-ethylated metabolite cross the placental barrier. It is not known whether fenfluramine is distributed into milk.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 97. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1997 (Plus Supplements)., p. 1770
Following oral administration, fenfluramine hydrochloride is readily absorbed from the GI tract. Correlation of blood concentrations with clinical effects has not been established. ... The rate of urinary excretion depends on urinary flow rate and pH ... Fenfluramine is also excreted in saliva and sweat to a small extent. /Fenfluramine hydrochloride/
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 97. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1997 (Plus Supplements)., p. 1770

8.5 Metabolism / Metabolites

Fenfluramine is metabolized primarily in the liver by CYP1A2, CYP2B6, CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 to yield the major active metabolite norfenfluramine and several other minor inactive metabolites.
Fenfluramine hydrochloride is metabolized to norfenfluramine by de-ethylation; this metabolite is further deaminated and oxidized to m-trifluoromethylbenzoic acid. The drug is excreted principally in the urine as m-trifluoromethylhippuric acid, a glycine conjugate of m-trifluoromethylbenzoic acid, and smaller quantities of norfenfluramine and unchanged drug. There are wide interindividual variations in rates of biotransformation and elimination of fenfluramine and its metabolites... /Fenfluramine hydrochloride/
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 97. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1997 (Plus Supplements)., p. 1770
/Fenfluramine/ is metabolized in the liver by N-dealkylation to the active metabolite norfenfluramine. Less than 15% of a therapeutic dose is excreted as parent compound or active metabolite; the remainder is nonactive benzoic acid and alcohol derivatives. ...
Dart, R.C. (ed). Medical Toxicology. Third Edition, Lippincott Williams & Wilkins. Philadelphia, PA. 2004., p. 874
99% of cerebral fenfluramine was dealkylated to norfenfluramine. N-acetylnorfenfluramine & m-trifluoromethyl hippuric acid were identified as cerebral metabolites.
Sherman AD, Gal EM; Cerebral Metabolism of Intraventricular (3) H-Fenfluramine; Neuropharmacology 16 (5): 309-15 (1977)

8.6 Biological Half-Life

Fenfluramine has an elimination half-life of 20 hours in healthy subjects.
In one study, the mean elimination half-life of fenfluramine in patient with uncontrolled pH was about 20 hr while elimination half-life was about 11 hr when an acidic urinary pH was maintained. /Fenfluramine hydrochloride/
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 97. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1997 (Plus Supplements)., p. 1770
Considerable first-pass effect due to rapid n-dealkylation of fenfluramine is apparent after per os doses. Rapid metabolism of derivative n-(2-benzoyloxyethyl)norfenfluramine has also been reported in man with apparent biological t/2 for total drug material of about 2 hr.
The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975., p. 158
The half life of fenfluramine is 13 to 30 hours and is urine pH dependent. ...
Dart, R.C. (ed). Medical Toxicology. Third Edition, Lippincott Williams & Wilkins. Philadelphia, PA. 2004., p. 875

8.7 Mechanism of Action

Dravet syndrome is a complex pediatric encephalopathy characterized by recurrent pharmacoresistant seizures of variable type, delayed development, and in many cases, impairment in speech, language, gait, and other neurocognitive functions. Despite substantial variation in presentation and severity, roughly 80% of patients with Dravet syndrome have mutations in the _SCN1A_ gene, which encodes the alpha subunit of a voltage-gated sodium channel (Nav1.1). This channel is predominantly localized in inhibitory GABAergic interneurons as well as in excitatory pyramidal neurons; it is thought that dysfunction of neurotransmission regulation results in the seizures and other corresponding symptoms of Dravet syndrome. Various _in vitro_ and _in vivo_ studies have demonstrated that fenfluramine is capable of acting as an agonist of multiple serotonin receptors including 5-HT1A, 5-HT1D, 5-HT2A, 5-HT2B, and 5-HT2C, as well as a σ1 receptor antagonist. This is at least partly because fenfluramine, as well as its active metabolite norfenfluramine, can act on sodium-dependent serotonin transporters (SERTs) to reverse transport direction and thereby increase extracellular serotonin levels. However, work in animal models of Dravet syndrome suggest that only the modulation of 5-HT1D, 5-HT2C, σ1, and possibly 5-HT2A receptors of fenfluramine result in the anti-epileptiform activity. Interestingly, 5-HT2B receptor agonism, which had previously been associated with cardiac valvulopathy, is not anticipated to have any therapeutic value in Dravet syndrome. Although the exact mechanism by which stimulation/inhibition of various receptors leads to the observed therapeutic benefit is unclear, it is hypothesized to be two-fold. Stimulation of 5-HT1D and 5-HT2C may result in increased GABAergic neurotransmission, while σ1 receptor antagonism may help to modulate responses to _N_-methyl-D-aspartate (NMDA).
The exact mechanism of action of fenfluramine has not been clearly defined. Results of animal studies indicate that its appetite-inhibiting may result from stimulation of the ventromedial nucleus of the hypothalamus. The mechanism by which this stimulation is mediated has not yet been determined. Although fenfluramine is used in the treatment of obesity as an anorexigenic, it has not been firmly established that the pharmacologic action is principally one of appetite suppression; other CNS actions and/or metabolic effects may be involved. ... Cardiovascular and autonomic effects produced by fenfluramine in animals appear to be qualitatively similar to those of amphetamine, but as a pressor agent it is 10-20 times less potent than dextroamphetamine. Some clinical studies have shown fenfluramine to have hypotensive effects in obese hypertensive patients. EEG studies, both awake and during sleep, show fenfluramine to be qualitatively different from amphetamine and other amphetamine congeners and suggest that fenfluramine may be more similar to sedative psychotherapeutic drugs rather than CNS or cerebral stimulants. There is some evidence that fenfluramine interferes with CNS pathway which regulate the release of human growth hormone.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 97. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1997 (Plus Supplements)., p. 1770
The neurochemical mechanisms by which drugs acting on central serotoninergic system modify feeding were reviewed. Fenfluramine, a clinically effective appetite suppressant, releases serotonin from nerve terminals and inhibits its reuptake, and considerable evidence suggests that these effects mediate its anorectic activity. The D isomer of fenfluramine is particularly specific in affecting serotonin mechanisms and causing anorexia. Transmitters other than serotonin such as acetylcholine, catecholamines and GABA are also affected by systemic administration of fenfluramine, but some of these effects are secondary to fenfluramine's action on serotoninergic mechanisms. Moreover, there is no evidence that these brain substances are involved in fenfluramine's ability to cause anorexia. Several studies with drugs affecting different serotonin mechanisms such as release and uptake or mimicking the action of serotonin at post-synaptic receptors suggest that increase serotonin release and direct stimulation of postsynaptic receptors are the most effective mechanisms for causing depression of food intake, although inhibition of serotonin uptake may also contribute in appropriate conditions. Development of serotonin receptor hyposensitivity and, in some instances, decreased serotonin levels may lead to tolerance to the anorectic activity of drugs enhancing serotonin transmission, the degree of this depending critically on the type of effect on serotonin mechanisms and intensity and duration of serotonin receptor activation. Recent evidence suggests that a decrease in serotonin function causes stimulation of feeding. This may lead to development of new strategies for the treatment of clinical anorexias.
Garattini S et al; Appetite 7 Suppl: 15-38 (1986)

9 Use and Manufacturing

9.1 Uses

MEDICATION
Appetite suppressant for the short-term (a few weeks) management of obesity. /Former use/
FDA: Center for Drug Evaluation and Research; Questions and Answers about Withdrawal of Fenfluramine (Pondimin) and Dexfenfluramine (Redux). Available from, as of March 30, 2006: https://www.fda.gov/cder/news/phen/fenphenqa2.htm

9.1.1 Use Classification

Human drugs -> Orphan -> Antiepileptics -> Human pharmacotherapeutic group -> EMA Drug Category
Pharmaceuticals
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664

9.2 Methods of Manufacturing

Preperation of optical isomers: US 3198834 (1965 to Sci. Union et Cie Soc. Franc. Recherche Med.)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 703
Preperation: L.G Beregi et al., FR M1658; eidem US 3198833 (1965 to Sci. Union et Cie Soc. Franc. Recherche Med.)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 703
Fenfluramine is prepared by reductive alkylation of norfenfluramine with acetaldehyde [18]. The nor compound is obtained by catalytic hydrogenation of the oxime made from 3-trifluoromethylphenyl acetone.
Ullmann's Encyclopedia of Industrial Chemistry. 6th ed.Vol 1: Federal Republic of Germany: Wiley-VCH Verlag GmbH & Co. 2003 to Present, p. V3 624 (2003)

9.3 Formulations / Preparations

Fenfluramine hydrochloride (Pondimin), 20 mg tablets ... /Fenfluramine hydrochloride; Former formulation/
Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975., p. 510

10 Identification

10.1 Clinical Laboratory Methods

Gas liquid chromatographic determination of fenfluramine in plasma.
Lindley TN, Sharman JR; Nzj Med Lab Technol 31 (3): 69-71 (1977)
Gas chromatographic/mass spectrometric identification of metabolites of amphetamines & analogs.
Coutts RT; Can Res 10 (3): 23, 25, 27-8 (1977)
Fenfluramine recovered from urine & identified by gas chromatography.
Campbell DB; Methodol Dev Biochem 5: 105-6 (1976)
Simultaneous determination of fenfluramine & norfenfluramine in human plasma & urine by a gas-liquid chromatographic-electron capture detector assay.
Midha KK et al; Can J Pharm Sci 14 (1): 18-21 (1979)
For more Clinical Laboratory Methods (Complete) data for FENFLURAMINE (6 total), please visit the HSDB record page.

11 Safety and Hazards

11.1 Hazards Identification

11.1.1 GHS Classification

Pictogram(s)
Acute Toxic
Signal
Danger
GHS Hazard Statements
H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]
Precautionary Statement Codes

P264, P270, P301+P316, P321, P330, P405, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 38 reports by companies from 1 notifications to the ECHA C&L Inventory.

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

11.1.2 Hazard Classes and Categories

Acute Tox. 3 (100%)

11.2 Handling and Storage

11.2.1 Storage Conditions

Tablets should be stored in well-closed containers between 15 to 30 °C. /Fenfluramine hydrochloride/
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 97. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1997 (Plus Supplements)., p. 1769

11.3 Regulatory Information

11.3.1 FDA Requirements

Fenfluramine used as a anorectic was marketed in the United States in 1973.
U.S. Department of Health and Human Services. Public Health Service. FDA. Drug Utilization in the United States: 1989. Eleventh Annual Review. p.17 (April, 1991)
Drug products withdrawn or removed from the market for reasons of safety or effectiveness. The following drug products were withdrawn or removed from the market because such drug products or components of such drug products were found to be unsafe or not effective. The following drug products may not be compounded under the exemptions provided by section 503A(a) of the Federal Food, Drug, and Cosmetic Act. Fenfluramine hydrochloride: All drug products containing fenfluramine hydrochloride is included on this list. /Fenfluramine Hydrochloride/
21 CFR 216.24; U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of October 26, 2005: https://www.ecfr.gov
Schedules of controlled substances are established by section 202 of the Controlled Substances Act (21 U.S.C. 812). Any material, compound, mixture, or preparation which contains any quantity of the following substances, including its salts, isomers (whether optical, position, or geometric), and salts of such isomers, whenever the existence of such salts, isomers, and salts of isomers is possible: Fenfluramine, Schedule IV, DEA Code #: 1670.
21 CFR 1308.14(d); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of October 26, 2005: https://www.ecfr.gov

11.4 Other Safety Information

Chemical Assessment

IMAP assessments - Benzeneethanamine, N-ethyl-.alpha.-methyl-3-(trifluoromethyl)-: Environment tier I assessment

IMAP assessments - Benzeneethanamine, N-ethyl-.alpha.-methyl-3-(trifluoromethyl)-: Human health tier I assessment

11.4.1 Special Reports

du Verglas G et al; Clinical Effects of Fenfluramine on Children with Autism: a Review of the Research. J Autism Dev Disord 18 (2): 297-308 (1988). A review of research studies published to date on the effects of fenfluramine on children with autism is presented. The current status of the fenfluramine research on children with autism is assessed. The review analyzed the methodological aspects of the research, the toxicity of fenfluramine, and the relationship between fenfluramine, neurotransmitter activity, cognitive ability, and subsequent behavioral change. The review of published data indicated that fenfluramine had positive effects on the reduction of hyperactivity and stereotypic behaviors in 33% of the subjects. The best responders were children with the highest baseline IQs. The conclusions address the need for appropriate subgrouping of autistic syndromes, which may lead to identification of responders to pharmacological treatments. The need for further study of the possible long-term adverse side effects of flenfluramine is noted. Further experimental research on the effects of fenfluramine on children with autism is endorsed.

12 Toxicity

12.1 Toxicological Information

12.1.1 Toxicity Summary

IDENTIFICATION: Fenfluramine hydrochloride is a centrally acting amphetamine antiobesity assent. HUMAN EXPOSURE: Main risks and target organs: Acute central nervous system stimulation, cardiotoxicity causing tachycardia, arrhythmias, hypertension and cardiovascular collapse. High risk of dependency and abuse. Summary of clinical effects: Cardiovascular: Palpitation, chest pain, tachycardia, arrhythmias and hypertension are common; cardiovascular collapse can occur in severe poisoning. Myocardial ischaemia, infarction and ventricular dysfunction are described. Central Nervous System (CNS): Stimulation of CNS, tremor, restlessness, agitation, insomnia, increased motor activity, headache, convulsions, coma and hyperreflexia are described. Stroke and cerebral vasculitis have been observed. Gastrointestinal: Vomiting, diarrhea and cramps may occur. Acute transient ischemic colitis has occurred with chronic methamphetamine abuse. Genitourinary: Increased bladder sphincter tone may cause dysuria, hesitancy and acute urinary retention. Renal failure can occur secondary to dehydration or rhabdomyolysis. Renal ischemia may be noted. Dermatologic: Skin is usually pale and diaphoretic, but mucous membranes appear dry. Endocrine: Transient hyperthyroxinemia may be noted. Metabolism: Increased metabolic and muscular activity may result in hyperventilation and hyperthermia. Weight loss is common with chronic use. Fluid/Electrolyte: Hypo- and hyperkalemia have been reported. Dehydration is common. Musculoskeletal: Fasciculations and rigidity may be noted. Rhabdomyolysis is an important consequence of severe amphetamine poisoning. Psychiatric: Agitation, confusion, mood elevation, increased wakefulness, talkativeness, irritability and panic attacks are typical. Chronic abuse can cause delusions and paranoia. A withdrawal syndrome occurs after abrupt cessation following chronic use. Contraindications: Anorexia, insomnia, psychopathic personality disorders, suicidal tendencies, Gilles de la Tourette syndrome and other disorders, hyperthyroidism, narrow angle glaucoma, diabetes mellitis and cardiovascular diseases such as angina, hypertension and arrythmias. Routes of exposure: Oral: Readily absorbed from the gastro-intestinal tract and buccal mucosa. It is resistant to metabolism by monoamine oxidase. Inhalation: Amphetamine is rapidly absorbed by inhalation and is abused by this route. Parenteral: Frequent route of entry in abuse situations. Absorption by route of exposure: Amphetamine is rapidly absorbed after oral ingestion. Peak plasma levels occur within 1 to 3 hours, varying with the degree of physical activity and the amount of food in the stomach. Absorption is usually complete by 4 to 6 hours. Sustained release preparations are available as resin-bound, rather than soluble, salts. These compounds display reduced peak blood levels compared with standard amphetamine preparations, but total amount absorbed and time to peak levels remain similar. Distribution by route of exposure: Amphetamines are concentrated in the kidney, lungs, cerebrospinal fluid and brain. They are highly lipid soluble and readily cross the blood-brain barrier. Protein binding and volume of distribution varies widely, but the average volume of distribution is 5 L/kg body weight. Biological half-life by route of exposure: Under normal conditions, about 30% of amphetamine is excreted unchanged in the urine but this excretion is highly variable and is dependent on urinary pH. When the urinary pH is acidic (pH 5.5 to 6.0), elimination is predominantly by urinary excretion with approximately 60% of a dose of amphetamine being excreted unchanged by the kidney within 48 hours. When the urinary pH is alkaline (pH 7.5 to 8.0), elimination is predominantly by deamination (less than 7% excreted unchanged in the urine); the half-life ranging from 16 to 31 hours. Metabolism: The major metabolic pathway for amphetamine involves deamination by cytochrome P450 to para-hydroxyamphetamine and phenylacetone; this latter compound is subsequently oxidized to benzoic acid and excreted as glucuronide or glycine (hippuric acid) conjugate. Smaller amounts of amphetamine are converted to norephedrine by oxidation. Hydroxylation produces an active metabolite, O-hyroxynorephedrine, which acts as a false neurotransmitter and may account for some drug effect, especially in chronic users. Elimination and excretion: Normally 5 to 30% of a therapeutic dose of amphetamine is excreted unchanged in the urine by 24 hours, but the actual amount of urinary excretion and metabolism is highly pH dependent. Mode of action: Toxicodynamics: Amphetamine appears to exert most or all of its effect in the CNS by causing release of biogenic amines, especially norepinephrine and dopamine, from storage sites in nerve terminals. It may also slow down catecholamine metabolism by inhibiting monoamine oxidase. Adults: The toxic dose varies considerably due to individual variations and the development of tolerance. Children: Children appear to be more susceptible than adults and are less likely to have developed tolerance. Teratogenicity: The use of amphetamine for medical indications does not pose a significant risk to the fetus for congenital anomalies. Amphetamines generally do not appear to be human teratogens. Mild withdrawal symptoms may be observed in the newborn, but the few studies of infant follow-up have not shown long-term sequelae. Illicit maternal use or abuse of amphetamine presents a significant risk to the fetus and newborn, including intrauterine growth retardation, premature delivery and the potential for increased maternal, fetal and neonatal morbidity. Cerebral injuries occurring in newborns exposed in utero appear to be directly related to the vasoconstrictive properties of amphetamines. Sixty-five children were followed whose mothers were addicted to amphetamine during pregnancy, at least during the first trimester. Intelligence, psychological function, growth, and physical health were all within the normal range at eight years, but those children exposed throughout pregnancy tended to be more aggressive. Interactions: Acetazolamide: administration may increase serum concentration of amphetamine. Alcohol: may increase serum concentration of amphetamine. Ascorbic acid: lowering urinary pH, may enhance amphetamine excretion Furazolidone: amphetamines may induce a hypertensive response in patients taking furazolidone. Guanethidine: amphetamine inhibits the antihypertensive response to guanethidine. Haloperidol: limited evidence indicates that haloperidol may inhibit the effects of amphetamine but the clinical importance of this interaction is not established. Lithium carbonate: isolated case reports indicate that lithium may inhibit the effects of amphetamine. Monoamine oxidase inhibitor: severe hypertensive reactions have followed the administration of amphetamines to patients taking monoamine oxidase inhibitors. Noradrenaline: amphetamine abuse may enhance the pressor response to noradrenaline. Phenothiazines: amphetamine may inhibit the antipsychotic effect of phenothiazines, and phenothiazines may inhibit the anorectic effect of amphetamines. Sodium bicarbonate: large doses of sodium bicarbonate inhibit the elimination of amphetamine, thus increasing the amphetamine effect. Tricyclic antidepressants - theoretically increases the effect of amphetamine, but clinical evidence is lacking. Clinical effects: Acute poisoning: Ingestion: Effects are most marked on the central nervous system, cardiovascular system, and muscles. The triad of hyperactivity, hyperpyrexia, and hypertension is characteristic of acute amphetamine overdosage. Agitation, confusion, headache, delirium, and hallucination, can be followed by coma, intracranial hemorrhage, stroke, and death. Chest pain, palpitation, hypertension, tachycardia, atrial and ventricular arrhythmia, and myocardial infarction can occur. Muscle contraction, bruxism (jaw-grinding), trismus (jaw clenching), fasciculation, rhabdomyolysis, are seen leading to renal failure; and flushing, sweating, and hyperpyrexia can all occur. Hyperpyrexia can cause disseminated intravascular coagulation. Inhalation: The clinical effects are similar to those after ingestion, but occur more rapidly. Parenteral exposure: Intravenous injection is a common mode of administration of amphetamine by abusers. Other clinical effects are similar to those observed after ingestion, but occur more rapidly. Ingestion: Tolerance to the euphoric effects and CNS stimulation induced by amphetamine develops rapidly, leading abusers to use larger and larger amounts to attain and sustain the desired affect. Habitual use or chronic abuse usually results in toxic psychosis classically characterised by paranoia, delusions and hallucinations, which are usually visual, tactile or olfactory in nature, in contrast to the typical auditory hallucinations of schizophrenia. The individual may act on the delusions, resulting in bizarre violent behavior, hostility and aggression, sometimes leading to suicidal or homicidal actions. Dyskinesia, compulsive behaviour and impaired performance are common in chronic abusers. The chronic abuser presents as a restless, garrulous, tremulous individual who is suspicious and anxious. Course, prognosis, cause of death: Symptoms and signs give a clinical guide to the severity of intoxication as follows: Mild toxicity: restlessness, irritability, insomnia, tremor, hyperreflexia, sweating, dilated pupils, flushing. Moderate toxicity: hyperactivity, confusion, hypertension, tachypnea, tachycardia, mild fever, sweating. Severe toxicity: delirium, mania, self-injury, marked hypertension, tachycardia, arrhythmia, hyperpyrexia, convulsion, coma, circulatory collapse. Death can be due to intracranial hemorrhage, acute heart failure or arrhythmia, hyperpyrexia, rhabdomyolysis and consequent hyperkalaemia or renal failure, and to violence related to the psychiatric effects. Systematic description of clinical effects: Cardiovascular: Cardiovascular symptoms of acute poisoning include palpitation and chest pain. Tachycardia and hypertension are common. Severe poisoning can cause acute myocardial ischemia, myocardial infarction and left ventricular failure. Chronic oral amphetamine abuse can cause a chronic cardiomyopathy; an acute cardiomyopathy has also been described. Hypertensive stroke is a well-recognized complication of amphetamine poisoning. Intra-arterial injection of amphetamine can cause severe burning pain, vasospasm, and gangrene. Respiratory: Pulmonary fibrosis, right ventricular hypertrophy and pulmonary hypertension are frequently found at post-mortem examination. Pulmonary function tests usually are normal except for the carbon monoxide diffusing capacity. Respiratory complications are sometimes caused by fillers or adulterants used in injections by chronic users. These can cause multiple microemboli to the lung, which can lead to restrictive lung disease. Pneumomediastinum has been reported after amphetamine inhalation. Neurological: Central nervous system (CNS): Main symptoms include agitation, confusion, delirium, hallucinations, dizziness, dyskinesia, hyperactivity, muscle fasciculation and rigidity, rigors, tics, tremors, seizures and coma. Both occlusive and hemorrhagic strokes have been reported after abuse of amphetamines. Patients with underlying arteriovenous malformations may be at particular risk. Stroke can occur after oral, intravenous, or nasal administration. Severe headache beginning within minutes of ingestion of amphetamine is usually the first symptom. In more than half the cases, hypertension which is sometimes extreme, accompanies other symptoms. A Cerebral vasculitis has also been observed. Dystonia and dyskinesia can occur, even with therapeutic dosages. Psychiatric effects, particularly euphoria and excitement, are the motives for abuse. Paranoia and a psychiatric syndrome indistinguishable from schizophrenia are sequelae of chronic use. Autonomic nervous system: Stimulation of alpha-adrenergic receptors produces mydriasis, increased metabolic rate, diaphoresis, increased sphincter tone, peripheral vasoconstriction and decreased gastrointestinal motility. Stimulation of ß-adrenergic receptors produces increased heart rate and contractility, increased automaticity and dilatation of bronchioles. Skeletal and smooth muscle: Myalgia, muscle tenderness, muscle contractions, and rhabdomyolysis, leading to fever, circulatory collapse, and myoglobinuric renal failure, can occur with amphetamines. Gastrointestinal: Most common symptoms are nausea, vomiting, diarrhea, and abdominal cramps. Anorexia may be severe. Epigastric pain and hematemesis have been described after intravenous amphetamine use. A case of ischemic colitis with normal mesenteric arteriography in a patient taking dexamphetamine has been described. Hepatic: Hepatitis and fatal acute hepatic necrosis have been described. Urinary: Renal: Renal failure, secondary to dehydration or rhabdomyolysis may be observed. Other: Spontaneous rupture of the bladder has been described in a young woman who took alcohol and an amphetamine-containing diet tablet. Endocrine and reproductive systems: Transient hyperthyroxinemia may result from heavy amphetamine use. Dermatological: Skin is usually pale and diaphoretic, but mucous membranes appear dry. Chronic users may display skin lesion, abscesses, ulcers, cellulitis or necrotising angiitis due to physical insult to skin, or dermatologic signs of dietary deficiencies, cheilosis and purpura. Eye, ear, nose, throat: local effects: Mydriasis may be noted. Diffuse hair loss may be noted. Chronic users may display signs of dietary deficiencies. Hematological: Disseminated intravascular coagulation is an important consequence of severe poisoning. Idiopathic thrombocytopenic purpura may occur. Metabolic: Fluid and electrolyte disturbance: Increase metabolic and muscular activity may result in dehydration. /Fenfluramine hydrochloride/
International Programme on Chemical Safety; Poisons Information Monograph: Fenfluramine Hydrochloride (PIM 938) (1998) Available from, as of May 19, 2005: https://www.inchem.org/pages/pims.html

12.1.2 Acute Effects

12.1.3 Interactions

Headache, neck stiffness, nausea, and collapse occurred following a single 20 mgdose of fenfluramine hydrochloride in a patient taking a monoamine oxidase inhibitor. In addition, neurologic and circulatory reactions, including hypertensive crises, have been reported in patients who have received sympathomimetic agents concomitantly with monoamine oxidase inhibitors and fatalities have occurred. Fenfluramine is, therefore, contraindicated during or within 14 days following the administration of monoamine oxidase inhibitors. /Fenfluramine hydrochloride/
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 97. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1997 (Plus Supplements)., p. 1770
Fenfluramine should be used with caution in patients taking CNS depressant drugs since the effects may be additive.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 97. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1997 (Plus Supplements)., p. 1771
'Fen-phen' refers to the off-label combination of the appetite suppressants fenfluramine and phentermine. The rationale for the fen-phen combination was that the two drugs exerted independent actions on brain satiety mechanisms so that it was possible to use lower doses of each drug and yet retain a common action on suppressing appetite while minimizing adverse drug effects. The focus of the present review is to consider whether fenfluramine and phentermine exert actions that are additive in nature or whether these two drugs exhibit drug-drug synergism. The fen-phen combination results in synergism for the suppression of appetite and body weight, the reduction of brain serotonin levels, pulmonary vasoconstriction and valve disease. Fen-phen synergism may reflect changes in the pharmacokinetics of drug distribution, common actions on membrane ion currents, or interactions between neuronal release and reuptake mechanisms with MAO-mediated transmitter degradation. The synergism between fenfluramine and phentermine highlights the need to more completely understand the pharmacology and neurochemistry of appetite suppressants prior to use in combination pharmacotherapy for the treatment of obesity.
Wellman PJ, Maher TJ; Int J Obes Relat Metab Disord 23 (7): 723-32 (1999)
... Prior treatment with diethylcarbamazine was found to potentiate the lethality of fenfluramine, while cyproheptadine pretreatment attenuated fenfluramine's toxic effects. Necropsies, conducted 24 hr after fenfluramine administration, revealed widespread alveolar and pulmonary interstitial hemorrhage in the cyproheptadine pretreated animals. The data suggest that high doses of fenfluramine directly result in pulmonary hypertension, which secondarily induces ischemic cardiac injury.
Hunsinger RN, Wright D; Pharmacol Res 22 (3): 371-8 (1990)

12.1.4 Antidote and Emergency Treatment

Treatment: Acute overdose can be rapidly fatal. The treatment is primarily supportive. All patients should have an adequate airway established, IV access, and cardiac monitoring.
Dart, R.C. (ed). Medical Toxicology. Third Edition, Lippincott Williams & Wilkins. Philadelphia, PA. 2004., p. 875
Decontamination: Induction of emesis is contraindicated due to the rapid onset of symptoms and possible loss of airway control. A single dose of activated charcoal should be administered if the patient presents within a couple of hours of exposure. Whole bowel irrigation may be of benefit for ingestion of sustained release tablets although its efficacy has not been studied.
Dart, R.C. (ed). Medical Toxicology. Third Edition, Lippincott Williams & Wilkins. Philadelphia, PA. 2004., p. 875
Antidotes: Cyproheptadine, a serotonin receptor antagonist, has been recommended as adjunct therapy for severe serotonin syndrome. ...
Dart, R.C. (ed). Medical Toxicology. Third Edition, Lippincott Williams & Wilkins. Philadelphia, PA. 2004., p. 875
Supportive Care: Benzodiazepine are indicated for muscle rigidity, seizure activity, or agitation ... . Hypotension should be managed with IV crystalloid fluid bolus ... followed by vasopressors as needed.
Dart, R.C. (ed). Medical Toxicology. Third Edition, Lippincott Williams & Wilkins. Philadelphia, PA. 2004., p. 875
For more Antidote and Emergency Treatment (Complete) data for FENFLURAMINE (8 total), please visit the HSDB record page.

12.1.5 Human Toxicity Excerpts

/HUMAN EXPOSURE STUDIES/ Not all the risk factors for primary pulmonary hypertension (PPH) are known. Appetite suppressants, including fenfluramine derivatives, are strongly suspected aetiological agents. In a 5 year retrospective study fenfluramine use was evaluated among patients referred to a medical centre specialising in the management of PPH. Fifteen (20%) of 73 patients with PPH had used fenfluramine: all of them were women and in 10 (67%) there was a close temporal relation between fenfluramine use and the development of exertional dyspnoea. Initial right heart catheterisation in the 15 women showed severe resting pulmonary hypertension (mean (SD)) with pulmonary artery pressure (PAP) 57 (9) mm Hg, cardiac index 2.1 (0.5) l/min/sq M, and pulmonary vascular resistance (PVR) 29 (10) U/sq m. Short-term epoprostenol infusion produced a significant vasodilator response in 10 patients (mean fall in PVR 24 (15%) compared with control values). Three fenfluramine users with PPH showed spontaneous clinical and haemodynamic improvement 3, 6 and 12 months after drug withdrawal but there was no significant difference in overall survival (transplant recipients excluded) between fenfluramine users and controls. Histological examination of lung tissue from five women who had used fenfluramine and 22 controls, with PPH showed features typical of advanced plexogenic pulmonary arteriopathy in all. These results do not accord with earlier reports that PPH associated with fenfluramine is less severe and has a better outcome. Fenfluramine may be one aetiological agent that can precipitate or hasten the development of PPH.
Brenot F et al; Br Heart J 70 (6): 537-41 (1993)
/HUMAN EXPOSURE STUDIES/ Three subjects given 240 mg of fenfluramine experienced brief but vivid hallucinogenic episodes characterized by olfactory, visual, & somatic hallucinations, abrupt polar changes in mood, time distortion, fleeting paranoia, & sexual ideation.
Griffth JD et al; Clin Pharmacol Ther 18: 563-70 (1975)
/HUMAN EXPOSURE STUDIES/ Fenfluramine doses of less than 5 mg/kg are toxic, and doses of 5-10 mg/kg may produce coma and seizures. ... Single overdoses reported have ranged from 300 mg to 2 g. The lowest reported fatal dose of fenfluramine hydrochloride was 400 mg in a small child and the highest reported nonfatal dose was 1.8 g in an adult.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 97. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1997 (Plus Supplements)., p. 1771
/SIGNS AND SYMPTOMS/ Emotional instability, cognitive deficits, and depression were reported in 27 patients taking fenfluramine and dexfenfluramine chronically. Psychosis has been reported after use of dexfenfluramine for 2 months. Headache, diarrhea, dizziness, dry mouth, impotence, palpitations , anxiety, insomnia, irritability, lethargy, and CNS excitation at higher doses have been reported with therapeutic use.
Dart, R.C. (ed). Medical Toxicology. Third Edition, Lippincott Williams & Wilkins. Philadelphia, PA. 2004., p. 875
For more Human Toxicity Excerpts (Complete) data for FENFLURAMINE (19 total), please visit the HSDB record page.

12.1.6 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ ... Negative teratolgic testing /was reported/ in rats, rabbits and mice. Doses of up to 45 mg per kg /of fenfluramine/ were given subcutaneously to rats on days 5 through 14 of gestation. Postnatal studies of rats whose mothers received 20 mg per kg daily during most of gestation were reported to be different from controls. Locomotor tests (pivoting) were the most altered. Brain weight, but not DNA, was significantly reduced in the pups at 70 days of postnatal life.
Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986., p. 256
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Studies in rats showed decreases in the rate of conception and survival rate at weaning and some potential teratogenicity; however, no adverse effects were reported in reproduction studies in other species (rabbits, monkeys, mice, and chickens).
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 97. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1997 (Plus Supplements)., p. 1770
/LABORATORY ANIMALS: Acute Exposure/ Fenfluramine is a potent serotonin releasing drug used primarily as an anorectic agent. The symptomatology of its acute lethality has been well documented in animal models such as the rat. A very prominent feature of this lethality profile is hypoxia, as demonstrated by the onset of severe cyanosis just prior to death. It is not clear in the literature whether this hypoxia is the result of a direct pulmonary effect or is secondary to cardiac injury. To further characterize this aspect of fenfluramine's toxicity, respiratory and electrocardiographic measurements were taken in anesthetized rats subjected to high doses of fenfluramine (129.6 mg/kg, ip). Death occurred in these animals within 15 min of drug administration, apparently as the result of abrupt respiratory cessation, followed by cardiac ischemia. No significant gross or histopathological lesions were evident in these animals.
Hunsinger RN, Wright D; Pharmacol Res 22 (3): 371-8 (1990)
/GENOTOXICITY/ Fenfluramine, an amphetamine derivative used in the treatment of obesity, has been evaluated in vivo in the bone marrow cells of Swiss albino mice using two cytogenetic endpoints for assessing its genotoxic and clastogenic potentials. Concentrations of 0.75, 1.5, 3.0, and 5.0 mg/kg b.w. were administered orally for the study of sister chromatid exchange frequencies and chromosome aberrations (CA). SCE frequencies showed a positive dose response; 1.5 mg/kg being the minimum effective concentration. Fen caused a prolongation of cell cycle at all concentrations. Except for the minimum therapeutic dose (0.75 mg), all other doses (1.5, 3.0, and 5.0 mg) showed a significant increase in the percentage of damaged cells over that of the vehicle control. The degree of clastogenicity was directly proportional to the dosage used and inversely related with the duration of treatment. A gradual reduction of the clastogenic potential was observed after 12 and 24 hr of exposure, indicating that the maximum effect occurs at the middle or late synthetic phase of the cell cycle. This study, probably the first detailed screening of the drug for its genotoxicity, shows that Fen is moderately clastogenic and a DNA damaging agent in vivo.
Agarwal K et al; Environ Mol Mutagen 19 (4): 323-6 (1992)

12.1.7 Populations at Special Risk

Clinical studies of dexfenfluramine did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients. Because geriatric patients generally are more sensitive to drugs that affect the CNS, dexfenfluramine should be used with caution in these patients. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly should also be considered. /Dexfenfluramine/
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 97. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1997 (Plus Supplements)., p. 1784

12.1.8 Protein Binding

Fenfluramine is 50% bound to plasma proteins independent of plasma drug concentration.

12.2 Ecological Information

12.2.1 Environmental Fate / Exposure Summary

Fenfluramine's former production and use as a pharmaceutical agent for the treatment of obesity may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 4.1X10-2 mm Hg at 25 °C indicates fenfluramine will exist solely as a vapor in the atmosphere. Vapor-phase fenfluramine will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 4 hours. Fenfluramine does not contain chromophores that absorb at wavelengths >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight. If released to soil, fenfluramine is expected to have low mobility based upon an estimated Koc of 1,600. The pKa of fenfluramine is 9.6, indicating that this compound will partially exist in the cation form in the environment and cations generally adsorb more strongly to organic carbon and clay than their neutral counterparts. Volatilization from moist soil surfaces is expected to be an important fate process based upon an estimated Henry's Law constant of 2.7X10-5 atm-cu m/mole. Biodegradation data were not available for fenfluramine. If released into water, fenfluramine is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is expected to be an important fate process based upon this compound's estimated Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 2 days and 20 days, respectively. An estimated BCF of 80 suggests the potential for bioconcentration in aquatic organisms is moderate. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions. Occupational exposure to fenfluramine may have occurred through dermal contact with this compound at workplaces where fenfluramine was produced or used. Exposure to fenfluramine among the general population may have been limited to those administered the drug. (SRC)

12.2.2 Artificial Pollution Sources

Fenfluramine's former production and use as a pharmaceutical agent for the treatment of obesity(1) may result in its release to the environment through various waste streams(SRC).
(1) FDA: Center for Drug Evaluation and Research; Questions and Answers about Withdrawal of Fenfluramine (Pondimin) and Dexfenfluramine (Redux). Available at https://www.fda.gov/cder/news/phen/fenphenqa2.htm as of March 30, 2006.

12.2.3 Environmental Fate

TERRESTRIAL FATE: Based on a classification scheme, an estimated Koc value of 1,600(SRC), determined from a log Kow of 3.36(2) and a regression-derived equation(3), indicates that fenfluramine is expected to have low mobility in soil(SRC). The pKa of fenfluramine is 9.6(4), indicating that this compound will partially exist in the cation form in the environment and cations generally adsorb more strongly to organic carbon and clay than their neutral counterparts(5). Volatilization of fenfluramine from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.7X10-5 atm-cu m/mole(SRC), using a fragment constant estimation method(6). Fenfluramine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.1X10-2 mm Hg(SRC), determined from a fragment constant method(7). Biodegradation data were not available(SRC, 2005).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) Sangster, J; Log Kow Data Bank. Montreal, Quebec, Canada: Sangster Res. Lab. (1993)
(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990)
(4) Hilal SH et al; pp. 291-353 in Quantitative Treatments of Solute/Solvent Interactions: Theoretical and Computational Chemistry Vol. 1 NY, NY: Elsevier (1994). SPARC pKa/property server available at https://ibmlc2.chem.uga.edu/sparc/ as of October 14, 2005.
(5) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds, Boca Raton, FL: Lewis Publ (2000)
(6) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(7) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1,600(SRC), determined from a log Kow of 3.36(2) and a regression-derived equation(3), indicates that fenfluramine is not expected to adsorb to suspended solids and sediment(SRC). The pKa of fenfluramine is 9.6(4), indicating that this compound will partially exist in the cation form in the environment and cations generally adsorb more strongly to organic carbon and clay than their neutral counterparts and do not volatilize(5). Volatilization of the unionized species from water surfaces is expected(3) based upon an estimated Henry's Law constant of 2.7X10-5 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). Using this Henry's Law constant and an estimation method(6), volatilization half-lives for a model river and model lake are 2 days and 20 days, respectively(SRC). According to a classification scheme(7), an estimated BCF of 80(SRC), from its log Kow(2) and a regression-derived equation(8), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Biodegradation data were not available(SRC, 2005).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) Sangster J; Log Kow Data Bank. Montreal, Quebec, Canada: Sangster Res. Lab. (1993)
(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990)
(4) Hilal SH et al; pp. 291-353 in Quantitative Treatments of Solute/Solvent Interactions: Theoretical and Computational Chemistry Vol. 1 NY, NY: Elsevier (1994). SPARC pKa/property server available at https://ibmlc2.chem.uga.edu/sparc/ as of October 14, 2005.
(5) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds, Boca Raton, FL: Lewis Publ (2000)
(6) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(7) Franke C et al; Chemosphere 29: 1501-14 (1994)
(8) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999)
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), fenfluramine, which has an estimated vapor pressure of 4.1X10-2 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase fenfluramine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 4 hours(SRC), calculated from its rate constant of 3.3X10-11 cu cm/molecule-sec at 25 °C (SRC) that was derived using a structure estimation method(3). Fenfluramine does not contain chromophores that absorb at wavelengths >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).
(1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988)
(2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)
(3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993)

12.2.4 Environmental Abiotic Degradation

The rate constant for the vapor-phase reaction of fenfluramine with photochemically-produced hydroxyl radicals has been estimated as 3.3X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 4 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Fenfluramine is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(2). Fenfluramine does not contain chromophores that absorb at wavelengths >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).
(1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993)
(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990)

12.2.5 Environmental Bioconcentration

An estimated BCF of 80 was calculated for fenfluramine(SRC), using a log Kow of 3.36(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is moderate(SRC), provided the compound is not metabolized by the organism(SRC).
(1) Sangster J; Log Kow Data Bank. Montreal, Quebec, Canada: Sangster Res. Lab. (1993)
(2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999)
(3) Franke C et al; Chemosphere 29: 1501-14 (1994)

12.2.6 Soil Adsorption / Mobility

The Koc of fenfluramine is estimated as 1,600(SRC), using a log Kow of 3.36(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that fenfluramine is expected to have low mobility in soil. The pKa of fenfluramine is 9.6(4), indicating that this compound will partially exist in the cation form in the environment and cations generally adsorb more strongly to organic carbon and clay than their neutral counterparts(5).
(1) Sangster J; Log Kow Data Bank. Montreal, Quebec, Canada: Sangster Res. Lab. (1993)
(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990)
(3) Swann RL et al; Res Rev 85: 17-28 (1983)
(4) Swann RL et al; Res Rev 85: 17-28 (1983)
(5) Sangster J; Log Kow Data Bank. Montreal, Quebec, Canada: Sangster Res. Lab. (1993)
(6) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990)
(7) Hilal SH et al; pp. 291-353 in Quantitative Treatments of Solute/Solvent Interactions: Theoretical and Computational Chemistry Vol. 1 NY, NY: Elsevier (1994). SPARC pKa/property server available at https://ibmlc2.chem.uga.edu/sparc/ as of October 14, 2005.
(8) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds, Boca Raton, FL: Lewis Publ (2000)
(9) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(10) Franke C et al; Chemosphere 29: 1501-14 (1994)
(11) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999)
(12) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds, Boca Raton, FL: Lewis Publ (2000)

12.2.7 Volatilization from Water / Soil

The Henry's Law constant for fenfluramine is estimated as 2.7X10-5 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that fenfluramine is expected to volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 2 days(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 20 days(SRC). Fenfluramine's Henry's Law constant indicates that volatilization from moist soil surfaces may occur(SRC). Fenfluramine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.1X10-2 mm Hg(SRC), determined from a fragment constant method(3).
(1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990)
(3) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)

12.2.8 Environmental Water Concentrations

While data on fenfluramine were not available (SRC, 2005), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Another concern is that selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through subsoils into aquifers(1).
(1) Heberer T; Tox Lett 131: 5-17 (2002)
(2) Koplin DW et al; Environ Sci Toxicol 36: 1202-211 (2002)

12.2.9 Other Environmental Concentrations

Specific data were not available on the environmental concentrations of fenfluramine; however, the compound has been selected for monitoring due to constant discharge into the environment through it's use as a pharmaceutical agent(1).
(1) Daughton CG, Ternes TA; Environ Hlth Perspect 107: 907-938 (1999)

12.2.10 Probable Routes of Human Exposure

Occupational exposure to fenfluramine may have occurred through dermal contact with this compound at workplaces where fenfluramine was produced or used. Exposure to fenfluramine among the general population may have been limited to those administered the drug as a treatment for obesity. (SRC)

13 Associated Disorders and Diseases

14 Literature

14.1 Consolidated References

14.2 NLM Curated PubMed Citations

14.3 Springer Nature References

14.4 Thieme References

14.5 Chemical Co-Occurrences in Literature

14.6 Chemical-Gene Co-Occurrences in Literature

14.7 Chemical-Disease Co-Occurrences in Literature

15 Patents

15.1 Depositor-Supplied Patent Identifiers

15.2 WIPO PATENTSCOPE

15.3 Chemical Co-Occurrences in Patents

15.4 Chemical-Disease Co-Occurrences in Patents

15.5 Chemical-Gene Co-Occurrences in Patents

16 Interactions and Pathways

16.1 Chemical-Target Interactions

16.2 Drug-Drug Interactions

16.3 Drug-Food Interactions

Take with or without food. The absorption is unaffected by food.

17 Biological Test Results

17.1 BioAssay Results

18 Classification

18.1 MeSH Tree

18.2 NCI Thesaurus Tree

18.3 ChEBI Ontology

18.4 KEGG: USP

18.5 KEGG: ATC

18.6 KEGG: Target-based Classification of Drugs

18.7 KEGG: Drug Groups

18.8 WHO ATC Classification System

18.9 ChemIDplus

18.10 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

18.11 ChEMBL Target Tree

18.12 UN GHS Classification

18.13 NORMAN Suspect List Exchange Classification

18.14 EPA DSSTox Classification

18.15 PFAS and Fluorinated Organic Compounds in PubChem

18.16 MolGenie Organic Chemistry Ontology

19 Information Sources

  1. Australian Industrial Chemicals Introduction Scheme (AICIS)
    Benzeneethanamine, N-ethyl-.alpha.-methyl-3-(trifluoromethyl)-
    https://services.industrialchemicals.gov.au/search-assessments/
  2. CAS Common Chemistry
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    https://creativecommons.org/licenses/by-nc/4.0/
  3. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  4. DrugBank
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    Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
    https://www.drugbank.ca/legal/terms_of_use
  5. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  6. European Chemicals Agency (ECHA)
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    https://echa.europa.eu/web/guest/legal-notice
  7. FDA Global Substance Registration System (GSRS)
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  8. Hazardous Substances Data Bank (HSDB)
  9. ChEBI
  10. NCI Thesaurus (NCIt)
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  11. Open Targets
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    https://platform-docs.opentargets.org/licence
  12. ChEMBL
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    http://www.ebi.ac.uk/Information/termsofuse.html
  13. ClinicalTrials.gov
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    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  14. Comparative Toxicogenomics Database (CTD)
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    http://ctdbase.org/about/legal.jsp
  15. IUPHAR/BPS Guide to PHARMACOLOGY
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    https://www.guidetopharmacology.org/about.jsp#license
    Guide to Pharmacology Target Classification
    https://www.guidetopharmacology.org/targets.jsp
  16. Therapeutic Target Database (TTD)
  17. DailyMed
  18. European Medicines Agency (EMA)
    LICENSE
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    https://www.ema.europa.eu/en/about-us/legal-notice
  19. Drugs@FDA
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  20. NORMAN Suspect List Exchange
    LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    Fenfluramine
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  21. EU Clinical Trials Register
  22. WHO Anatomical Therapeutic Chemical (ATC) Classification
    LICENSE
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  23. FDA Medication Guides
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  24. Human Metabolome Database (HMDB)
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    http://www.hmdb.ca/citing
  25. NIST Mass Spectrometry Data Center
    LICENSE
    Data covered by the Standard Reference Data Act of 1968 as amended.
    https://www.nist.gov/srd/public-law
  26. Japan Chemical Substance Dictionary (Nikkaji)
  27. KEGG
    LICENSE
    Academic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial license
    https://www.kegg.jp/kegg/legal.html
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
    Target-based classification of drugs
    http://www.genome.jp/kegg-bin/get_htext?br08310.keg
  28. MassBank Europe
  29. MassBank of North America (MoNA)
    LICENSE
    The content of the MoNA database is licensed under CC BY 4.0.
    https://mona.fiehnlab.ucdavis.edu/documentation/license
  30. Metabolomics Workbench
  31. National Drug Code (NDC) Directory
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  32. SpectraBase
  33. NLM RxNorm Terminology
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    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  34. PharmGKB
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    https://www.pharmgkb.org/page/policies
  35. Springer Nature
  36. Thieme Chemistry
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  37. Wikidata
  38. Wikipedia
  39. Medical Subject Headings (MeSH)
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    https://www.nlm.nih.gov/copyright.html
    Selective Serotonin Reuptake Inhibitors
    https://www.ncbi.nlm.nih.gov/mesh/68017367
  40. PubChem
  41. GHS Classification (UNECE)
  42. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  43. PATENTSCOPE (WIPO)
  44. NCBI
CONTENTS