U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry RACEMIC
Molecular Formula C12H16F3N
Molecular Weight 231.2573
Optical Activity ( + / - )
Defined Stereocenters 0 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of FENFLURAMINE

SMILES

CCNC(C)CC1=CC(=CC=C1)C(F)(F)F

InChI

InChIKey=DBGIVFWFUFKIQN-UHFFFAOYSA-N
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

HIDE SMILES / InChI

Molecular Formula C12H16F3N
Molecular Weight 231.2573
Charge 0
Count
Stereochemistry RACEMIC
Additional Stereochemistry No
Defined Stereocenters 0 / 1
E/Z Centers 0
Optical Activity ( + / - )

Description
Curator's Comment: description was created based on several sources, including https://www.drugs.com/international/fenfluramine.html | https://www.ncbi.nlm.nih.gov/pubmed/24790728 | https://clinicaltrials.gov/ct2/show/NCT02655198 | https://www.ncbi.nlm.nih.gov/pubmed/27264138 | https://www.ncbi.nlm.nih.gov/pubmed/22554283 | https://www.ncbi.nlm.nih.gov/pubmed/26600876

Fenfluramine (former brand names Pondimin, Ponderax and Adifax), also known as 3-trifluoromethyl-N-ethylamphetamine, is an anorectic that is no longer marketed. In combination with phentermine, it was part of the anti-obesity medication Fen-phen. Fenfluramine was introduced on the U.S. market in 1973 and withdrawn in 1997. It is the racemic mixture of two enantiomers, dexfenfluramine, and levofenfluramine. The drug increases the level of serotonin, a neurotransmitter that regulates mood, appetite and other functions. Fenfluramine causes the release of serotonin by disrupting vesicular storage of the neurotransmitter and reversing serotonin transporter function. The drug was withdrawn from the U.S. market in 1997 after reports of heart valve disease and pulmonary hypertension, including a condition known as cardiac fibrosis. It was subsequently withdrawn from other markets around the world. In this small exploratory and retrospective study, remarkably good results were reported on the use of fenfluramine as an add-on medication for controlling seizures in patients with the Dravet syndrome. The side effects were rare and nonserious and did not result in termination of the treatment. It is possible that this drug may have anticonvulsive effects for other severe epilepsy syndromes, especially in those characterized by photosensitive or induced seizures.

Originator

Curator's Comment: Journal of the Chemical Society, Transactions Volume 55, Pages412-443, Journal, 1889

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Pondimin

Approved Use

Unknown
Primary
Pondimin

Approved Use

Unknown
Primary
Pondimin

Approved Use

Unknown
Primary
Pondimin

Approved Use

Unknown
Primary
Pondimin

Approved Use

Unknown
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
68 ng/mL
0.35 mg/kg 2 times / day steady-state, oral
dose: 0.35 mg/kg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
FENFLURAMINE plasma
Homo sapiens
population: UNHEALTHY
age: CHILD
sex: UNKNOWN
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
1390 ng × h/mL
0.35 mg/kg 2 times / day steady-state, oral
dose: 0.35 mg/kg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
FENFLURAMINE plasma
Homo sapiens
population: UNHEALTHY
age: CHILD
sex: UNKNOWN
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
20 h
0.35 mg/kg 2 times / day steady-state, oral
dose: 0.35 mg/kg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
FENFLURAMINE plasma
Homo sapiens
population: UNHEALTHY
age: CHILD
sex: UNKNOWN
food status: UNKNOWN
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
50%
0.35 mg/kg 2 times / day steady-state, oral
dose: 0.35 mg/kg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
FENFLURAMINE plasma
Homo sapiens
population: UNHEALTHY
age: CHILD
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
60 mg/day 1 times / day steady, oral
Highest studied dose
Dose: 60 mg/day, 1 times / day
Route: oral
Route: steady
Dose: 60 mg/day, 1 times / day
Sources:
unhealthy, 11 years
n = 1
Health Status: unhealthy
Condition: Valsalva's maneuver
Age Group: 11 years
Sex: F
Population Size: 1
Sources:
0.2 mg/kg/day 2 times / day steady, oral
Studied dose
Dose: 0.2 mg/kg/day, 2 times / day
Route: oral
Route: steady
Dose: 0.2 mg/kg/day, 2 times / day
Sources:
unhealthy, 11.7 ± 4.4 years (range: 3‐17 years)
n = 13
Health Status: unhealthy
Condition: Lennox‐Gastaut syndrome (LGS)
Age Group: 11.7 ± 4.4 years (range: 3‐17 years)
Sex: M+F
Population Size: 13
Sources:
Other AEs: Decreased appetite...
Other AEs:
Decreased appetite (2 patients)
Sources:
0.7 mg/kg/day 1 times / day steady, oral
Studied dose
Dose: 0.7 mg/kg/day, 1 times / day
Route: oral
Route: steady
Dose: 0.7 mg/kg/day, 1 times / day
Sources:
unhealthy
n = 40
Health Status: unhealthy
Sex: unknown
Population Size: 40
Sources:
Disc. AE: Somnolence...
AEs leading to
discontinuation/dose reduction:
Somnolence (3.3%)
Sources:
AEs

AEs

AESignificanceDosePopulation
Decreased appetite 2 patients
0.2 mg/kg/day 2 times / day steady, oral
Studied dose
Dose: 0.2 mg/kg/day, 2 times / day
Route: oral
Route: steady
Dose: 0.2 mg/kg/day, 2 times / day
Sources:
unhealthy, 11.7 ± 4.4 years (range: 3‐17 years)
n = 13
Health Status: unhealthy
Condition: Lennox‐Gastaut syndrome (LGS)
Age Group: 11.7 ± 4.4 years (range: 3‐17 years)
Sex: M+F
Population Size: 13
Sources:
Somnolence 3.3%
Disc. AE
0.7 mg/kg/day 1 times / day steady, oral
Studied dose
Dose: 0.7 mg/kg/day, 1 times / day
Route: oral
Route: steady
Dose: 0.7 mg/kg/day, 1 times / day
Sources:
unhealthy
n = 40
Health Status: unhealthy
Sex: unknown
Population Size: 40
Sources:
OverviewDrug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
minor
minor
unlikely (co-administration study)
Comment: The effect of coadministration of CBD on fenfluramine and norfenfluramine PK was evaluated in Study 1604. The study demonstrated that co-administration of CBD with ZX008 increased fenfluramine AUC0-t by approximately 59% and the Cmax was not changed significantly.
Page: 6.0
minor
unlikely (co-administration study)
Comment: The effect of coadministration of CBD on fenfluramine and norfenfluramine PK was evaluated in Study 1604. The study demonstrated that co-administration of CBD with ZX008 increased fenfluramine AUC0-t by approximately 59% and the Cmax was not changed significantly.
Page: 6.0
no
no
no
no
no
no
no
no
no
no
no
no
yes
yes
unlikely (co-administration study)
Comment: The effect of coadministration of CBD on fenfluramine and norfenfluramine PK was evaluated in Study 1604. The study demonstrated that co-administration of CBD with ZX008 increased fenfluramine AUC0-t by approximately 59% and the Cmax was not changed significantly.
Page: 6.0
yes
unlikely (co-administration study)
Comment: The effect of coadministration of CBD on fenfluramine and norfenfluramine PK was evaluated in Study 1604. The study demonstrated that co-administration of CBD with ZX008 increased fenfluramine AUC0-t by approximately 59% and the Cmax was not changed significantly.
Page: 6.0
Tox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
PubMed

PubMed

TitleDatePubMed
Dose effect of fenfluramine-phentermine in the production of valvular heart disease.
1999 Apr
Echocardiographic improvement over time after cessation of use of fenfluramine and phentermine.
1999 Dec
Echocardiographic prevalence of mitral and/or aortic regurgitation in patients exposed to either fenfluramine-phentermine combination or to dexfenfluramine.
1999 Dec 1
Valve replacement for appetite suppressant-induced valvular heart disease.
1999 Jun
Pharmaceutical cost savings of treating obesity with weight loss medications.
1999 Nov
[Appetite suppressants and heart valve disorders].
1999 Sep
Beneficial effects of pharmacotherapy on weight loss, depressive symptoms, and eating patterns in obese binge eaters and non-binge eaters.
1999 Sep
The promotion effect of anorectic drugs on aflatoxin B(1)-induced hepatic preneoplastic foci.
1999 Sep
Valvular abnormalities and cardiovascular status following exposure to dexfenfluramine or phentermine/fenfluramine.
2000 Apr 5
[Obesity: principles of drug therapy].
2000 Aug
[Anorectics and pulmonary hypertension].
2000 Feb 16
The effect of fenfluramine on the pulmonary disposition of 5-hydroxytryptamine in the isolated perfused rat lung: a comparison with chlorphentermine.
2000 Jan
Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine.
2000 Jan
Dose and duration of fenfluramine-phentermine therapy impacts the risk of significant valvular heart disease.
2000 Jul 1
Complex vascular lesions at autopsy in a patient with phentermine-fenfluramin.
2000 Jun
Anorexigens and pulmonary hypertension in the United States: results from the surveillance of North American pulmonary hypertension.
2000 Mar
Diet drug-related cardiac valve disease: the Mayo Clinic echocardiographic laboratory experience.
2000 May
Fenfluramine and phentermine and cardiovascular findings: effect of treatment duration on prevalence of valve abnormalities.
2000 May 2
Effects of repeated systemic administration of d-Fenfluramine on serotonin and glutamate release in rat ventral hippocampus: comparison with methamphetamine using in vivo microdialysis.
2001 Apr
The quest for biological correlates of social phobia: an interim assessment.
2001 Apr
Comparison of [(18)F]altanserin and [(18)F]deuteroaltanserin for PET imaging of serotonin(2A) receptors in baboon brain: pharmacological studies.
2001 Apr
Anorectic drugs and pulmonary hypertension from the bedside to the bench.
2001 Apr
Appetite suppressants and valvular heart disease.
2001 Apr
Cataleptic effect of neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one in mice: modulation by serotonergic agents.
2001 Apr 13
Aortic and mitral fenfluramine-phentermine valvulopathy in 64 patients treated with anorectic agents.
2001 Dec
PET neuroimaging of clomipramine challenge in humans: focus on the thalamus.
2001 Feb 16
Elevations in plasmatic titers of corticosterone and aldosterone, in the absence of changes in ACTH, testosterone, or glial fibrillary acidic protein, 72 h following D,L-fenfluramine or D-fenfluramine administration to rats.
2001 Jan-Feb
Low risk of significant echocardiographic valvulopathy in patients treated with anorectic drugs.
2001 Jul
Pharmacologic options for the treatment of obesity.
2001 Jul 15
3,4-Methylenedioxymethamphetamine (MDMA) as a unique model of serotonin receptor function and serotonin-dopamine interactions.
2001 Jun
Echocardiographic examination of women previously treated with fenfluramine: long-term follow-up of a randomized, double-blind, placebo-controlled trial.
2001 Jun 11
Bitter pills, bad medicine.
2001 Jun 4
Rapid clot formation and abnormal fibrin structure in a symptomatic patient taking fenfluramine--a case report.
2001 May
Decreased tryptophan availability but normal post-synaptic 5-HT2c receptor sensitivity in chronic fatigue syndrome.
2001 May
Serotonin transporter promoter polymorphism is associated with attenuated prolactin response to fenfluramine.
2001 May 8
Too late, again?
2001 May-Jun
LY393558, a 5-hydroxytryptamine reuptake inhibitor and 5-HT(1B/1D) receptor antagonist: effects on extracellular levels of 5-hydroxytryptamine in the guinea pig and rat.
2001 Nov 30
Fenfluramine and phentermine.
2001 Nov 6
Operation for anorexigen-associated valvular heart disease.
2001 Oct
High performance liquid chromatography with UV detection for the simultaneous determination of sympathomimetic amines using 4-(4,5-diphenyl-1H-imidazole-2-yl)benzoyl chloride as a label.
2001 Oct
Clinical and echocardiographic follow-up of patients previously treated with dexfenfluramine or phentermine/fenfluramine.
2001 Oct 24-31
The relationship between health-related quality of life and weight loss.
2001 Sep
Anorexigen-induced pulmonary hypertension and the serotonin (5-HT) hypothesis: lessons for the future in pathogenesis.
2002
Retest reliability of prolactin response to dl-fenfluramine challenge in adults.
2002 Feb
Is long-term heavy alcohol consumption toxic for brain serotonergic neurons? Relationship between years of excessive alcohol consumption and serotonergic neurotransmission.
2002 Jan 1
Inhibition of cocaine self-administration by fluoxetine or D-fenfluramine combined with phentermine.
2002 Jan-Feb
Patents

Sample Use Guides

0.12–0.90 mg/kg/day
Route of Administration: Oral
Rat midbrain slices were used to make intracellular recordings from dopaminergic neurons of the substantia nigra and the ventral tegmental area. Gamma-aminobutyric acid (GABA)-mediated synaptic transmission was assessed from the inhibitory postsynaptic potentials (IPSPs) mediated by GABAA and GABAB receptors. Intracellular recordings from midbrain SNpc and VTA dopaminergic neurons were performed at 33.0 +/- 0.5°C in a recording chamber submerged with aCSF flowing at a rate of 2.5–3 mL•min-1 and continuously oxygenated, on the stage of an upright (inverted) microscope (Axioscope FS, Zeiss, Gottingen, Germany), equipped for infrared video microscopy (Hamamatsu, Tokyo, Japan) in order to allow a direct visualization of the recorded cells. Neurons, selected for their morphology, were identified as dopaminergic by their electrophysiological properties such as the presence of a regular spontaneous firing activity (0.5–4 Hz), a large inward current (Ih) in response to hyperpolarizing voltages and a membrane hyperpolarization due to dopamine (10–30 mmol•L-1) application . The recording electrodes were filled with 2 mol•L-1 KCl and had a tip resistance of 30–80 MW. GABAB synaptic potentials were evoked using a bipolar tungsten stimulating electrode with a tip separation of 300–700 mkm. Representative recordings showing the effect of fenfluramine in reducing the GABAB-mediated IPSP. Such effects were evident at concentrations below 1 mmol•L-1. The amplitude of synaptic potentials was halved by fenfluramine at concentration around 10 mmol•L-1 and was completely blocked by CGP (1 mmol•L-1), a selective GABAB receptor antagonist. Fenfluramine and sibutramine induce a concentration-dependent reduction of the GABAB-mediated inhibitory postsynaptic potentials (IPSPs).
Substance Class Chemical
Created
by admin
on Fri Dec 15 15:10:04 GMT 2023
Edited
by admin
on Fri Dec 15 15:10:04 GMT 2023
Record UNII
2DS058H2CF
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
FENFLURAMINE
HSDB   INN   MI   VANDF   WHO-DD  
INN  
Official Name English
PONDERAX
Brand Name English
S-768
Code English
2-ETHYLAMINO-1-(3-TRIFLUOROMETHYLPHENYL)PROPANE
Systematic Name English
PONDERAX PA
Common Name English
FENFLURAMINE [VANDF]
Common Name English
FENFLURAMINE [MI]
Common Name English
BRABAFEN
Brand Name English
N-ETHYL-.ALPHA.-METHYL-3-(TRIFLUOROMETHYL)BENZENEETHANAMINE
Systematic Name English
N-ETHYL-.ALPHA.-METHYL-M-(TRIFLUOROMETHYL)PHENETHYLAMINE
Systematic Name English
Z008
Code English
BENZENEETHANAMINE, N-ETHYL-.ALPHA.-METHYL-3-(TRIFLUOROMETHYL)-
Systematic Name English
Z-008
Code English
OBEDREX
Common Name English
fenfluramine [INN]
Common Name English
PHENFLURAMINE
Common Name English
PESOS
Common Name English
ROTONDIN
Common Name English
J5.760F
Code English
FENFLURAMIN
Common Name English
ACINO
Common Name English
ZX008
Code English
FENFLURAMINE [HSDB]
Common Name English
ZX-008
Code English
Fenfluramine [WHO-DD]
Common Name English
Classification Tree Code System Code
FDA ORPHAN DRUG 584217
Created by admin on Fri Dec 15 15:10:04 GMT 2023 , Edited by admin on Fri Dec 15 15:10:04 GMT 2023
NCI_THESAURUS C29728
Created by admin on Fri Dec 15 15:10:04 GMT 2023 , Edited by admin on Fri Dec 15 15:10:04 GMT 2023
WHO-VATC QA08AA02
Created by admin on Fri Dec 15 15:10:04 GMT 2023 , Edited by admin on Fri Dec 15 15:10:04 GMT 2023
WHO-ATC A08AA02
Created by admin on Fri Dec 15 15:10:04 GMT 2023 , Edited by admin on Fri Dec 15 15:10:04 GMT 2023
DEA NO. 1670
Created by admin on Fri Dec 15 15:10:04 GMT 2023 , Edited by admin on Fri Dec 15 15:10:04 GMT 2023
Code System Code Type Description
PUBCHEM
3337
Created by admin on Fri Dec 15 15:10:04 GMT 2023 , Edited by admin on Fri Dec 15 15:10:04 GMT 2023
PRIMARY
MESH
D005277
Created by admin on Fri Dec 15 15:10:04 GMT 2023 , Edited by admin on Fri Dec 15 15:10:04 GMT 2023
PRIMARY
RXCUI
4328
Created by admin on Fri Dec 15 15:10:04 GMT 2023 , Edited by admin on Fri Dec 15 15:10:04 GMT 2023
PRIMARY RxNorm
SMS_ID
100000081293
Created by admin on Fri Dec 15 15:10:04 GMT 2023 , Edited by admin on Fri Dec 15 15:10:04 GMT 2023
PRIMARY
CAS
5220-89-3
Created by admin on Fri Dec 15 15:10:04 GMT 2023 , Edited by admin on Fri Dec 15 15:10:04 GMT 2023
SUPERSEDED
DRUG CENTRAL
1150
Created by admin on Fri Dec 15 15:10:04 GMT 2023 , Edited by admin on Fri Dec 15 15:10:04 GMT 2023
PRIMARY
HSDB
3080
Created by admin on Fri Dec 15 15:10:04 GMT 2023 , Edited by admin on Fri Dec 15 15:10:04 GMT 2023
PRIMARY
NCI_THESAURUS
C81418
Created by admin on Fri Dec 15 15:10:04 GMT 2023 , Edited by admin on Fri Dec 15 15:10:04 GMT 2023
PRIMARY
WIKIPEDIA
FENFLURAMINE
Created by admin on Fri Dec 15 15:10:04 GMT 2023 , Edited by admin on Fri Dec 15 15:10:04 GMT 2023
PRIMARY
FDA UNII
2DS058H2CF
Created by admin on Fri Dec 15 15:10:04 GMT 2023 , Edited by admin on Fri Dec 15 15:10:04 GMT 2023
PRIMARY
INN
1596
Created by admin on Fri Dec 15 15:10:04 GMT 2023 , Edited by admin on Fri Dec 15 15:10:04 GMT 2023
PRIMARY
CHEBI
5000
Created by admin on Fri Dec 15 15:10:04 GMT 2023 , Edited by admin on Fri Dec 15 15:10:04 GMT 2023
PRIMARY
DAILYMED
2DS058H2CF
Created by admin on Fri Dec 15 15:10:04 GMT 2023 , Edited by admin on Fri Dec 15 15:10:04 GMT 2023
PRIMARY
ChEMBL
CHEMBL87493
Created by admin on Fri Dec 15 15:10:04 GMT 2023 , Edited by admin on Fri Dec 15 15:10:04 GMT 2023
PRIMARY
IUPHAR
4613
Created by admin on Fri Dec 15 15:10:04 GMT 2023 , Edited by admin on Fri Dec 15 15:10:04 GMT 2023
PRIMARY
CAS
458-24-2
Created by admin on Fri Dec 15 15:10:04 GMT 2023 , Edited by admin on Fri Dec 15 15:10:04 GMT 2023
PRIMARY
ECHA (EC/EINECS)
207-276-3
Created by admin on Fri Dec 15 15:10:04 GMT 2023 , Edited by admin on Fri Dec 15 15:10:04 GMT 2023
PRIMARY
EVMPD
SUB07561MIG
Created by admin on Fri Dec 15 15:10:04 GMT 2023 , Edited by admin on Fri Dec 15 15:10:04 GMT 2023
PRIMARY
DRUG BANK
DB00574
Created by admin on Fri Dec 15 15:10:04 GMT 2023 , Edited by admin on Fri Dec 15 15:10:04 GMT 2023
PRIMARY
CAS
25990-46-9
Created by admin on Fri Dec 15 15:10:04 GMT 2023 , Edited by admin on Fri Dec 15 15:10:04 GMT 2023
SUPERSEDED
MERCK INDEX
m5274
Created by admin on Fri Dec 15 15:10:04 GMT 2023 , Edited by admin on Fri Dec 15 15:10:04 GMT 2023
PRIMARY Merck Index
EPA CompTox
DTXSID4023044
Created by admin on Fri Dec 15 15:10:04 GMT 2023 , Edited by admin on Fri Dec 15 15:10:04 GMT 2023
PRIMARY
Related Record Type Details
OFF-TARGET->AGONIST
5-HT2B receptors, which were subsequently identified as the target for cardiac valvulopathy and pulmonary hypertension. Release of serotonin leads to 5-HT2B signaling.
TARGET -> AGONIST
STIMULATES THE RELEASE OF SEROTONIN RESULTS IN APPETITE SUPPRESSION; LEAD TO 6-16 FOLD INCREASE IN SEROTONIN IN THE HYPOTHALMUS
TRANSPORTER -> INHIBITOR
SALT/SOLVATE -> PARENT
TRANSPORTER -> SUBSTRATE
STIMULATES SEROTONIN RELEASE.
Related Record Type Details
METABOLITE -> PARENT
Percent of dose excreted in urine as metabolite.
AMOUNT EXCRETED
URINE
METABOLITE TOXIC -> PARENT
Responsible for
MAJOR
METABOLITE -> PARENT
Metabolite to parent drug ratio in non-uraemic human plasma. A positive correlation exists between plasma norfenfluramine levels and weight loss in man.
METABOLITE TO PARENT DRUG RATIO
PLASMA; URINE
Related Record Type Details
ACTIVE MOIETY