Fenfluramine

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Weight loss: Pondimin, Ponderax, Ponderal, othersSerotonin–norepinephrine releasing agent; Serotonin 5-HT_2A, 5-HT_2B, and 5-HT_2C receptor agonist; Anoretic; AnticonvulsantA08Template:ATC | _legal_data=<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>F4<ref name="Fintepla EPAR">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>Rx-only<ref name="Fintepla FDA label" />Rx-only

| _other_data=(RS)-N-Ethyl- 1-[3-(trifluoromethyl)phenyl]propan-2-amine

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Fenfluramine, sold under the brand name Fintepla, is a serotonergic medication used for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome.<ref name="Fintepla FDA label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="FDA PR">Template:Cite press release Template:PD-notice</ref><ref name="Fintepla EPAR" /> It was formerly used as an appetite suppressant in the treatment of obesity, but was discontinued for this use due to cardiovascular toxicity before being repurposed for new indications.<ref name="Barceloux2012" /><ref name="pmid33895186" /> Fenfluramine was used for weight loss both alone under the brand name Pondimin and in combination with phentermine commonly known as fen-phen.<ref name="Barceloux2012" /><ref name="SwissPharmaceuticalSociety2000">Template:Cite book</ref><ref>Template:Cite news</ref>

Side effects of fenfluramine in people treated for seizures include decreased appetite, somnolence, sedation, lethargy, diarrhea, constipation, abnormal echocardiogram, fatigue, malaise, asthenia, ataxia, balance disorder, gait disturbance, increased blood pressure, drooling, excessive salivation, fever, upper respiratory tract infection, vomiting, appetite loss, weight loss, falls, and status epilepticus.<ref name="Fintepla FDA label" /> Fenfluramine acts as a serotonin and norepinephrine releasing agent, agonist of the serotonin 5-HT₂ receptors, and sigma σ₁ receptor positive modulator.<ref name="RothmanBaumann2000">Template:Cite journal</ref><ref name="pmid34445144">Template:Cite journal</ref><ref name="pmid32169824" /> Its mechanism of action in the treatment of seizures is unknown,<ref name="Fintepla FDA label" /> but may involve increased activation of certain serotonin receptors and the sigma σ₁ receptor.<ref name="pmid34445144" /><ref name="pmid33895186">Template:Cite journal</ref><ref name="pmid30269941">Template:Cite journal</ref> Chemically, fenfluramine is a phenethylamine and amphetamine.<ref name="RothmanBaumann2000" />

Fenfluramine was developed in the early 1960s and was first introduced for medical use as an appetite suppressant in France in 1963 followed by approval in the United States in 1973.<ref name="Barceloux2012" /> In the 1990s, fenfluramine came to be associated with cardiovascular toxicity, and because of this, was withdrawn from the United States market in 1997.<ref name="Barceloux2012" /><ref name="pmid11307869" /> Subsequently, it was repurposed for the treatment of seizures and was reintroduced in the United States and the European Union in 2020.<ref name="FDA PR" /><ref name="Fintepla EPAR" /><ref name="pmid33895186" /> Fenfluramine was previously a schedule IV controlled substance in the United States.<ref name="FDA PR" /> However, the substance has since no-longer been subject to control pursuant to rule-making issued on 23 December 2022.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Medical uses

Seizures

Fenfluramine is indicated for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome in people age two and older.<ref name="Fintepla FDA label" /><ref name="FDA PR" /><ref name="Fintepla EPAR" />

Dravet syndrome is a life-threatening, rare and chronic form of epilepsy.<ref name="FDA PR" /> It is often characterized by severe and unrelenting seizures despite medical treatment.<ref name="FDA PR" />

Research is indicating a potential of fenfluramine to treat those with Sunflower syndrome, a rare form of epilepsy often manifesting in distinct hand waiving in front of the face and a tendency to stare at or face the sun.<ref>Geenen, K. R., Doshi, S. P., Patel, S., Sourbron, J., Falk, A., Morgan, A., Vu, U., Bruno, P. L., & Thiele, E. A. (2021). Fenfluramine for seizures associated with Sunflower syndrome. Developmental medicine and child neurology, 63(12), 1427–1432. https://doi.org/10.1111/dmcn.14965</ref>

Obesity

Fenfluramine was formerly used as an appetite suppressant in the treatment of obesity, but was withdrawn for this use due to cardiovascular toxicity.<ref name="Barceloux2012" />

Adverse effects

The most common adverse reactions in people with seizures include decreased appetite; drowsiness, sedation and lethargy; diarrhea; constipation; abnormal echocardiogram; fatigue or lack of energy; ataxia (lack of coordination), balance disorder, gait disturbance (trouble with walking); increased blood pressure; drooling, salivary hypersecretion (saliva overproduction); pyrexia (fever); upper respiratory tract infection; vomiting; decreased weight; risk of falls; and status epilepticus.<ref name="FDA PR" />

The U.S. Food and Drug Administration (FDA) fenfluramine labeling includes a boxed warning stating the drug is associated with valvular heart disease (VHD) and pulmonary arterial hypertension (PAH).<ref name="FDA PR" /> Because of the risks of VHD and PAH, fenfluramine is available only through a restricted drug distribution program, under a risk evaluation and mitigation strategy (REMS).<ref name="FDA PR" /> The fenfluramine REMS requires health care professionals who prescribe fenfluramine and pharmacies that dispense fenfluramine to be specially certified in the fenfluramine REMS and that patients be enrolled in the REMS.<ref name="FDA PR" /> As part of the REMS requirements, prescribers and patients must adhere to the required cardiac monitoring with echocardiograms to receive fenfluramine.<ref name="FDA PR" />

At higher therapeutic doses, headache, diarrhea, dizziness, dry mouth, erectile dysfunction, anxiety, insomnia, irritability, lethargy, and [[psychostimulant|Template:Abbr stimulation]] have been reported with fenfluramine.<ref name="Dart2004" />

There have been reports associating chronic fenfluramine treatment with emotional instability, cognitive deficits, depression, psychosis, exacerbation of pre-existing psychosis (schizophrenia), and sleep disturbances.<ref name="Dart2004" /><ref name="D.)Ahuja2005">Template:Cite book</ref> It has been suggested that some of these effects may be mediated by serotonergic neurotoxicity/depletion of serotonin with chronic administration or activation of serotonin 5-HT_2A receptors.<ref name="D.)Ahuja2005" /><ref>Template:Cite book</ref><ref>Template:Cite bookTemplate:Dead link</ref><ref name="MullerJacobs2009">Template:Cite book</ref>

Heart valve disease

The distinctive valvular abnormality seen with fenfluramine is a thickening of the leaflet and chordae tendineae. One mechanism used to explain this phenomenon involves heart valve serotonin receptors, which are thought to help regulate growth. Since fenfluramine and its active metabolite norfenfluramine stimulate serotonin receptors, this may have led to the valvular abnormalities found in patients using fenfluramine. In particular norfenfluramine is a potent inhibitor of the re-uptake of 5-HT into nerve terminals.<ref name="pmid11489456 ">Template:Cite journal</ref> Fenfluramine and its active metabolite norfenfluramine affect the 5-HT_2B receptors, which are plentiful in human cardiac valves. The suggested mechanism by which fenfluramine causes damage is through over or inappropriate stimulation of these receptors leading to inappropriate valve cell division. Supporting this idea is the fact that this valve abnormality has also occurred in patients using other drugs that act on 5-HT_2B receptors.<ref name="pmid17202450">Template:Cite journal</ref><ref name="pmid19505264">Template:Cite journal</ref>

According to a study of 5,743 former users conducted by a plaintiff's expert cardiologist, damage to the heart valve continued long after stopping the medication.<ref name="pmid18990200">Template:Cite journal</ref> Of the users tested, 20% of women, and 12% of men were affected. For all ex-users, there was a 7-fold increase of chances of needing surgery for faulty heart valves caused by the drug.<ref name="pmid18990200" />

Overdose

In overdose, fenfluramine can cause serotonin syndrome and rapidly result in death.<ref name="Barceloux2012" /><ref name="MannCaroff2008">Template:Cite book</ref>

Pharmacology

Pharmacodynamics

Template:Nowrap

Compound	Template:Abbrlink	Template:Abbrlink	Template:Abbrlink	Ref
Dextroamphetamine	6.6–7.2	5.8–24.8	698–1,765	<ref name="RothmanBaumannDersch2001">Template:Cite journal</ref><ref name="BaumannPartillaLehner2013">Template:Cite journal</ref><ref name="Blough2008">Template:Cite book</ref><ref name="Liu2018">Template:Cite journal</ref>
Dextroethylamphetamine	28.8	44.1	333.0	<ref name="FitzgeraldGannonWalther2024">Template:Cite journal</ref><ref name="Nicole2022">{{#invoke:citation/CS1|citation	CitationClass=web }}</ref>
Fenfluramine	739	>10,000 (Template:Abbr)	79.3–108	<ref name="RothmanBaumann2006" /><ref name="RothmanBaumann2009" /><ref name="RothmanBaumannDersch2001" /><ref name="RothmanClarkPartilla2003">Template:Cite journal</ref>
Template:NbspTemplate:NbspDexfenfluramine	302	>10,000	51.7	<ref name="RothmanBaumann2006" /><ref name="RothmanBaumann2009" /><ref name="RothmanBaumannDersch2001" /><ref name="RothmanClarkPartilla2003" />
Template:NbspTemplate:NbspLevfenfluramine	>10,000	>10,000	147	<ref name="RothmanBaumann2006" /><ref name="RothmanBaumann2009" /><ref name="RothmanClarkPartilla2003" /><ref name="RothmanBaumann2002a">Template:Cite journal</ref>
Norfenfluramine	168–170	1,900–1,925	104	<ref name="RothmanBaumann2006" /><ref name="RothmanBaumann2009" /><ref name="RothmanClarkPartilla2003" />
Template:NbspTemplate:NbspDexnorfenfluramine	72.7	924	59.3	<ref name="RothmanBaumann2006" /><ref name="RothmanBaumann2009" /><ref name="RothmanClarkPartilla2003" />
Template:NbspTemplate:NbspLevnorfenfluramine	474	>10,000	287	<ref name="RothmanBaumann2006" /><ref name="RothmanBaumann2009" /><ref name="RothmanClarkPartilla2003" />
Phentermine	28.8–39.4	262	2,575–3,511	<ref name="RothmanBaumannDersch2001" /><ref name="Blough2008" /><ref name="PartillaDerschBaumann1999">Template:Cite book</ref>
Chlorphentermine	>10,000 (Template:Abbr)	935–2,650	18.2–30.9	<ref name="RothmanBaumannDersch2001" /><ref name="PartillaDerschBaumann1999" />
Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. The assays were done in rat brain synaptosomes and human potencies may be different. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. Refs: <ref name="RothmanBaumann2003">Template:Cite journal</ref><ref name="RothmanBaumann2006">Template:Cite journal</ref><ref name="RothmanBaumann2009">Template:Cite journal</ref>

Fenfluramine acts primarily as a serotonin releasing agent (SRA).<ref name="RothmanClarkPartilla2003" /><ref name="SetolaHufeisenGrande-Allen2003">Template:Cite journal</ref> It increases the level of serotonin, a neurotransmitter that regulates mood, appetite and other functions.<ref name="RothmanClarkPartilla2003" /><ref name="SetolaHufeisenGrande-Allen2003" /> Fenfluramine causes the release of serotonin by disrupting vesicular storage of the neurotransmitter, and reversing serotonin transporter function.<ref>Template:Cite book</ref> The drug also acts as a norepinephrine releasing agent (NRA) to a lesser extent, particularly via its active metabolite norfenfluramine.<ref name="RothmanClarkPartilla2003" /><ref name="SetolaHufeisenGrande-Allen2003" /> At high concentrations, norfenfluramine, though not fenfluramine, also acts as a dopamine releasing agent (DRA), and so fenfluramine may do this at very high doses as well.<ref name="RothmanClarkPartilla2003" /><ref name="SetolaHufeisenGrande-Allen2003" /> In addition to monoamine release, while fenfluramine binds only very weakly to the serotonin 5-HT₂ receptors, norfenfluramine binds to and activates the serotonin 5-HT_2B and 5-HT_2C receptors with high affinity and the serotonin 5-HT_2A receptor with moderate affinity.<ref name="GiovanniMatteo2008">Template:Cite book</ref><ref name="pmid10617681">Template:Cite journal</ref> The result of the increased serotonergic and noradrenergic neurotransmission is a feeling of fullness and reduced appetite.

In spite of acting as a serotonin 5-HT_2A receptor agonist, fenfluramine has been described as non-hallucinogenic.<ref name="GumpperRoth2024">Template:Cite journal</ref> However, psychedelic effects and hallucinations have occasionally been reported when large doses of fenfluramine are taken.<ref name="GumpperRoth2024" /> Similarly to the psychedelic amphetamine DOI, it is the R-Enatiomer (Levofenfluramine) that is more likely to elicit psychedelia, this also holds true for 3,4-Methylenedioxyamphetamine (MDA)<ref name="RothmanBaumannSavage2000" /><ref name="RothmanBaumann2009" />

Fenfluramine was identified as a potent positive modulator of the σ₁ receptor in 2020 and this action may be involved in its therapeutic benefits in the treatment of seizures.<ref name="pmid34445144" /><ref name="pmid32169824">Template:Cite journal</ref>

Fenfluramine is inactive as an agonist of the rodent trace amine-associated receptor 1 (TAAR1).<ref name="ZucchiChielliniScanlan2006">Template:Cite journal</ref><ref name="BunzowSondersArttamangkul2001">Template:Cite journal</ref> Norfenfluramine is an agonist of the human TAAR1, with dexnorfenfluramine acting as a very weak agonist of the receptor (43% of maximum at a concentration of 10,000Template:NbspnM) and levonorfenfluramine being inactive.<ref name="LewinMillerGilmour2011">Template:Cite journal</ref>

The combination of fenfluramine with phentermine, a norepinephrine–dopamine releasing agent (NDRA) acting primarily on norepinephrine, results in a well-balanced serotonin–norepinephrine releasing agent (SNRA) with weaker effects of dopamine release.<ref name="RothmanClarkPartilla2003" /><ref name="SetolaHufeisenGrande-Allen2003" />

Template:Nowrap

Compound	5-HT2A			5-HT2B			5-HT2C
	Ki (nM)	Template:Abbrlink (nM)	Template:Abbrlink (%)	Ki (nM)	Template:Abbrlink (nM)	Template:Abbrlink (%)	Ki (nM)	Template:Abbrlink (nM)	Template:Abbrlink (%)
Fenfluramine	5,216	4,131	15%	4,134	Template:Abbr	Template:Abbr	3,183	Template:Abbr	Template:Abbr
Template:NbspTemplate:NbspDexfenfluramine	11,107	>10,000	Template:Abbr	5,099	379	38%	6,245	362	80%
Template:NbspTemplate:NbspLevofenfluramine	5,463	5,279	43%	5,713	1,248	47%	3,415	360	84%
Norfenfluramine	2,316	Template:Abbr	Template:Abbr	52.1	Template:Abbr	Template:Abbr	557	Template:Abbr	Template:Abbr
Template:NbspTemplate:NbspDexnorfenfluramine	1,516	630	88%	11.2	18.4	73%	324	13	100%
Template:NbspTemplate:NbspLevonorfenfluramine	3,841	1,565	93%	47.8	357	71%	814	18	80%
Phentermine	>10,000	Template:Abbr or Template:Abbr	Template:Abbr or Template:Abbr	>10,000	Template:Abbr or Template:Abbr	Template:Abbr or Template:Abbr	>10,000	1,394	66%
Chlorphentermine	Template:Abbr	>10,000	Template:Abbr	Template:Abbr	5,370	Template:Abbr	Template:Abbr	6,456	Template:Abbr
Notes: (1) The smaller the Ki or EC50 value, the more avidly the drug binds to or activates the receptor. The higher the Emax value, the more effectively the drug activates the receptor. (2) All values are for human receptors except for the 5-HT2A and 5-HT2C Ki values, which are for the rat receptors. Refs: <ref name="RothmanBaumannSavage2000">Template:Cite journal</ref><ref name="RothmanBaumann2009" /><ref name="RothmanBaumann2006" />

Pharmacokinetics

The elimination half-life of fenfluramine has been reported as ranging from 13 to 30 hours.<ref name="Dart2004">Template:Cite book</ref> The mean elimination half-lives of its enantiomers have been found to be 19 hours for dexfenfluramine and 25 hours for levfenfluramine.<ref name="Barceloux2012" /> Norfenfluramine, the major active metabolite of fenfluramine, has an elimination half-life that is about 1.5 to 2 times as long as that of fenfluramine, with mean values of 34 hours for dexnorfenfluramine and 50 hours for levnorfenfluramine.<ref name="Barceloux2012" />

Chemistry

Fenfluramine is a substituted amphetamine and is also known as 3-trifluoromethyl-N-ethylamphetamine.<ref name="Barceloux2012" /> It is a racemic mixture of two enantiomers, dexfenfluramine and levofenfluramine.<ref name="Barceloux2012" /> Some analogues of fenfluramine include norfenfluramine, benfluorex, flucetorex, and fludorex.

History

Fenfluramine was developed in the early 1960s and was introduced in France in 1963.<ref name="Barceloux2012" /> Approximately 50 million Europeans were treated with fenfluramine for appetite suppression between 1963 and 1996.<ref name="Barceloux2012" /> Fenfluramine was approved in the United States in 1973.<ref name="Barceloux2012" /> The combination of fenfluramine and phentermine was proposed in 1984.<ref name="Barceloux2012" /> Approximately 5 million people in the United States were given fenfluramine or dexfenfluramine with or without phentermine between 1996 and 1998.<ref name="Barceloux2012" />

In the early 1990s, French researchers reported an association of fenfluramine with primary pulmonary hypertension and dyspnea in a small sample of patients.<ref name="Barceloux2012" /> Fenfluramine was withdrawn from the U.S. market in 1997 after reports of heart valve disease<ref name="pmid9271479">Template:Cite journal</ref><ref name="pmid11307869">Template:Cite journal</ref> and continued findings of pulmonary hypertension, including a condition known as cardiac fibrosis.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It was subsequently withdrawn from other markets around the world. It was banned in India in 1998.<ref name=ban>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Fenfluramine was an appetite suppressant which was used to treat obesity.<ref name="Barceloux2012">Template:Cite book</ref> It was used both on its own and, in combination with phentermine, as part of the anti-obesity medication Fen-Phen.<ref name="Barceloux2012" />

In June 2020, fenfluramine was approved for medical use in the United States with an indication to treat Dravet syndrome.<ref name="FDA PR" /><ref>Template:Cite press release</ref>

The effectiveness of fenfluramine for the treatment of seizures associated with Dravet syndrome was demonstrated in two clinical studies in 202 subjects between ages two and eighteen.<ref name="FDA PR" /> The studies measured the change from baseline in the frequency of convulsive seizures.<ref name="FDA PR" /> In both studies, subjects treated with fenfluramine had significantly greater reductions in the frequency of convulsive seizures during the trials than subjects who received placebo (inactive treatment).<ref name="FDA PR" /> These reductions were seen within 3–4 weeks, and remained generally consistent over the 14- to 15-week treatment periods.<ref name="FDA PR" />

The U.S. Food and Drug Administration (FDA) granted the application for fenfluramine priority review and orphan drug designations.<ref name="FDA PR" /><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The FDA granted approval of Fintepla to Zogenix, Inc.<ref name="FDA PR" />

On 15 October 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Fintepla, intended for the treatment of seizures associated with Dravet syndrome.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> Fenfluramine was approved for medical use in the European Union in December 2020.<ref name="Fintepla EPAR" />

Society and culture

Legal status

Fenfluramine is a prescription medication in the US. Fenfluramine was removed from Schedule IV of the Controlled Substances Act in December 2022.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Recreational use and effects

Unlike various other amphetamine derivatives, fenfluramine is reported to be dysphoric, "unpleasantly lethargic", and non-addictive at therapeutic doses.<ref name="Brust2004">Template:Cite book</ref> However, it has been reported to be used recreationally at high doses ranging between 80 and 400 mg, which have been described as producing euphoria, amphetamine-like effects, sedation, and hallucinogenic effects, along with anxiety, nausea, diarrhea, and sometimes panic attacks, as well as depressive symptoms once the drug had worn off.<ref name="Brust2004" /><ref name="Activities1976">Template:Cite book</ref><ref name="Gunne1977" /> At very high doses (e.g., 240 mg, or between 200 and 600 mg), fenfluramine induces a psychedelic state resembling that produced by lysergic acid diethylamide (LSD).<ref name="Gunne1977">Template:Cite book</ref><ref name="Connell1979">Template:Cite journal</ref><ref name="Griffith1977">Template:Cite book</ref><ref name="GriffithNuttJasinski1975">Template:Cite journal</ref>

Fenfluramine has been found to produce acute effects in humans including decreased arousal, elation, and positive mood, decreased anxiety at lower doses and increased anxiety at higher doses, drug disliking, confusion, reduced psychomotor performance, reduced impulsivity, and decreased aggression.<ref name="Carhart-HarrisNutt2017">Template:Cite journal</ref><ref name="RothmanBaumann2000" /><ref name="BrauerJohanssonSchuster1996">Template:Cite journal</ref><ref name="CherekLane2001">Template:Cite journal</ref><ref name="HetemdeSouzaGuimarães1996">Template:Cite journal</ref> Whereas fenfluramine alone decreases positive mood and phentermine alone increases positive mood similarly to amphetamine, the combination of fenfluramine and phentermine results in a neutral impact on mood.<ref name="RothmanBaumann2000" /><ref name="BrauerJohanssonSchuster1996" /> Similarly fenfluramine diminishes the subjective effects of phentermine and amphetamine.<ref name="RothmanBloughBaumann2008">Template:Cite journal</ref><ref name="RothmanBloughBaumann2006">Template:Cite journal</ref> In contrast to other serotonin releasers like MDMA and mephedrone, fenfluramine does not produce euphoria.<ref name="Carhart-HarrisNutt2017" /> The differing effects with fenfluramine may be attributable to its lack of concomitant dopamine release and its potent serotonin 5-HT_2C receptor agonism via its metabolite norfenfluramine.<ref name="Carhart-HarrisNutt2017" />

Research

Social deficits

Fenfluramine has been reported to improve social deficits in children with autism.<ref name="HeifetsSalgadoTaylor2019">Template:Cite journal</ref><ref name="AmanKern1989">Template:Cite journal</ref> In addition, it has been found to produce prosocial behavior similarly to the entactogen MDMA in animals.<ref name="BeheraJogaYerram2024">Template:Cite journal</ref><ref name="HeifetsSalgadoTaylor2019" /> However, fenfluramine has shown limited effectiveness in treating the symptoms of autism generally.<ref name="MarkopoulosInserraDeGregorio2021">Template:Cite journal</ref> Moreover, the cardiovascular toxicity and neurotoxicity of fenfluramine<ref name="Kostrzewa2022">Template:Cite book</ref><ref name="McCannSeidenRubin1997">Template:Cite journal</ref><ref name="RothmanBaumann2002">Template:Cite journal</ref><ref name="JohnsonNichols1990">Template:Cite journal</ref> make it unsuitable for clinical use in the treatment of social deficits.<ref name="HeifetsSalgadoTaylor2019" />

Further reading

• Template:Cite journal
• Template:Cite journal

External links

• Inchem.org - Fenfluramine hydrochloride

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