Fenfluramine

Source: Wikipedia, the free encyclopedia.

Fenfluramine
Clinical data
Trade namesSeizures: Fintepla
Weight loss: Pondimin, Ponderax, Ponderal, others
Other namesZX008; 3-Trifluoromethyl-N-ethylamphetamine
AHFS/Drugs.comProfessional Drug Facts
MedlinePlusa620045
License data
Pregnancy
category
  • AU: B2
Anoretic; Anticonvulsant
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life13–30 hours[5]
Identifiers
  • (RS)-N-Ethyl- 1-[3-(trifluoromethyl)phenyl]propan-2-amine
JSmol)
ChiralityRacemic mixture
SMILES
  • CCNC(C)Cc1cccc(C(F)(F)F)c1
  • 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 checkY
  • Key:DBGIVFWFUFKIQN-UHFFFAOYSA-N checkY
  (verify)

Fenfluramine, sold under the brand name Fintepla, is a

cardiovascular toxicity before being repurposed for new indications.[7][8] Fenfluramine was used for weight loss both alone under the brand name Pondimin and in combination with phentermine commonly known as fen-phen.[7][9][10]

positive modulator.[11][12][13] Its mechanism of action in the treatment of seizures is unknown,[2] but may involve increased activation of certain serotonin receptors and the sigma σ1 receptor.[12][8][14] Chemically, fenfluramine is a phenethylamine and amphetamine.[11]

Fenfluramine was developed in the early 1960s and was first introduced for medical use as an appetite suppressant in

withdrawn from the United States market in 1997.[7][15] Subsequently, it was repurposed for the treatment of seizures and was reintroduced in the United States and the European Union in 2020.[6][3][8] Fenfluramine was previously a schedule IV controlled substance in the United States.[6] However, the substance has since no-longer been subject to control pursuant to rule-making issued on 23 December 2022.[16]

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.[2][6][3]

Dravet syndrome is a life-threatening, rare and chronic form of epilepsy.[6] It is often characterized by severe and unrelenting seizures despite medical treatment.[6]

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.[17]

Obesity

Fenfluramine was formerly used as an

withdrawn for this use due to cardiovascular toxicity.[7]

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.[6]

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).[6] 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).[6] 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.[6] As part of the REMS requirements, prescribers and patients must adhere to the required cardiac monitoring with echocardiograms to receive fenfluramine.[6]

At higher therapeutic doses,

CNS stimulation have been reported with fenfluramine.[5]

There have been reports associating chronic fenfluramine treatment with

sleep disturbances.[5][18] 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-HT2A receptors.[18][19][20][21]

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.[22] Fenfluramine and its active metabolite norfenfluramine affect the 5-HT2B 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-HT2B receptors.[23][24]

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.[25] 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.[25]

Overdose

In

overdose, fenfluramine can cause serotonin syndrome and rapidly result in death.[7][26]

Pharmacology

Pharmacodynamics

EC50
Tooltip Half maximal effective concentration, nM)
Compound NETooltip Norepinephrine DATooltip Dopamine 5-HTTooltip Serotonin Ref
Dextroamphetamine 6.6–7.2 5.8–24.8 698–1,765 [27][28][29][30]
Dextroethylamphetamine
 28.8 44.1 333.0 [31][32]
Fenfluramine 739 >10,000 (RI) 79.3–108 [33][34][27][35]
  Dexfenfluramine 302 >10,000 51.7 [33][34][27][35]
  
Levfenfluramine
 >10,000 >10,000 147 [33][34][35][36]
Norfenfluramine 168–170 1,900–1,925 104 [33][34][35]
  
Dexnorfenfluramine
 72.7 924 59.3 [33][34][35]
  
Levnorfenfluramine
 474 >10,000 287 [33][34][35]
Phentermine 28.8–39.4 262 2,575–3,511 [27][29][37]
Chlorphentermine >10,000 (RI) 935–2,650 18.2–30.9 [27][37]
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: [38][33][34]

Fenfluramine acts primarily as a

noradrenergic neurotransmission
is a feeling of fullness and reduced appetite.

In spite of acting as a serotonin 5-HT2A receptor agonist, fenfluramine has been described as non-hallucinogenic.[43] However, psychedelic effects and hallucinations have occasionally been reported when large doses of fenfluramine are taken.[43] 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)[44][34]

Fenfluramine was identified as a

positive modulator of the σ1 receptor in 2020 and this action may be involved in its therapeutic benefits in the treatment of seizures.[12][13]

Fenfluramine is inactive as an agonist of the rodent

levonorfenfluramine being inactive.[47]

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.[35][39]

Fenfluramine and related agents at the serotonin 5-HT2 receptors
Compound 5-HT2A 5-HT2B 5-HT2C
Ki
(nM)
EC50
Tooltip Half-maximal effective concentration (nM)
Emax
Tooltip Maximal efficacy (%)
Ki
(nM)
EC50
Tooltip Half-maximal effective concentration (nM)
Emax
Tooltip Maximal efficacy (%)
Ki
(nM)
EC50
Tooltip Half-maximal effective concentration (nM)
Emax
Tooltip Maximal efficacy (%)
Fenfluramine 5,216 4,131 15% 4,134 ND ND 3,183 ND ND
  Dexfenfluramine 11,107 >10,000 ND 5,099 379 38% 6,245 362 80%
  Levofenfluramine 5,463 5,279 43% 5,713 1,248 47% 3,415 360 84%
Norfenfluramine 2,316 ND ND 52.1 ND ND 557 ND ND
  
Dexnorfenfluramine
 1,516 630 88% 11.2 18.4 73% 324 13 100%
  
Levonorfenfluramine
 3,841 1,565 93% 47.8 357 71% 814 18 80%
Phentermine >10,000 IA or ND IA or ND >10,000 IA or ND IA or ND >10,000 1,394 66%
Chlorphentermine ND >10,000 ND ND 5,370 ND ND 6,456 ND
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: [44][34][33]

Pharmacokinetics

The

elimination half-life of fenfluramine has been reported as ranging from 13 to 30 hours.[5] The mean elimination half-lives of its enantiomers have been found to be 19 hours for dexfenfluramine and 25 hours for levfenfluramine.[7] 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.[7]

Chemistry

Fenfluramine is a substituted amphetamine and is also known as 3-trifluoromethyl-N-ethylamphetamine.[7] It is a racemic mixture of two enantiomers, dexfenfluramine and levofenfluramine.[7] 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.[7] Approximately 50 million Europeans were treated with fenfluramine for appetite suppression between 1963 and 1996.[7] Fenfluramine was approved in the United States in 1973.[7] The combination of fenfluramine and phentermine was proposed in 1984.[7] Approximately 5 million people in the United States were given fenfluramine or dexfenfluramine with or without phentermine between 1996 and 1998.[7]

In the early 1990s, French researchers reported an association of fenfluramine with primary

dyspnea in a small sample of patients.[7] Fenfluramine was withdrawn from the U.S. market in 1997 after reports of heart valve disease[48][15] and continued findings of pulmonary hypertension, including a condition known as cardiac fibrosis.[49] It was subsequently withdrawn from other markets around the world. It was banned in India in 1998.[50]

Fenfluramine was an appetite suppressant which was used to treat obesity.[7] It was used both on its own and, in combination with phentermine, as part of the anti-obesity medication Fen-Phen.[7]

In June 2020, fenfluramine was approved for medical use in the United States with an indication to treat Dravet syndrome.[6][51]

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.[6] The studies measured the change from baseline in the frequency of convulsive seizures.[6] 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).[6] These reductions were seen within 3–4 weeks, and remained generally consistent over the 14- to 15-week treatment periods.[6]

The U.S. Food and Drug Administration (FDA) granted the application for fenfluramine priority review and orphan drug designations.[6][52][53] The FDA granted approval of Fintepla to Zogenix, Inc.[6]

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.[54] Fenfluramine was approved for medical use in the European Union in December 2020.[3]

Society and culture

Fenfluramine is a prescription medication in the US. Fenfluramine was removed from Schedule IV of the Controlled Substances Act in December 2022.[55]

Recreational use and effects

Unlike various other amphetamine derivatives, fenfluramine is reported to be

lysergic acid diethylamide (LSD).[58][59][60][61]

Fenfluramine has been found to produce acute effects in humans including decreased

confusion, reduced psychomotor performance, reduced impulsivity, and decreased aggression.[62][11][63][64][65] 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.[11][63] Similarly fenfluramine diminishes the subjective effects of phentermine and amphetamine.[66][67] In contrast to other serotonin releasers like MDMA and mephedrone, fenfluramine does not produce euphoria.[62] The differing effects with fenfluramine may be attributable to its lack of concomitant dopamine release and its potent serotonin 5-HT2C receptor agonism via its metabolite norfenfluramine.[62]

Research

Social deficits

Fenfluramine has been reported to improve

prosocial behavior similarly to the entactogen MDMA in animals.[70][68] However, fenfluramine has shown limited effectiveness in treating the symptoms of autism generally.[71] Moreover, the cardiovascular toxicity and neurotoxicity of fenfluramine[72][73][74][75] make it unsuitable for clinical use in the treatment of social deficits.[68]

References

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    . However, LEVIN recently (1972, 1974) reported on abuse of fenfluramine among LSD and cannabis abusers in South Africa. This group of abusers seems to have appreciated the hallucinogenic LSD-like effects, which fenfluramine exerts when applied in high doses (200—600 mg). At this dose level, the fenfluramine abusers (a total of 115) experienced euphoria with laughing attacks, followed some hours later by depressive symptoms. They reported visual and olfactory hallucinations, anxiety, sometimes with attacks of panic, nausea, and diarrhea.
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    . Griffith et al.6 compared fenfluramine with d-amphetamine and noted that fenfluramine was usually identified as LSD by subjects, and LSD scale scores after fenfluramine were significantly elevated. Three subjects receiving 240 mg fenfluramine experienced a psychedelic state characterized by visual and olfactory hallucination, cyclic alterations of mood, distorted time sense, fleeting paranoia, and sexual ideation. They noted that fenfluramine was a weak hallucinogen and, although sharing some features in common with amphetamine, "its overall profile of effects is quite different".
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    . Fenfluramine (60, 120, 240 mg orally) [...] caused a marked dilation of pupils and elevation of the LSD Scale. [...] Fenfluramine was more often identified as an "LSD" or "barbiturate-like" substance. An unexpected response [...] was observed among 3 subjects who manifested hallucinatory states characterized by visual and olfactory hallucinations, rapid and polar changes of mood, distorted time sense, fleeting paranoia, and sexual hallucinations. [...] The remaining five subjects receiving the largest dose of fenfluramine experienced a chlorpromazine-like sedation without hallucinations or other psychedelic effects (Griffith, Nutt, and Jasinski, 1975). Chlorphentermine (50, 100, 200 mg) was similarly assessed. In certain respects, chlorphentermine resembles fenfluramine (Fig. 4), especially in terms of its mydriatic and sedative effects [...] On the other hand, chlorphentermine [...] is not hallucinogenic. [...] the utility of [amphetamine aromatic ring substitution] may be limited by the emergence of certain side-effects [...] e.g., dysphoria, sedation, and/or psychedelic properties.
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    . dl-Fenfluramine hydrochloride (60, 120, 240 mg), d-amphetamine sulfate (20, 40 mg), and placebo were compared in 8 postaddict volunteers, each dose given orally [...] Fenfluramine [...] caused a marked dilation of pupils [...] While fenfluramine produced euphoria in some subjects, its overall effects were unpleasant, sedative, and qualitatively different from amphetamine. Three subjects given 240 mg of fenfluramine experienced brief but vivid hallucinogenic episodes characterized by olfactory, visual, and somatic hallucinations, abrupt polar changes in mood, time distortion, fleeting paranoia, and sexual ideation. These observations indicate that fenfluramine is a hallucinogenic agent with a pharmacologic profile in man that is not amphetamine-like.
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    . Fenfluramine, a serotonin-releasing agent, enhances serotonin signaling in the brain. While few small-sample, placebo-controlled studies found moderate efficacy in fenfluramine's ability to increase IQ in individuals with ASD (Geller et al., 1982; Ritvo et al., 1984), far more have found that this treatment is only effective in mildy reducing some of the motor and attentional atypicalities in people with ASD. This data suggests that increasing brain serotonin levels (and consequently serotonin signaling) is generally ineffective in improving the behavioural condition of individuals with ASD.
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Further reading
Retrieved from "https://en.wikipedia.org/w/index.php?title=Fenfluramine&oldid=1293362374"