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. 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. Fenfluramine was used for weight loss both alone under the brand name Pondimin and in combination with phentermine commonly known as fen-phen.
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. Fenfluramine acts as a serotonin and norepinephrine releasing agent, agonist of the serotonin 5-HT2 receptors, and sigma σ1 receptor positive modulator. Its mechanism of action in the treatment of seizures is unknown, but may involve increased activation of certain serotonin receptors and the sigma σ1 receptor. Chemically, fenfluramine is a phenethylamine and amphetamine.
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. In the 1990s, fenfluramine came to be associated with cardiovascular toxicity, and because of this, was withdrawn from the United States market in 1997. Subsequently, it was repurposed for the treatment of seizures and was reintroduced in the United States and the European Union in 2020. Fenfluramine was previously a schedule IV controlled substance in the United States. However, the substance has since no-longer been subject to control pursuant to rule-making issued on 23 December 2022.
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.
Dravet syndrome is a life-threatening, rare and chronic form of epilepsy. It is often characterized by severe and unrelenting seizures despite medical treatment.
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.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
Obesity Fenfluramine was formerly used as an appetite suppressant in the treatment of obesity, but was withdrawn for this use due to cardiovascular toxicity.
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.
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). 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). 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. As part of the REMS requirements, prescribers and patients must adhere to the required cardiac monitoring with echocardiograms to receive fenfluramine.
At higher therapeutic doses, headache, diarrhea, dizziness, dry mouth, erectile dysfunction, anxiety, insomnia, irritability, lethargy, and stimulation have been reported with fenfluramine.
There have been reports associating chronic fenfluramine treatment with emotional instability, cognitive deficits, depression, psychosis, exacerbation of pre-existing psychosis (schizophrenia), and sleep disturbances. 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.
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. 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.
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. 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.
Overdose In overdose, fenfluramine can cause serotonin syndrome and rapidly result in death.
Pharmacology Pharmacodynamics + Compound Ref Dextroamphetamine 6.6–7.2 5.8–24.8 698–1,765 Dextroethylamphetamine 28.8 44.1 333.0 Fenfluramine 739 >10,000 () 79.3–108 Dexfenfluramine 302 >10,000 51.7 Levfenfluramine >10,000 >10,000 147 Norfenfluramine 168–170 1,900–1,925 104 Dexnorfenfluramine 72.7 924 59.3 Levnorfenfluramine 474 >10,000 287 Phentermine 28.8–39.4 262 2,575–3,511 Chlorphentermine >10,000 () 935–2,650 18.2–30.9 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:
Fenfluramine acts primarily as a serotonin releasing agent (SRA). It 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 also acts as a norepinephrine releasing agent (NRA) to a lesser extent, particularly via its active metabolite norfenfluramine. 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. 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-HT2B and 5-HT2C receptors with high affinity and the serotonin 5-HT2A receptor with moderate affinity. 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-HT2A receptor agonist, fenfluramine has been described as non-hallucinogenic. However, psychedelic effects and hallucinations have occasionally been reported when large doses of fenfluramine are taken. Similarly to the psychedelic amphetamines DOI and MDA, it is the (R)- enantiomer of fenfluramine, known as levofenfluramine, that is more likely to elicit psychedelic effects. Fenfluramine and dexfenfluramine produce the head-twitch response, a behavioral proxy of psychedelic effects, in rodents. This effect could be reduced by the serotonin synthesis inhibitor para-chlorophenylalanine and by the serotonin reuptake inhibitors sertraline and clomipramine, suggesting that it is mediated by induction of serotonin release. In any case, fenfluramine is also known to be a direct agonist of the serotonin 5-HT2A receptor via its metabolite norfenfluramine, and this action could contribute to induction of the head-twitch response as well.
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.
Fenfluramine is inactive as an agonist of the rodent trace amine-associated receptor 1 (TAAR1). 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 10,000nM) and levonorfenfluramine being inactive.
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.
Fenfluramine produces hypothermia in rodents, rather than the hyperthermia that occurs with MDMA. When serotonin reuptake inhibitors like fluoxetine are given with fenfluramine, its induction of serotonin release is blocked in rodents. In spite of this however, the anorectic effects of fenfluramine are unchanged. On the other hand, selective serotonin 5-HT2C receptor antagonists block the anorectic effects of dexfenfluramine in rodents. These and other findings suggest that the appetite-suppressing effects of fenfluramine are due to direct serotonin 5-HT2C receptor agonism rather than due to induction of serotonin release.
Fenfluramine has been found to increase oxytocin levels in rodents and humans.
+ Compound 5-HT2A 5-HT2B 5-HT2C Ki (nM) (nM) (%) Ki (nM) (nM) (%) Ki (nM) (nM) (%) Fenfluramine 5,216 4,131 15% 4,134 3,183 Dexfenfluramine 11,107 >10,000 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 52.1 557 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 or or >10,000 or or >10,000 1,394 66% Chlorphentermine >10,000 5,370 6,456 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:
Pharmacokinetics The elimination half-life of fenfluramine has been reported as ranging from 13 to 30 hours. The mean elimination half-lives of its enantiomers have been found to be 19 hours for dexfenfluramine and 25 hours for levfenfluramine. 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.
Chemistry Fenfluramine is a substituted amphetamine and is also known as 3-trifluoromethyl-N-ethylamphetamine. It is a racemic mixture of two enantiomers, dexfenfluramine and levofenfluramine. Some analogues of fenfluramine include norfenfluramine, benfluorex, flucetorex, and fludorex.
History