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Fenfluramine, sold under the brand name Fintepla, is a Serotonin medication used for the treatment of 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 combination drug with phentermine commonly known as fen-phen.
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, pyrexia, 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 receptor 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 In the 1990s, fenfluramine came to be associated with cardiovascular toxicity, and because of this, was withdrawn drug from the United States market in 1997.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.
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
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 psychostimulant 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 Serotonin neurotoxicity/depletion of serotonin with chronic administration or activation of serotonin 5-HT2A 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.
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| Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. The bioassay were done in rat brain 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 releasing agent of serotonin by disrupting synaptic vesicle 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. (2025). 9780444532350, Elsevier. ISBN 9780444532350 The result of the increased Serotonin 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-. However, psychedelic drug effects and have occasionally been reported when large doses of fenfluramine are taken. Similarly to the psychedelic amphetamine DOI, it is the Stereochemistry (Levofenfluramine) that is more likely to elicit psychedelia, this also holds true for 3,4-Methylenedioxyamphetamine (MDA)
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.
In the early 1990s, French researchers reported an association of fenfluramine with primary pulmonary hypertension and dyspnea in a small sample of patients. Fenfluramine was withdrawn from the U.S. market in 1997 after reports of heart valve disease and continued findings of pulmonary hypertension, including a condition known as cardiac fibrosis. It was subsequently withdrawn from other markets around the world. It was banned in India in 1998.
Fenfluramine was an anorectic which was used to treat obesity. It was used both on its own and, in combination with phentermine, as part of the anti-obesity medication Fen-Phen.
In June 2020, fenfluramine was approved for medical use in the United States with an indication to treat Dravet syndrome.
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. The studies measured the change from baseline in the frequency of convulsive seizures. 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). These reductions were seen within 3–4 weeks, and remained generally consistent over the 14- to 15-week treatment periods.
The U.S. Food and Drug Administration (FDA) granted the application for fenfluramine priority review and orphan drug designations. The FDA granted approval of Fintepla to Zogenix, Inc.
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. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. Fenfluramine was approved for medical use in the European Union in December 2020.
Fenfluramine has been found to produce acute effects in humans including decreased arousal, Happiness, and positive mood, decreased anxiety at lower doses and increased anxiety at higher doses, drug liking, mental confusion, reduced psychomotor performance, reduced impulsivity, and decreased aggression. Whereas fenfluramine alone decreases positive mood and phentermine alone increases positive mood similarly to amphetamine, the combination drug of fenfluramine and phentermine results in a neutral impact on mood. Similarly fenfluramine diminishes the subjective effects of phentermine and amphetamine. In contrast to other serotonin releasers like MDMA and mephedrone, fenfluramine does not produce euphoria. The differing effects with fenfluramine may be attributable to its lack of concomitant dopamine release and its potent serotonin 5-HT2C receptor agonist via its metabolite norfenfluramine.
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