[3][7][4] 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.
[8][10][11] 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.
[12] 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.
[8] 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.
[7] At higher therapeutic doses, headache, diarrhea, dizziness, dry mouth, erectile dysfunction, anxiety, insomnia, irritability, lethargy, and CNS stimulation have been reported with fenfluramine.
One mechanism used to explain this phenomenon involves heart valve serotonin receptors, which are thought to help regulate growth.
[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.
For all ex-users, there was a 7-fold increase of chances of needing surgery for faulty heart valves caused by the drug.
[40] The drug also acts as a norepinephrine releasing agent (NRA) to a lesser extent, particularly via its active metabolite norfenfluramine.
[43] 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.
[8] In the early 1990s, French researchers reported an association of fenfluramine with primary pulmonary hypertension and dyspnea in a small sample of patients.
[8] Fenfluramine was withdrawn from the U.S. market in 1997 after reports of heart valve disease[48][16] and continued findings of pulmonary hypertension, including a condition known as cardiac fibrosis.
[8] In June 2020, fenfluramine was approved for medical use in the United States with an indication to treat Dravet syndrome.
[7][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.
[55] Unlike various other amphetamine derivatives, fenfluramine is reported to be dysphoric, "unpleasantly lethargic", and non-addictive at therapeutic doses.
[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.
[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.