Actions and spectrum: 

fenfluramine is a serotonergic drug that is used in the treatment of obesity as an appetite suppressant. It acts as a selective serotonin-releasing agent (SSRA) and indirectly increases the levels of serotonin in the brain.

This results in reduced food intake and increased satiety, leading to weight loss. fenfluramine also has mild sympathomimetic effects, leading to increased metabolic rate and energy expenditure. 

However, fenfluramine was withdrawn from the market in the late 1990s due to the discovery of its association with heart valve disease and pulmonary hypertension, which led to serious health complications and even death in some cases. As a result, fenfluramine is no longer used as a therapeutic agent. 

DRUG INTERACTION

Frequency defined 

>10% 

Dravet syndrome 

• Decreased appetite (23-49%) 
• Fatigue, malaise, asthenia (15-30%) 
• Abnormal ECHO (9-23%) 
• Upper respiratory tract infection (5-21%) 
• Drooling, salivary hypersecretion (8-13%) 
• Status epilepticus (3-12%) 

Lennox-Gastaut syndrome 

• Decreased appetite (20-36%) 
• Somnolence, sedation, lethargy (12-22%) 
• Vomiting (8-14%) 
• Fatigue, malaise, asthenia (14-24%) 
• Diarrhea (11-13%)

1-10% 

Dravet syndrome 

• Fall (10%) 
• Vomiting (5-10%) 
• Decreased blood glucose (9%) 
• Ear infection (3-9%) 
• Tremor (3-9%) 
• Hypotonia (8%) 
• Rash (5-8%) 
• Gastroenteritis (2-8%) 
• Decreased activity (5%) 
• Insomnia (5%) 
• Contusion (5%) 
• Enuresis (5%) 
• Negativism (5%) 
• Viral infection (5%) 
• Increased heart rate (3-5%) 
• Chills (2-5%) 
• Ataxia (7-10%) 
• Constipation (3-10%) 
• Abnormal behavior (8-9%) 
• Irritability (3-9%) 
• Bronchitis (3-9%) 
• Headache (8%) 
• Rhinitis (3-8%) 
• Blood prolactin increased (5%) 
• Dehydration (5%) 
• Stereotypy (5%) 
• Eczema (5%) 
• Laryngitis (5%) 
• Urinary tract infection (5%) 
• Croup (3-5%) 
• Urinary incontinence (3-5%)

Lennox-Gastaut syndrome 

• Constipation (6-9%) 
• Upper respiratory tract infection (7-8%) 
• Weight decreased (2-8%) 
• Seizure (5-9%) 
• Irritability (3-8%) 

Black Box Warning: 

fenfluramine has been withdrawn from the market due to serious adverse events. In 1997, the US FDA requested the withdrawal of fenfluramine and dexfenfluramine, both appetite suppressants, from the market due to evidence of their association with valvular heart disease and pulmonary hypertension.

The FDA also warned against the use of fenfluramine with other weight loss drugs, such as phentermine, which can increase the risk of these adverse events. 

Contraindication/Caution: 

Contraindication: 

• Hypersensitivity: fenfluramine is contraindicated in patients with a history of hypersensitivity to fenfluramine or any of its components. 
• Pulmonary hypertension: fenfluramine is contraindicated in patients with primary pulmonary hypertension or pulmonary arterial hypertension. 
• Concurrent use of serotonergic drugs: fenfluramine is contraindicated in patients receiving concurrent treatment with other serotonergic drugs, such as serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and lithium. 
• History of heart valve disease: fenfluramine is contraindicated in patients with a history of heart valve disease or pulmonary hypertension associated with valvular heart disease. 
• Pregnancy: fenfluramine is contraindicated during pregnancy as it may harm the developing fetus.

Caution: 

• Serotonin syndrome: fenfluramine acts on the serotonin system and can cause serotonin syndrome when combined with other medications that also affect serotonin levels. 
• Pulmonary hypertension: fenfluramine has been associated with the development of pulmonary hypertension, a serious and life-threatening condition in which blood pressure in the lungs is elevated. 
• Cardiac valve disease: fenfluramine has been associated with the development of cardiac valve disease, which can lead to heart failure. 
• Depression: fenfluramine has been linked to depression in some patients, and caution is recommended in patients with a history of depression or other psychiatric disorders. 
• Use in pregnancy and breastfeeding: fenfluramine is not recommended in pregnant or breastfeeding women, as its safety and efficacy have not been established.

Comorbidities: 

fenfluramine is a medication that was previously used for weight loss, but it was withdrawn from the market due to safety concerns. The use of fenfluramine is contraindicated in patients with a history of pulmonary arterial hypertension (PAH) and in those who have used a monoamine oxidase inhibitor (MAOI) within 14 days.

The medication should be used with caution in patients having a history of valvular heart disease, pulmonary hypertension, or other cardiac conditions. 

Pregnancy consideration: pregnancy category C 

Lactation: safety and efficacy not established 

Pregnancy category: 

• Category A: Satisfactory and well-controlled studies show no risk to the fetus in the first or later trimester. 
• Category B: There is no evidence of risk to the fetus found in animal reproduction studies and there are not enough studies on pregnant women. 
• Category C: Adverse effects on the fetus found with evidence in animal reproduction studies and no adequate evidence for an effect in humans, care must be taken for potential risks in pregnant women 
• Category D: There is adequate data available with sufficient evidence of human fetal risk from various platforms, but despite potential risks may be used only in emergency cases for potential benefits. 
• Category X: Drugs listed in this category outweigh risks over benefits These category drugs should be prohibited for pregnant women. 
• Category N: There is no data available for the drug under this category. 

Pharmacology: 

fenfluramine is a serotonin-releasing agent that works by increasing the release of serotonin in the brain. It is believed to act on serotonergic neurons in the hypothalamus and cortex, causing an increase in serotonin release. This leads to a reduction in appetite, which is the desired effect for its use in the treatment of obesity. 

fenfluramine also has some activity as a dopamine and norepinephrine-releasing agent, although this activity is much weaker than its serotonin-releasing effects. Additionally, it can act as a weak inhibitor of serotonin and norepinephrine reuptake.  

Pharmacodynamics: 

fenfluramine is a centrally acting serotoninergic agent. It exerts its pharmacodynamic effects by increasing the release of serotonin, a neurotransmitter that is involved in regulating mood, appetite, and other physiological processes. fenfluramine acts as a selective serotonin-releasing agent (SSRA), which means that it enhances the release of serotonin from presynaptic neurons. 

fenfluramine has been found to cause a decrease in appetite and subsequent weight loss. fenfluramine has also been shown to have some sedative and anxiolytic effects, which may be due to its modulation of serotonin levels in the brain. 

fenfluramine has been used in the treatment of obesity and, in combination with phentermine, as a weight-loss medication. However, its use has been discontinued due to concerns over its association with cardiac valvulopathy, a condition characterized by the thickening and narrowing of heart valves.  

Pharmacokinetics: 

Absorption 

fenfluramine is well absorbed from the gastrointestinal tract, with peak plasma concentrations achieved within 2 to 4 hours after oral administration. The bioavailability of fenfluramine is reported to be about 60%. However, its absorption can be affected by the presence of food, which can delay the time to reach peak plasma concentration and reduce its bioavailability.  

Distribution 

fenfluramine is rapidly and extensively distributed throughout the body following oral administration. The plasma protein binding of fenfluramine is moderate, 60-70%. fenfluramine crosses the blood-brain barrier and placenta and is also secreted into breast milk.  

Metabolism 

fenfluramine is extensively metabolized in the liver via N-dealkylation, resulting in the formation of its major active metabolite, norfenfluramine, and several inactive metabolites. Norfenfluramine has a longer half-life than fenfluramine and is responsible for most of the anorectic effect of fenfluramine.

The metabolism of fenfluramine is primarily mediated by the cytochrome P450 (CYP) enzyme system, particularly CYP3A4, and CYP2B6. fenfluramine and its metabolites are excreted in the urine, with only small amounts eliminated in the feces.  

Elimination and excretion 

fenfluramine is metabolized in the liver by N-dealkylation and deamination processes, and the major metabolite, norfenfluramine, is also pharmacologically active. The elimination half-life of fenfluramine is about 20 to 30 hours. The drug and its metabolites are excreted primarily in the urine, with about 60% of a dose recovered within 72 hours. 

Administration: 

fenfluramine is no longer available for medical use due to safety concerns related to cardiovascular and pulmonary toxicity. It was previously administered orally in the form of tablets or capsules, typically two to three times a day, as prescribed by a healthcare provider. 

Patient information leaflet 

Generic Name: fenfluramine 

Pronounced: [ fen-flur-a-meen ]  

Why do we use fenfluramine? 

fenfluramine was previously used as an appetite suppressant for weight loss in obese patients. However, it was withdrawn from the market due to serious concerns about its safety, including the risk of pulmonary hypertension and heart valve damage. Currently, fenfluramine is not approved for any medical use in most countries.