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A08AA02 — Fenfluramine

ATC class and general pharmacology

ATC code A08AA02 corresponds to fenfluramine, historically classified among centrally acting anti-obesity medicines. The WHO ATC/DDD Index lists fenfluramine within A08AA and gives an oral defined daily dose of 0.12 g.atcddd.fhi

Fenfluramine is a serotonergic agent and an amphetamine derivative supplied as a racemic mixture. It was formerly used as an appetite suppressant, including in combination with phentermine, but its obesity indication was withdrawn because of serious cardiovascular toxicity at the doses then used. It has subsequently been repurposed, at substantially lower and carefully monitored doses, as an antiseizure medicine for seizures associated with Dravet syndrome and Lennox–Gastaut syndrome.pmc.ncbi.nlm.nih+1

Its pharmacodynamic effects result mainly from enhanced serotonergic neurotransmission. Fenfluramine increases extracellular serotonin by interacting with the serotonin transporter and promoting serotonin release. Fenfluramine and its active metabolite, norfenfluramine, also influence several serotonin receptor subtypes. In epilepsy, therapeutic activity is thought to involve 5-HT1D, 5-HT2A, and 5-HT2C receptor-mediated mechanisms and modulation of sigma-1 receptors; the exact antiseizure mechanism remains incompletely defined.pmc.ncbi.nlm.nih+1

After oral administration, fenfluramine has an absolute bioavailability of approximately 75–83%, reaches peak plasma concentration at about 3 hours, and is extensively metabolised to the active metabolite norfenfluramine, primarily through CYP1A2, CYP2B6, and CYP2D6. Fenfluramine has an approximate elimination half-life of 20 hours, while norfenfluramine has a half-life of about 30 hours. More than 90% of an oral dose is eliminated in urine, principally as metabolites.europa

Toxicological profile

The defining toxicological concern is serotonergic cardiovascular toxicity. Historical exposure to fenfluramine at higher doses for obesity was associated with valvular heart disease, particularly involving the mitral and aortic valves, and with pulmonary arterial hypertension. These effects are linked to serotonergic activity, including 5-HT2B receptor agonism, with norfenfluramine considered especially relevant to valvular risk.pmc.ncbi.nlm.nih+1

At current antiseizure doses, patients require baseline, periodic, and post-treatment echocardiographic surveillance. FDA product information specifies echocardiograms before treatment, every 6 months during treatment, and 3–6 months after the final dose. In controlled clinical studies and extension studies lasting up to approximately 3 years, no cases of valvular heart disease or pulmonary arterial hypertension were identified; however, these historical and mechanistic risks justify ongoing monitoring.accessdata.fda

Frequent adverse effects include reduced appetite, weight loss, diarrhoea, constipation, vomiting, fatigue, somnolence, sedation, lethargy, fever, ataxia, balance disturbance, and behavioural changes. Appetite suppression and weight reduction are clinically important because they can affect nutritional status and growth, particularly in children. In controlled trials in Dravet syndrome, decreased appetite was reported in approximately 37% of fenfluramine-treated patients, and approximately 9% experienced weight decrease as an adverse reaction.accessdata.fda

Other clinically significant toxicities include increased blood pressure, serotonin syndrome, mydriasis with potential acute angle-closure glaucoma, and possible aggravation of central nervous system depression when combined with sedatives. Concomitant use with monoamine oxidase inhibitors is contraindicated because of the risk of serotonin syndrome. Abrupt cessation should be avoided in people receiving fenfluramine for epilepsy because seizure frequency or status epilepticus may increase.accessdata.fda+1

In overdose, reported manifestations include agitation, drowsiness, confusion, flushing, tremor, hyperthermia, sweating, abdominal pain, hyperventilation, and dilated poorly reactive pupils. Management is supportive, with close monitoring for convulsions, arrhythmias, and respiratory complications.europa

Lactation pharmacology and infant exposure

There are no adequate human data defining fenfluramine concentrations in breast milk, milk-to-plasma ratios in humans, relative infant dose, infant serum concentrations, or clinical outcomes in breastfed infants exposed to maternal therapy. A review of antiseizure medicine use during breastfeeding found no identified breast-milk or infant serum concentration data for fenfluramine.onlinelibrary.wiley

Animal data demonstrate transfer of fenfluramine-related compounds into milk. In lactating rats given radiolabelled dexfenfluramine, dexfenfluramine and nordexfenfluramine were detected in milk within 2 hours. The radioactivity milk-to-plasma ratio was 9 ± 2 at 2 hours and 5 ± 1 at 24 hours. Although direct extrapolation from rats to humans is not valid, these results establish the potential for secretion of fenfluramine and/or active metabolites into milk.europa

Several pharmacokinetic features increase concern about potentially persistent infant exposure if transfer occurs: clinically relevant systemic availability after oral administration, approximately 50% plasma-protein binding, extensive maternal metabolism to pharmacologically active norfenfluramine, and long elimination half-lives of approximately 20 hours for fenfluramine and 30 hours for norfenfluramine.europa

A breastfed infant could theoretically experience serotonergic and central nervous system effects, including sedation or unusual sleepiness, poor feeding, reduced appetite, irritability, vomiting or diarrhoea, tremor, altered muscle tone, tachycardia, blood-pressure effects, and impaired weight gain. These potential effects are extrapolated from known pharmacology and toxicity rather than documented infant cases. The absence of human exposure data is therefore a major evidence limitation rather than evidence of lactational safety.

Lactological safety assessment and clinical recommendations

Fenfluramine should be regarded as a medicine requiring individualized specialist risk–benefit assessment during breastfeeding. Current European product information states that it is unknown whether fenfluramine or its metabolites are excreted in human milk, that animal data show milk excretion, and that a risk to the suckling child cannot be excluded. It advises a decision between discontinuing breastfeeding and discontinuing or avoiding therapy, taking account of both the benefits of breastfeeding and the clinical benefit of treatment for the mother.europa

Routine use during breastfeeding is not preferred when treatment can reasonably be postponed, particularly for a newborn, preterm infant, medically fragile infant, or an infant with impaired drug clearance. A non-pharmacological or better-characterised treatment option should be considered whenever clinically suitable. This is especially relevant when fenfluramine would be used for weight management, an indication for which maternal treatment can usually be deferred until after breastfeeding.

However, for a mother with severe epilepsy, particularly Dravet syndrome or Lennox–Gastaut syndrome, abruptly stopping or withholding an effective antiseizure medicine may create substantial maternal risk. Maternal seizure control, safety, capacity to care for the infant, and the risk of seizure recurrence must be weighed against the uncertain risk from milk exposure. Fenfluramine used for epilepsy should not be stopped suddenly solely because of lactation concerns; dose reduction and discontinuation require supervision by the treating epilepsy specialist.accessdata.fda+1

When continued breastfeeding is chosen despite the uncertainty, management should involve the prescriber, a paediatrician, and a lactation pharmacology specialist. Clinical surveillance of the infant should include:

• Sedation, lethargy, poor arousal, or altered sleep pattern
• Poor suck, feeding difficulty, vomiting, diarrhoea, or reduced appetite
• Irritability, agitation, tremor, or unusual neurological behaviour
• Inadequate weight gain or poor growth trajectory
• Tachycardia, pallor, sweating, breathing difficulty, or other autonomic symptoms

Prompt paediatric assessment is warranted for marked sedation, feeding refusal, persistent vomiting or diarrhoea, tremor, unexplained irritability, poor weight gain, rapid heartbeat, or respiratory symptoms. No evidence-based interval for “pump and dump” or for timing feeds around dosing can currently be recommended, because no human milk pharmacokinetic data are available and the parent compound and active metabolite have prolonged elimination.