Fenfluramine

Fenfluramine is a serotonergic medication, chemically a substituted amphetamine, that has had two very different careers in medicine ^[1][2]. Introduced in the 1960s and 1970s, it was marketed as an appetite suppressant and became extremely popular in the 1990s as half of the 'fen-phen' weight-loss combination with phentermine ^[2]. That popularity ended abruptly in 1997, when the drug was withdrawn from the United States market after it was tied to serious heart valve disease and pulmonary hypertension ^[2].

The cardiac danger was documented in a well-known case series describing valvular heart disease in women treated with fenfluramine and phentermine, whose damaged valves resembled those seen in carcinoid disease ^[2]. The injury was later understood to arise from serotonin acting on receptors in heart valve tissue, and this history is why any modern use of the drug now involves careful heart monitoring ^[1].

Decades later, fenfluramine was repurposed for epilepsy after observations that it could reduce seizures. In a randomized, placebo-controlled trial in children with Dravet syndrome, a rare and severe developmental epileptic encephalopathy, fenfluramine added to existing therapy produced a large reduction in convulsive seizure frequency, and echocardiograms during the trial showed no valve disease or pulmonary hypertension at the doses studied ^[1]. On the strength of such evidence it was approved around 2020 under the brand name Fintepla for seizures in Dravet syndrome and later Lennox-Gastaut syndrome, and expert consensus now lists it among the recommended add-on therapies for Dravet syndrome ^[1][3]. A network meta-analysis found it to be one of the more effective add-on options for convulsive seizures in that condition ^[4].

Fenfluramine is a prescription-only medicine. In the United States it had been a Schedule IV controlled substance and was removed from that schedule in December 2022 ^[2]. It is given as an oral solution, and its labeling still carries a warning about valvular heart disease and pulmonary hypertension, so patients undergo periodic echocardiographic monitoring ^[1].

This is the drug that taught cardiology about serotonin and heart valves. At the old diet-drug doses it caused valvulopathy and pulmonary hypertension; the modern epilepsy use is at lower doses with mandatory echocardiogram monitoring for exactly that reason. It also carries appetite-suppression and the usual serotonergic cautions (do not combine with MAOIs or other strong serotonergics). Prescription only, and its history is the whole point of the caution.

The contraindication carrying the most weight is with monoamine oxidase inhibitors. Fenfluramine releases serotonin, and use within fourteen days of an MAOI can cause serotonin syndrome. The same serotonergic mechanism underlies the drug's association with valvular heart disease and pulmonary arterial hypertension, risks that other serotonergic agents may compound.

Fenfluramine is metabolized mainly by CYP1A2, CYP2B6 and CYP2D6. Paroxetine, a strong CYP2D6 inhibitor, raises fenfluramine exposure by about 81 percent, and strong CYP1A2 inhibitors such as fluvoxamine act similarly. Strong inducers of CYP1A2, CYP2B6 or CYP3A, including rifampin and carbamazepine, push concentrations down and can cost seizure control.

The combination seen most often in practice is with stiripentol, clobazam and valproate. In a healthy-volunteer crossover study, that three-drug regimen moderately raised fenfluramine Cmax and AUC while lowering exposure to norfenfluramine, its major metabolite; fenfluramine did not meaningfully alter any of the three. Agents that block 5-HT2 receptors, cyproheptadine among them, may reduce its anticonvulsant effect.

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