Fenfluramine-associated pulmonary hypertension: a study of adverse events reporting system FAERS

Extract Fenfluramine is an amphetamine derivative first available in 1963 in France and 1973 in US as an appetite suppressant. Fenfluramine is a chiral molecule and has been marketed as a racemate (Pondimin) or a d-enantiomer, dexfenfluramine (Isomeride, Redux). Fenfluramine and its active metabolite, norfenfluramine, are 5-HT1B, 5-HT2C and 5-HT2B receptor agonists, increasing serotonergic transmission. Cardiovascular toxicity of fenfluramine is thought to result from excessive serotonergic stimulation, notably through activation of 5-HT2B receptors [1]. After a worldwide use of 30 to 40 years and 50 million patients exposed, both fenfluramine and dexfenfluramine were withdrawn from the US and French market in 1997 due to serious cardiovascular adverse effects. Indeed, the International Primary Pulmonary Hypertension Study notably demonstrated an increased risk of primary pulmonary hypertension, now known as idiopathic pulmonary arterial hypertension (PAH), and was followed by reports of valvular heart disease in fenfluramine users [2–4]. A third related drug, benfluorex, which shares norfenfluramine as a metabolite, remained available for several years in France but was finally withdrawn in 2009 for the same reasons [5, 6].