Treating rare inborn errors of metabolism: From theory to practice

2013 e117 of similar structural and pharmacologic characteristics, such as fenfluramine and dexfenfluramine (brand names Ponderal, Isomeride; Servier, Redux; Wyeth) have been withdrawn from the world market since 1997. Indeed, these compounds, derived from the amphetamines, are known to be responsible for pulmonary arterial hypertension (PAH) and valvular heart disease (VHD). Subsequent studies published in 2000 have shown the determinant role of their common active metabolite, norfenfluramine, which is present at equal plasma concentrations after fenfluramine, dexfenfluramine, or benfluorex intake at recommended dosages. Norfenfluramine induces VHD and PAH by stimulation of a serotonin receptor subtype, expressed on both aortic and mitral valve leaflets as well as in pulmonary arteries. Despite several case reports stressing the association of PAH and/or VHD with benfluorex exposure, benfluorex remained available in France until November 2009. Our initial case-control study published in 2010 put forward the toxicity and the VHD risk of benfluorex, thus leading to the withdrawal of benfluorex from the European and world market, respectively. This pilot study opened the avenue to further pharmacoepidemiologic studies validating our results and giving detailed data on the benfluorex risks in larger populations. Actual human consequences of longer than 33 years of marketing authorization of benfluorex on patients only in France are estimated at ~1300 to 1800 deaths and 3100 to 4200 VHD-related hospitalizations. To date, there is no estimation of worldwide mortality due to benfluorex use. Disclosure of Interest: None declared.