On 18 December 2009, the European Medicines Agency (EMEA) recommended the withdrawal of all medicines containing benfluorex in the European Union, because their risks, particularly the risk of heart valve disease (fenfluramine-like cardiovascular side-effects), are greater than their benefits. Thus Frachon et al. showed a significantly higher prevalence of unexplained valvular heart disease in patients taking benfluorex compared to controls. and Weill et al. looked at over 1 million diabetic patients demonstrating a higher hospitalization rate in benfluorex takers for valvular heart disease.
In France the medication had been marketed as by Servier as an adjuvant antidiabetic under the name Mediator. The drug was on the market between 1976 and 2009 and is thought to have caused between 500 – 2,000 deaths. The drug was also used in Spain (trade name, Modulator), Portugal and Cyprus.
Fenfluramine, a related drug, had been withdrawn from the market in 1997 after reports of heart valve disease,pulmonary hypertension, and development of cardiac fibrosis. This side effect is mediated by the metabolite norfenfluramine on 5HT2B receptors of heart valves (Rothman et al., Circulation 2000), leading to a characteristic pattern of heart failure following proliferation of cardiac fibroblasts on the tricuspid valve. Both fenfluramine and benfluorex form norfenfluramine as a metabolite. This side effect led to the withdrawal of fenfluramine as an anorectic drug worldwide, and later to the withdrawal of benfluorex in Europe.
^Roger, P.; Auclair, J.; Drain, P. (1999). "Addition of Benfluorex to Biguanide Improves Glycemic Control in Obese Non-Insulin-Dependent Diabetes: A Double-Blind Study versus Placebo". Journal of Diabetes and its Complications13 (2): 62–67. doi:10.1016/S1056-8727(98)00004-X. PMID10432168.
^Weill, A.; Païta, M.; Tuppin, P.; Fagot, J. P.; Neumann, A.; Simon, D.; Ricordeau, P.; Montastruc, J. L.; Allemand, H. (2010). "Benfluorex and Valvular Heart Disease: A Cohort Study of a Million People with Diabetes Mellitus". Pharmacoepidemiology and Drug Safety19 (12): 1256–1262. doi:10.1002/pds.2044. PMID20945504.edit
10. Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, Roth BL.(2000). "Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications." Circulation 102(23):2836-41. PMID: 11104741