Fenfluramine-Derived Drug Responsible for Deaths in France

Joe Barber Jr, PhD

February 10, 2012

February 10, 2012 — Benfluorex, a derivative of the drug fenfluramine (a component of the Fen-Phen treatment that was withdrawn from the US market in 1997), was responsible for an estimated 3100 hospitalizations and 1300 deaths in France through 2009, according to the findings of a retrospective study.

Agnès Fournier and Mahmoud Zureik, MD, from the French National Institute of Health and Medical Research in Paris, published their findings online February 9 in Pharmacoepidemiology and Drug Safety.

The authors note that although benfluorex, which was not available in the United States but was marketed in other countries under the name Mediator (Servier), was related to the drug fenfluramine, it continued to remain available in France until 2009. "As for benfluorex, its marketing authorization was suspended in France in 2009 when its implication in the appearance of valvular insufficiencies was considered convincing by the French health products safety agency, after several cases of valvular disease after benfluorex use had been spontaneously reported into the pharmacovigilance system database, and after the results regarding valvular heart disease of three epidemiological studies had been transmitted to the agency," the authors write.

Benfluorex was marketed in France for the treatment of hyperlipidemia and among overweight patients with type 2 diabetes. It was used off-label as an appetite suppressant.

Based on the findings of a previous study indicating that benfluorex use was associated with a 3.1-fold increased risk for valvular insufficiency (95% confidence interval [CI], 2.4 - 4.0) among 303,336 benfluorex users, the authors estimated that benfluorex use was associated with 3069 hospitalizations (95% CI, 2652 - 3551) resulting from valvular insufficiency between 1976 and 2009 among individuals who had consumed at least 30 boxes (equal to 900 pills). Considering that 43% of individuals diagnosed with valvular insufficiency by echocardiography die prematurely because of the disease, they attributed 1320 deaths resulting from valvular insufficiency to benfluorex use.

In this study, the authors extrapolated the number of benfluorex-attributable hospitalizations for valvular insufficiency in the period of 2006 to 2009 to the entire period of benfluorex use in France (from 1976 to 2009).The authors assumed that the risk ratio of 3.1 calculated in a study of patients with diabetes was applicable to all benfluorex users, and that it remained unchanged over time.

The authors suggest that their data underestimate the true incidence of valvular insufficiency–related hospitalization and death associated with benfluorex use. "These figures are probably underestimations, mainly because our calculation did not take into account valvular insufficiencies that occurred in individuals who consumed fewer than 30 benfluorex boxes (corresponding to 1.5 years of use, based on 1.67 box per month on average), as we lacked data on the excess risk among such individuals," the authors write. "This led us to consider almost half of the benfluorex boxes sold in France as devoid of valvular insufficiency increase in risk, whereas relatively short durations of exposure may well cause valvular disease, as suggested by studies on other fenfluramine derivatives."

The authors have disclosed no relevant financial relationships.

Pharmacoepidemiol Drug Safety. Published online February 9, 2012. Full text