Fenfluramine-like cardiovascular side-effects of benfluorex

Boutet, Kim; Frachon, Irène; Jobic, Yannick; Gut-Gobert, Christophe; Leroyer, Christophe; Carlhant-Kowalski, D.; Sitbon, Olivier; Simonneau, Gérald; Humbert, Marc

doi:10.1183/09031936.00086308

Cited by 69 publications

(45 citation statements)

References 19 publications

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“…In recent years, this database has facilitated the study of PAH occurring in patients exposed to fenfluramine or fenfluramine derivatives such as dexfenfluramine and benfluorex. [33][34][35] The number of patients in France treated by dasatinib was relatively small at the time of our report (Ͻ3000). Thus, the occurrence of 9 incident cases of severe precapillary PH in dasatinib-exposed individuals between 2008 and 2010 in our registry plus 4 additional cases reported at the French pharmacovigilance level indicated that this complication may affect at least 0.45% of chronically dasatinib-exposed individuals.…”

Section: Discussionmentioning

confidence: 99%

Pulmonary Arterial Hypertension in Patients Treated by Dasatinib

et al. 2012

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Background-The French pulmonary hypertension (PH) registry allows the survey of epidemiological trends. Isolated cases of precapillary PH have been reported in patients who have chronic myelogenous leukemia treated with the tyrosine kinase inhibitor dasatinib. Methods and Results-This study was designed to describe incident cases of dasatinib-associated PH reported in the French PH registry. From the approval of dasatinib (November 2006) to September 30, 2010, 9 incident cases treated by dasatinib at the time of PH diagnosis were identified. At diagnosis, patients had moderate to severe precapillary PH with functional and hemodynamic impairment. No other incident PH cases were exposed to other tyrosine kinase inhibitors at the time of PH diagnosis. Clinical, functional, or hemodynamic improvements were observed within 4 months of dasatinib discontinuation in all but 1 patient. Three patients required PH treatment with endothelin receptor antagonist (nϭ2) or calcium channel blocker (nϭ1). After a median follow-up of 9 months (min-max 3-36), the majority of patients did not demonstrate complete clinical and hemodynamic recovery, and no patients reached a normal value of mean pulmonary artery pressure (Յ20 mm Hg). Two patients (22%) died at follow-up (1 of unexplained sudden death and 1 of cardiac failure in the context of septicemia, respectively, 8 and 12 months after dasatinib withdrawal). The lowest estimate of incident PH occurring in patients exposed to dasatinib in France was 0.45%. Conclusions-Dasatinib may induce severe precapillary PH fulfilling the criteria of pulmonary arterial hypertension, thus suggesting a direct and specific effect of dasatinib on pulmonary vessels. Improvement is usually observed after withdrawal of dasatinib. (Circulation. 2012;125:2128-2137.)

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Section: Discussionmentioning

confidence: 99%

Pulmonary Arterial Hypertension in Patients Treated by Dasatinib

et al. 2012

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“…Benfluorex was not marketed as an anorexigen, therefore, it could evade the restrictions imposed in late 1990s after the proven association between fenfluramine derivatives and PAH or cardiac valvular diseases. In 2009, a case series provided evidence of possible cardiotoxic effects of benfluorex [17]. In addition, a case-control study demonstrated that benfluorex is associated with valvular heart diseases, and premature deaths [18].…”

Section: Benfluorexmentioning

confidence: 99%

Drug-induced pulmonary arterial hypertension: a recent outbreak

Montani¹,

Seferian²,

Savale³

et al. 2013

Eur Respir Rev

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Pulmonary arterial hypertension (PAH) is a rare disorder characterised by progressive obliteration of the pulmonary microvasculature resulting in elevated pulmonary vascular resistance and premature death. According to the current classification PAH can be associated with exposure to certain drugs or toxins, particularly to appetite suppressant intake drugs, such as aminorex, fenfluramine derivatives and benfluorex. These drugs have been confirmed to be risk factors for PAH and were withdrawn from the market. The supposed mechanism is an increase in serotonin levels, which was demonstrated to act as a growth factor for the pulmonary artery smooth muscle cells. Amphetamines, phentermine and mazindol were less frequently used, but are considered possible risk factors, for PAH. Dasatinib, dual Src/Abl kinase inhibitor, used in the treatment of chronic myelogenous leukaemia was associated with cases of severe PAH, potentially in part reversible after dasatinib withdrawal. Recently, several studies have raised the issue of potential endothelial dysfunction that could be induced by interferon, and a few cases of PAH have been reported with interferon therapy. PAH remains a rare complication of these drugs, suggesting possible individual susceptibility, and further studies are needed to identify patients at risk of drug-induced PAH. @ERSpublications Drug-associated PAH remains a clinical challenge: understanding the mechanisms and identifying drugs at-risk for PAH

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“…However, benfluorex was not subjected to the same restrictions as the fenfluramine derivatives in 1997 in France, at least in part because it was approved as an agent for the treatment of diabetes and the metabolic syndrome and not an anorexigen. As a result, and in spite of case reports, benfluorex remained available in France until November 2009, until compelling data were brought from a case-control study by FRACHON et al [15] that highlighted the potential cardiotoxic effects, even though benfluorex had been withdrawn from commercial use in other European countries several years previously [15,16] We have previously reported a small series of patients with PAH that had prior exposure to benfluorex [17]. The aim of the current study was to establish the clinical and haemodynamic characteristics and outcomes of patients identified by the French Network of Pulmonary Hypertension with prior exposure to benfluorex and confirmed PH.…”

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confidence: 99%

Pulmonary hypertension associated with benfluorex exposure

Savale¹,

Chaumais²,

Cottin³

et al. 2012

Eur Respir J

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Benfluorex was marketed in France until 2009, despite its similar pharmacological properties with fenfluramine and its derivatives known to be a cause of pulmonary arterial hypertension (PAH).The aim of this study is to report clinical and haemodynamic characteristics for patients suffering from pulmonary hypertension (PH) associated with benfluorex exposure that had been identified by the French PAH Network.85 cases of PH associated with benfluorex exposure were identified by the French PAH Network from June 1999 to March 2011. Of these, 70 patients had confirmed pre-capillary PH. The median duration of exposure was 30 months, with a median of 108 months between start of exposure and diagnosis of the pulmonary vascular disease. 33% of all patients also had prior exposure to fenfluramine or dexfenfluramine, and an additional risk factor for PH was identified in 20 (30%) out of 70 patients with pre-capillary PH. A quarter of patients in this current series showed coexisting PH and mild-to-moderate cardiac valve involvement.The results of our study, together with the accumulated data regarding the known toxic effects of fenfluramine and dexfenfluramine, strongly suggest that benfluorex exposure is a potent trigger for PAH.

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Fenfluramine-like cardiovascular side-effects of benfluorex

Cited by 69 publications

References 19 publications

Pulmonary Arterial Hypertension in Patients Treated by Dasatinib

Pulmonary Arterial Hypertension in Patients Treated by Dasatinib

Drug-induced pulmonary arterial hypertension: a recent outbreak

Pulmonary hypertension associated with benfluorex exposure

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