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Litigation trends in the EU, EU Member States, and UK
Published in Andrea Parziale, The Law of Off-label Uses of Medicines, 2023
Among the factors to be considered in assessing product defectiveness, Article 6 PLD also mentions the product “presentation”. In particular, the information and warnings included in the medicinal product’s leaflet directly shape consumers’ safety expectations. Thus, the lack of information on an adverse reaction may establish product defectiveness, sometimes referred to as an information or warning defect. This may also apply to adverse reactions to off-label uses. Indeed, the French Mediator case law mostly found the product defective due to lack of information and warnings for the public. Several decisions estimated that, by the time Mediator was administered to the victim (i.e., in 2003 and 2006), the risks of pulmonary arterial hypertension and valvulopathies induced by benfluorex could not be ignored in light of the state of scientific knowledge. Consequently, the manufacturer should have informed patients and physicians about such suspected risks.
Lifestyle and Diet
Published in Chuong Pham-Huy, Bruno Pham Huy, Food and Lifestyle in Health and Disease, 2022
Chuong Pham-Huy, Bruno Pham Huy
In France, benfluorex (Mediator®), a derivative of amphetamine or fenfluramine, used in the therapy of Type 2 diabetes, hyperlipidemia and obesity since 1976, was withdrawn from circulation in 2009 because of its side effects on cardiac valves. The number of victims of Mediator® is about 2,000 deaths in France and some 10,000 patients having valvular heart disease caused by this prescription drug during its tumultuous 33 years on the market (149).
Towards precision medicine
Published in Yann Joly, Bartha Maria Knoppers, Routledge Handbook of Medical Law and Ethics, 2014
In 2009, French regulators withdrew Mediator (benfluorex), a drug licensed for diabetes but used off-label for weight loss, which caused between 500 and 2,000 deaths over a period of 33 years (Mullard 2011). The recent French law, Loi n° 2011-2012 du 29 décembre 2011 relative au renforcement de la sécurité sanitaire du médicament et des produits de santé (Loi n° 2011-2012 du 29 décembre 2011), aims to improve risk-benefit management and provide a better regulatory process for off-label prescriptions. Applicants under this law can apply only for diseases with severe prognosis and must follow strict criteria concerning the quality of scientific evidence and drug safety, but they may claim reimbursement from France’s public health insurance system if the drug is approved (Loi n°2011-2012 du 29 décembre 2011, articles 15 and 18.2.4). Off-label marketing authorization is granted for a period of three years (Loi n°2011-2012 du 29 décembre 2011, article 18.1).
A transcriptional regulatory network of HNF4α and HNF1α involved in human diseases and drug metabolism
Published in Drug Metabolism Reviews, 2022
Jianxin Yang, Xue Bai, Guiqin Liu, Xiangyang Li
HNF4A mutations cause pancreatic β-cell dysfunction, induce MODY1 (Yamagata et al. 1996), and may promote the development of type 2 diabetes (Gupta and Kaestner 2004). The mechanism might be due to the mutated HNF4α protein losing its ability to bind the HNF4α binding site, consequently leading to the abnormal expression of genes during glucose transport and glycolysis, and affecting the enterohepatic circulation of glucose and uptake into liver cells and insulin secretion by pancreatic β-cell (Stoffel and Duncan 1997; Gupta et al. 2005). To date, the Human Gene Mutation Database (HGMD) has reported more than 100 HNF4A mutations, of which single amino acid mutations are directly associated with MODY1 phenotypes. Several rare phenotypes, including hyperinsulinemia, hypoglycemia, and renal Fanconi syndrome, are also associated with HNF4A mutations (Cubuk and Yalcin 2021). Moreover, alverine and benfluorex are agonists of HNF4α, and these are well-known drugs that have been used to treat irritable bowel syndrome and type 2 diabetes, respectively (Lee et al. 2013). Benfluorex has been studied in clinical trials for type 2 diabetes and was proven to be effective in reducing hemoglobin A1c (Del et al. 2003; Moulin et al. 2006). Therefore, HNF4α agonists might be potential drugs to treat some metabolic diseases, such as diabetes, dyslipidemia, and cholestasis (Chiang 2009).
The safety of pharmacologic treatment for pediatric obesity
Published in Expert Opinion on Drug Safety, 2018
Ariana M. Chao, Thomas A. Wadden, Robert I. Berkowitz
Several medications tested in pediatric and adult samples have been withdrawn from the market due to serious adverse events. For example, sibutramine, a serotonin and norepinephrine reuptake inhibitor, was effective when combined with a family-based lifestyle program in inducing and maintaining weight loss in adolescents with obesity [10,11]. The medication also was associated with improved cardiometabolic risk factors. However, the drug was withdrawn from the market in 2010 because of findings that it increased the risk of non-fatal myocardial infarction and nonfatal stroke in adults with a history of cardiovascular disease [12]. Other medications, such as fenfluramine, benfluorex, dexfenfluramine, and rimonabant have also been withdrawn due to concerns about cardiovascular and psychiatric effects [13–17]. Thus, there is heightened concern about the potential toxicity of weight loss medications.
Drug-induced retroperitoneal fibrosis: a case/non-case study in the French PharmacoVigilance Database
Published in Expert Opinion on Drug Safety, 2020
Diana Brasselet, Laurent Chouchana, Thierry Vial, Marlène Damin-Pernik, Bénédicte Lebrun-Vignes
The association between beta-blockers and RPF is currently not well established. Various cases were published in the 70s and 80s [64–66]. Some authors suggested that beta-blockers were probably being used to treat hypertension associated with RPF rather than to induce directly RPF [67]. Indeed, hypertension induced by RPF is probably diagnosed and treated by antihypertensive drugs before the underlying disease diagnose. The hypothesis of a protopathic bias (and also a notoriety bias, for the same reasons as DEA) could explain the important signal found with beta-blockers and especially because beta-blockers indication in our study is always hypertension excepting for one patient with a medical history of myocardial infarction and probable heart failure. However, in our study patients treated by antihypertensive drugs including beta-blockers were not more affected by ureteral obstruction. This does not support the protopathic bias hypothesis. A significant disproportionality was also found with other antihypertensive drugs – e.g. diuretics, agents acting on the renin-angiotensin system and lipid-modifying agents, platelet antiaggregants, and antidiabetic drugs. Except for some cases described in the 70s and 80s with prolonged treatment of an analgesic dose of aspirin [68] and a case reported with hydrochlorothiazide [69] there is no association between these drugs and RPF occurrence in literature. It should be noted that benfluorex has a known risk of valvular lesions explained by 5-HT2B serotonin receptor activation by one of its metabolites, norfenfluramine. Lugosi and al. describe that near than half patients with RPF have at least two cardiovascular risk factors [57] that could explain the use of these drugs in patients with RPF even if the absence of a significant signal found with calcium antagonists limits this hypothesis.