Benfluorex

Last updated

Benfluorex
Benfluorex.svg
Clinical data
Trade names Mediator
AHFS/Drugs.com International Drug Names
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Excretion Kidney
Identifiers
  • (RS)-2-({1-[3-(trifluoromethyl)phenyl]propan- 2-yl}amino)ethyl benzoate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.041.601 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C19H20F3NO2
Molar mass 351.369 g·mol−1
3D model (JSmol)
Chirality Racemic mixture
  • FC(F)(F)c1cccc(c1)CC(NCCOC(=O)c2ccccc2)C
  • InChI=1S/C19H20F3NO2/c1-14(12-15-6-5-9-17(13-15)19(20,21)22)23-10-11-25-18(24)16-7-3-2-4-8-16/h2-9,13-14,23H,10-12H2,1H3 Yes check.svgY
  • Key:CJAVTWRYCDNHSM-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Benfluorex, sold under the brand name Mediator, is an anorectic and hypolipidemic agent that is structurally related to fenfluramine (a substituted amphetamine). It acts mostly as a prodrug to norfenfluramine. It was fraudulently claimed to improve glycemic control and decrease insulin resistance in people with poorly controlled type-2 diabetes through norfenfluramine acting as a 5-HT2B receptor agonist [2] [3] [4]

It was on the market between 1976 and 2009, and is thought to have caused between 500 and 2,000 deaths. [5] It was patented and manufactured by the French pharmaceutical company Servier. However, Servier is suspected of having marketed benfluorex at odds with the drug's medical properties. [6] In fact, Benfluorex acts as a prodrug to norfenfluramine, a worldwide withdrawn anorectic because of its high incidence of cardiac fibrosis [2] which is completely out of line for treating type 2 diabetes.

In 2023, a French court fined Servier €415m on appeal after finding it guilty of deception and manslaughter, as benfluorex's mechanism of action was fraudulently concealed, as Bbenfluorex was marketed after withdrawal of the any marketed fenfluramine anorectic (fenfluramine/phentermine, dexfenfluramine, clobenzorex, mefenorex, etc) because of their serious side effects like cardiac fibrosis and pulmonary hypertension (Benfluorex also shares the same side effects, but they were completely concealed, even though there was several reports of heart failure). [7]

Drug withdrawn

On 18 December 2009, the European Medicines Agency 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. [8] Thus Frachon et al. showed a higher rate of unexplained valvular heart disease in people taking benfluorex. [2] Weill et al. looked at over 1 million people with diabetes demonstrating a higher hospitalization rate in benfluorex takers for valvular heart disease. [9] In France, the medication had been marketed 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 and 2,000 deaths. [5] The drug was also used in Spain, Portugal, and Cyprus.

On March 29, 2021, a French court fined Servier €2.7m (£2.3m) after finding it guilty of deception and manslaughter, with Mediator linked to the deaths of up to 2,000 people. The former executive Jean-Philippe Seta was sentenced to a suspended jail sentence of four years. The French medicines agency, accused of failing to act quickly enough on warnings about the drug, was fined €303,000. [10] The pharmaceutical group was later additionally convicted of charges of fraud. [11]

Fenfluramine, a related drug, had been withdrawn from the market in 1997 after reports of heart valve disease, [12] [13] pulmonary hypertension, and development of cardiac fibrosis. This side effect is mediated by the metabolite norfenfluramine on 5HT2B receptors of heart valves, [14] 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.

References

  1. ↑ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  2. 1 2 3 Frachon I, Etienne Y, Jobic Y, Le Gal G, Humbert M, Leroyer C (2010). "Benfluorex and unexplained valvular heart disease: a case-control study". PLOS ONE. 5 (4) e10128. Bibcode:2010PLoSO...510128F. doi: 10.1371/journal.pone.0010128 . ISSN   1932-6203. PMC   2853566 . PMID   20405030.
  3. ↑ Moulin P, Andre M, Alawi H, dos Santos LC, Khalid AK, Koev D, et al. (March 2006). "Efficacy of benfluorex in combination with sulfonylurea in type 2 diabetic patients: an 18-week, randomized, double-blind study". Diabetes Care. 29 (3): 515–520. doi: 10.2337/diacare.29.03.06.dc05-1439 . PMID   16505498.
  4. ↑ 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 Complications. 13 (2): 62–67. doi:10.1016/S1056-8727(98)00004-X. PMID   10432168.
  5. 1 2 Schofield H (2011-01-11). "France braced for diabetic drug scandal report". BBC News.
  6. ↑ Mullard A (March 2011). "Mediator scandal rocks French medical community". Lancet. 377 (9769): 890–892. doi: 10.1016/s0140-6736(11)60334-6 . PMID   21409784. S2CID   5325085.
  7. ↑ "Affaire du Mediator : le groupe Servier condamné en appel pour escroquerie à rembourser plus de 415 millions d'euros à l'assurance-maladie et aux mutuelles". Franceinfo (in French). 20 December 2023. Retrieved 23 August 2025.
  8. ↑ "European Medicines Agency recommends withdrawal of benfluorex from the market in European Union" (PDF). European Medicines Agency. 2009-12-18. Archived from the original (PDF) on 2009-12-22. Retrieved 2015-01-12.
  9. ↑ Weill A, Païta M, Tuppin P, Fagot JP, Neumann A, Simon D, et al. (December 2010). "Benfluorex and valvular heart disease: a cohort study of a million people with diabetes mellitus". Pharmacoepidemiology and Drug Safety. 19 (12): 1256–1262. doi: 10.1002/pds.2044 . PMID   20945504. S2CID   15979457.
  10. ↑ Willsher K (29 March 2021). "French pharma firm found guilty over medical scandal in which up to 2,000 died". TheGuardian.com .
  11. ↑ "Mediator° trial appeal: a judgement that better reflects the harm done". Prescrire Int. 33 (261): 194. 2024. Retrieved 2024-08-20.
  12. ↑ Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, et al. (August 1997). "Valvular heart disease associated with fenfluramine-phentermine". The New England Journal of Medicine. 337 (9): 581–588. doi: 10.1056/NEJM199708283370901 . PMID   9271479.
  13. ↑ Weissman NJ (April 2001). "Appetite suppressants and valvular heart disease". The American Journal of the Medical Sciences. 321 (4): 285–291. doi:10.1097/00000441-200104000-00008. PMID   11307869. S2CID   46466276.
  14. ↑ Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, et al. (December 2000). "Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications". Circulation. 102 (23): 2836–2841. doi: 10.1161/01.cir.102.23.2836 . PMID   11104741.
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