Benfluorex

Benfluorex, sold under the brand name Mediator, is an anorectic and hypolipidemic agent that is structurally related to fenfluramine (a substituted amphetamine). It acts solely 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]

Benfluorex

Clinical data
Trade names	Mediator
AHFS/Drugs.com	International Drug Names
Routes of administration	By mouth
ATC code	A10BX06 (WHO)
Legal status
Legal status	BR: Class C1 (Other controlled substances)[1]
Pharmacokinetic data
Excretion	Kidney
Identifiers
IUPAC name (RS)-2-({1-[3-(trifluoromethyl)phenyl]propan- 2-yl}amino)ethyl benzoate
CAS Number	23602-78-0 Y
PubChem CID	2318
DrugBank	DB09022 N
ChemSpider	2228 Y
UNII	403FO0NQG3
KEGG	D07192 Y
ChEMBL	ChEMBL400599 Y
CompTox Dashboard (EPA)	DTXSID5048471
ECHA InfoCard	100.041.601
Chemical and physical data
Formula	C19H20F3NO2
Molar mass	351.369 g·mol−1
3D model (JSmol)	Interactive image
Chirality	Racemic mixture
SMILES FC(F)(F)c1cccc(c1)CC(NCCOC(=O)c2ccccc2)C
InChI 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 Y Key:CJAVTWRYCDNHSM-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

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at odds with the drug's medical properties.^[6] In fact, Benfluorex acts as a prodrug to Norfenfluramine, a worldwide withdrawn Anorectic because of its high incidence of Cardiac fibrosis ^[2] which is completely out of line for treating Type 2 diabetes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 Benfluorex 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Drug withdrawn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 5HT_2B 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.