Benfluorex: Difference between revisions

{{Short description|Withdrawn diabetes drug}}

{{Drugbox

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 413885213

| IUPAC_name = (''RS'')-2-({1-[3-(trifluoromethyl)phenyl]propan- 2-yl}amino)ethyl benzoate

| image = Benfluorex.svg

| chirality = [[Racemic mixture]]

<!--Clinical data-->

| tradename = Mediator

| Drugs.com = {{drugs.com|international|benfluorex}}

| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->

| pregnancy_US = <!-- A / B / C / D / X -->

| pregnancy_category =

| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->

| legal_BR = C1

| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-04-04}}</ref>

| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->

| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->

| legal_status =

| routes_of_administration = By mouth

<!--Pharmacokinetic data-->

| bioavailability =

| protein_bound =

| metabolism =

| elimination_half-life =

| excretion = [[Kidney]]

<!--Identifiers-->

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 23602-78-0

| ATC_prefix = A10

| ATC_suffix = BX06

| PubChem = 2318

| DrugBank_Ref = {{drugbankcite|changed|drugbank}}

| DrugBank = DB09022

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 2228

<!--Chemical data-->

| C=19 | H=20 | F=3 | N=1 | O=2

| smiles = FC(F)(F)c1cccc(c1)CC(NCCOC(=O)c2ccccc2)C

'''Benfluorex''', sold under the brand name '''Mediator''', is an [[anorectic]] and [[hypolipidemic agent]] that is structurally related to [[fenfluramine]] (a [[substituted amphetamine]]). It may improve [[glycemic control]] and decrease [[insulin resistance]] in people with poorly controlled [[diabetes mellitus type 2|type-2 diabetes]].<ref>{{cite journal | vauthors = Moulin P, Andre M, Alawi H, dos Santos LC, Khalid AK, Koev D, Moore R, Serban V, Picandet B, Francillard M | display-authors = 6 | title = Efficacy of benfluorex in combination with sulfonylurea in type 2 diabetic patients: an 18-week, randomized, double-blind study | journal = Diabetes Care | volume = 29 | issue = 3 | pages = 515–20 | date = March 2006 | pmid = 16505498 | doi = 10.2337/diacare.29.03.06.dc05-1439 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Roger P, Auclair J, Drain P | title = Addition of benfluorex to biguanide improves glycemic control in obese non-insulin-dependent diabetes: a double-blind study versus placebo | journal = Journal of Diabetes and Its Complications | volume = 13 | issue = 2 | pages = 62–7 | year = 1999 | pmid = 10432168 | doi = 10.1016/S1056-8727(98)00004-X }}</ref>

It was on the market between 1976 and 2009, and is thought to have caused between 500 and 2,000 deaths.<ref name=BCC2011/> 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.<ref>{{cite journal | vauthors = Mullard A | title = Mediator scandal rocks French medical community | journal = Lancet | volume = 377 | issue = 9769 | pages = 890–2 | date = March 2011 | pmid = 21409784 | doi = 10.1016/s0140-6736(11)60334-6 | s2cid = 5325085 | doi-access = free }}</ref>

On March 29, 2021, a French court fined Servier €2.7m (£2.3m) after finding it guilty of deception and manslaughter.<ref>{{Cite news|url=https://www.bbc.co.uk/news/world-europe-56562909|title=Mediator drug: French pharmaceutical firm fined over weight loss pill|work=BBC News|date=29 March 2021}}</ref>

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.<ref>{{ cite web | title = European Medicines Agency recommends withdrawal of benfluorex from the market in European Union | url = http://www.emea.europa.eu/pdfs/human/referral/benfluorex/Benfluorex_81503309en.pdf | publisher = European Medicines Agency | date = 2009-12-18 | access-date = 2015-01-12 | archive-url = https://web.archive.org/web/20091222213737/http://www.emea.europa.eu/pdfs/human/referral/benfluorex/Benfluorex_81503309en.pdf | archive-date = 2009-12-22 | url-status = dead }}</ref> Thus Frachon ''et al.'' showed a higher rate of unexplained valvular heart disease in people taking benfluorex.<ref>{{cite journal | vauthors = Frachon I, Etienne Y, Jobic Y, Le Gal G, Humbert M, Leroyer C | title = Benfluorex and unexplained valvular heart disease: a case-control study | journal = PLOS ONE | volume = 5 | issue = 4 | pages = e10128 | date = April 2010 | pmid = 20405030 | pmc = 2853566 | doi = 10.1371/journal.pone.0010128 | editor1-last = Lexchin | bibcode = 2010PLoSO...510128F | editor1-first = J. | doi-access = free }}</ref> Weill ''et al.'' looked at over 1 million people with diabetes demonstrating a higher hospitalization rate in benfluorex takers for valvular heart disease.<ref>{{cite journal | vauthors = Weill A, Païta M, Tuppin P, Fagot JP, Neumann A, Simon D, Ricordeau P, Montastruc JL, Allemand H | display-authors = 6 | title = Benfluorex and valvular heart disease: a cohort study of a million people with diabetes mellitus | journal = Pharmacoepidemiology and Drug Safety | volume = 19 | issue = 12 | pages = 1256–62 | date = December 2010 | pmid = 20945504 | doi = 10.1002/pds.2044 | s2cid = 15979457 | doi-access = free }}</ref>

In France, the medication had been marketed by Servier as an adjuvant [[anti-diabetic drug|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.<ref name=BCC2011>{{ cite web | url = https://www.bbc.co.uk/news/world-europe-12155639 | title = France braced for diabetic drug scandal report | work = BBC News | date = 2011-01-11 }}</ref> 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. The pharmaceutical group was acquitted of charges of fraud.

<ref>{{Cite web|url=https://www.theguardian.com/world/2021/mar/29/french-pharma-firm-found-guilty-over-medical-scandal-in-which-up-to-2000-died|title=French pharma firm found guilty over medical scandal in which up to 2,000 died|website=[[TheGuardian.com]]|date=29 March 2021}}</ref>

Fenfluramine, a related drug, had been withdrawn from the market in 1997 after reports of [[heart valve]] disease,<ref name="pmid9271479">{{cite journal | vauthors = Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, Schaff HV | title = Valvular heart disease associated with fenfluramine-phentermine | journal = The New England Journal of Medicine | volume = 337 | issue = 9 | pages = 581–8 | date = August 1997 | pmid = 9271479 | doi = 10.1056/NEJM199708283370901 | doi-access = free }}</ref><ref name="pmid11307869">{{cite journal | vauthors = Weissman NJ | title = Appetite suppressants and valvular heart disease | journal = The American Journal of the Medical Sciences | volume = 321 | issue = 4 | pages = 285–91 | date = April 2001 | pmid = 11307869 | doi = 10.1097/00000441-200104000-00008 | s2cid = 46466276 }}</ref> [[pulmonary hypertension]], and development of [[cardiac fibrosis]]. This side effect is mediated by the metabolite [[norfenfluramine]] on [[5-HT2B receptor|5HT_2B receptor]]s of heart valves,<ref>{{cite journal|author7-link=Bryan Roth | vauthors = Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A, Hufeisen SJ, Roth BL | title = Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications | journal = Circulation | volume = 102 | issue = 23 | pages = 2836–41 | date = December 2000 | pmid = 11104741 | doi = 10.1161/01.cir.102.23.2836 | doi-access = free }}</ref> 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 ==

{{Anorectics}}

{{Phenethylamines}}

[[Category:5-HT2B agonists]]

[[Category:Experimental anti-obesity drugs]]

[[Category:Benzoate esters]]

[[Category:Substituted amphetamines]]

[[Category:Trifluoromethyl compounds]]

[[Category:Monoamine releasing agents]]

[[Category:Serotonin receptor agonists]]

[[Category:World Anti-Doping Agency prohibited substances]]

[[Category:Withdrawn drugs]]