Post-marketing withdrawal of anti-obesity medicinal products because of adverse drug reactions: a systematic review

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Liraglutide 1 endocrinologydiseasesdrugs
diabetes mellitus 1 endocrinologydiseases
chlorphentermine 1 endocrinologydiseasesdrugs
diethylpropion 2 endocrinologydiseasesdrugs
obesity 52 endocrinologydiseases
phenmetrazine 1 endocrinologydiseasesdrugs
phentermine 4 endocrinologydiseasesdrugs
Phendimetrazine 2 endocrinologydiseasesdrugs
amphetamine 6 endocrinologydiseasesdrugs

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Select Drug Character Offset Drug Term Instance
Liraglutide 30046 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate glutamate receptors, and inhibits carbonic anhydrase2012Saxenda, Victozaa Liraglutide Glucagon-like peptide-1 receptor agonist2014Tenuate DospanDiethylpropionPrecise mechanism unknown: norepinephrine-dopamine
Phendimetrazine 11259 (desoxyephedrine)cSNDRAADHD, obesity194419711973USA, Turkey, Oman, NigeriaDrug abuse, drug dependence4 Phendimetrazine NDRA196119791982TurkeyDrug abuse4PhenmetrazineNDRAObesity195619591982Turkey, Oman, NigeriaDrug abuse4Phentermineb,cNDRAObesity195919641981Sweden,
Phendimetrazine 29603 (POMC)2014DidrexBenzphetaminePrecise mechanism unknown: norepinephrine-dopamine releasing agent1960Obezine Phendimetrazine Precise mechanism unknown: norepinephrine-dopamine releasing agent1961Qsymia, QnexaaPhentermine + topiramateThe
amphetamine 3151 neurotransmitters, prescribed as appetite suppressants, were introduced [[8]]. One such drug, Hydrin ( amphetamine ), gained FDA approval under controversial circumstances, because the FDA’s then acting medical director
amphetamine 3566 [[10]]. This was followed by the development of other anti-obesity medications, mainly congeners of amphetamine and monoamine re-uptake inhibitors [[11]].In recent years, there has been a growing focus on the development
amphetamine 10880 psychiatric4Iodinated casein strophanthinThyroxine analogueObesity194419641964USAEndocrine, metabolism4Lev amphetamine SNDRAObesity194419541973USA, Oman, UAEDrug abuse and dependence4MazindolNRDAObesity197019801987Oman,
amphetamine 11145 lithium)4Mefenorex (methylphenethylamine)SNDRAObesity196619951999Europe, OmanDrug abuse, psychiatric4Meth amphetamine (desoxyephedrine)cSNDRAADHD, obesity194419711973USA, Turkey, Oman, NigeriaDrug abuse, drug dependence4PhendimetrazineNDRA196119791982TurkeyDrug
amphetamine 21629 association between fenfluramine and pulmonary hypertension [[54]]• Withdrawn worldwide in 1997Meth amphetamine (desoxyephedrine)• First introduced in 1944• Within 10 years of its introduction, cases of its
amphetamine 27504 mechanisms of action are specifically targeted against abnormal pathways. For example, several analogues of amphetamine are available for treating attention deficit hyperactivity disorder (ADHD) and narcolepsy [[25], [26]].There
chlorphentermine 13822 instances (80%), and Level 3 evidence in two instances (8%) (Table 1). The withdrawal of one product, chlorphentermine , was based on evidence from animal studies. Cardiotoxicity accounted for 8 withdrawals (32%) and psychiatric
diethylpropion 9758 reportYear first withdrawnCountries withdrawnPrimary reason for withdrawalLevel of evidenceaAmfepramone ( diethylpropion )bSNDRAObesity195719741975Turkey, Sweden, Oman, UAE, Norway, Venezuela, EU, France, UK, BrazilCardiotoxicity4AmphetamineSNDRAObesity,
diethylpropion 33916 experts should be given responsibility for assessing harms [[43]]. The re-introduction of amfepramone ( diethylpropion ) and phentermine in Europe, based on a long-standing legal action, unrelated to new information on benefits
phenmetrazine 17128 IQR interquartile rangeThe longest interval between first report and first withdrawal was 23 years ( phenmetrazine ), while the shortest interval was less than 1 year in three cases (aminorex fumarate, cloforex, and
phentermine 10159 Switzerland, AustriaCardiotoxicity4BenfluorexcSRIObesity, diabetes197620032009EuropeCardiotoxicity3Chlor phentermine SRIObesity19621969Germany, VenezuelaCardiotoxicity5ClobenzorexSNDRAObesity196619862000Mauritius, USA,
phentermine 13827 instances (80%), and Level 3 evidence in two instances (8%) (Table 1). The withdrawal of one product, chlor phentermine , was based on evidence from animal studies. Cardiotoxicity accounted for 8 withdrawals (32%) and psychiatric
phentermine 29789 agent1961Qsymia, QnexaaPhentermine + topiramateThe precise mechanism of action for both drugs is unknown: phentermine is a norepinephrine-dopamine releasing agent; topiramate augments gamma-aminobutyrate (GABA), inhibits
phentermine 33936 responsibility for assessing harms [[43]]. The re-introduction of amfepramone (diethylpropion) and phentermine in Europe, based on a long-standing legal action, unrelated to new information on benefits or harms,
Select Disease Character Offset Disease Term Instance
diabetes mellitus 21020 aminorex from the marketBenfluorex• Approved in 1976 as an add-on treatment in obese patients with diabetes mellitus • Cases of valvulopathy attributed to its use began to appear from 2003• Was withdrawn in 2009 following
obesity 53 Title: BMC MedicinePost-marketing withdrawal of anti- obesity medicinal products because of adverse drug reactions: a systematic reviewIgho J. OnakpoyaCarl J. HeneghanJeffrey
obesity 328 date (pmc-release): 11/2016Publication date (collection): /2016AbstractBackgroundWe identified anti- obesity medications withdrawn since 1950 because of adverse drug reactions after regulatory approval, and examined
obesity 810 authorities, and selected full texts, and we hand searched references in retrieved documents. We included anti- obesity medications that were withdrawn between 1950 and December 2015 and assessed the levels of evidence used
obesity 1044 decisions using the Oxford Centre for Evidence-Based Medicine criteria.ResultsWe identified 25 anti- obesity medications withdrawn between 1964 and 2009; 23 of these were centrally acting, via monoamine neurotransmitters.
obesity 1729 reaction.ConclusionsMost of the drugs that affect monoamine neurotransmitters licensed for the treatment of obesity over the past 65 years have been withdrawn because of adverse reactions. The reasons for withdrawal
obesity 1954 about the wisdom of using pharmacological agents that target monoamine neurotransmitters in managing obesity . Greater transparency in the assessment of harms from anti-obesity medications is therefore warranted.Electronic
obesity 2021 monoamine neurotransmitters in managing obesity. Greater transparency in the assessment of harms from anti- obesity medications is therefore warranted.Electronic supplementary materialThe online version of this article
obesity 2279 supplementary material, which is available to authorized users.BackgroundThe prevalence of corpulence and obesity has more than tripled in the last decade [[1]], giving rise to substantially increased healthcare costs
obesity 2468 increased healthcare costs [[2], [3]]. According to the World Health Organization (WHO), corpulence and obesity are the fifth leading cause of mortality worldwide [[4]]. Strategies to reduce weight include diet and
obesity 2702 behavioural techniques, and drug therapy [[5]]; however, they have had little effect on the growing obesity epidemic.Modern drug therapy for obesity treatment began in 1933 with the use of 2,4-dinitrophenol (2,4-DNP),
obesity 2743 [[5]]; however, they have had little effect on the growing obesity epidemic.Modern drug therapy for obesity treatment began in 1933 with the use of 2,4-dinitrophenol (2,4-DNP), a thermogenic agent, for weight
obesity 3525 Hydrin, citing lack of evidence on harms [[10]]. This was followed by the development of other anti- obesity medications, mainly congeners of amphetamine and monoamine re-uptake inhibitors [[11]].In recent years,
obesity 3727 recent years, there has been a growing focus on the development of novel therapies for the treatment of obesity [[12]], including drug combinations, a few of which have recently gained marketing approvals from regulatory
obesity 3902 gained marketing approvals from regulatory authorities [[13]].However, at the same time several anti- obesity products have been withdrawn from the market after approval because of adverse reactions [[14]]. To
obesity 4067 approval because of adverse reactions [[14]]. To date, the patterns of and reasons for withdrawal of anti- obesity products have not been systematically analysed. Therefore, our objectives were to identify anti-obesity
obesity 4171 anti-obesity products have not been systematically analysed. Therefore, our objectives were to identify anti- obesity products withdrawn from the market because of adverse reactions, to examine the evidence used for withdrawals,
obesity 4452 occurred, and explore the patterns in withdrawal over time.MethodsSearch strategyWe searched for anti- obesity medications that had been withdrawn from the market after regulatory approval because of adverse drug
obesity 5094 FDA websiteDatabase of withdrawn drugs of the European Medicines Agency (EMA)For each withdrawn anti- obesity medicine identified, we searched the following sources for the first reported adverse drug reaction:
obesity 5418 Stephens' Detection of New Adverse Drug Reactions, 5th edition. Search terms used included “anti- obesity ”, “withdrawal”, “fatal*”, “adverse reaction”, “adverse event”, “toxicity”, “voluntary
obesity 5859 search strategies used for searching scientific databases.) If we could not find information for an anti- obesity medication when using its chemical name for searches, we used trade or code names. We also hand searched
obesity 6185 about an earlier reported date, that date was chosen as the first adverse reaction date. If an anti- obesity medicine was withdrawn because of two or more adverse reactions, we used the date of the first reported
obesity 6372 date of the first reported reaction.Inclusion/exclusion criteriaTo be included in the review, an anti- obesity medicinal product must have been withdrawn from the market because of reports of suspected adverse reaction(s)
obesity 6549 reports of suspected adverse reaction(s) or problems related to hazards or harms. We excluded anti- obesity medicines for which there was documented regulatory evidence that they had been voluntarily withdrawn
obesity 7056 evidenceWe documented the highest level of available evidence before the year of first withdrawal of anti- obesity medicines, based on the Oxford Centre for Evidence-Based Medicine (OCEBM) criteria [[15]], which rank
obesity 7634 reviewer (JKA). Disagreements were resolved through discussion.Data extractionFor each withdrawn anti- obesity product, we extracted data on the marketing authorization or launch date (or the date of first recorded
obesity 8998 considered statistically significant.ResultsWe identified 47 withdrawn medicinal products used for treating obesity (Additional file 2). We excluded 11 products because they were plant-based “herbal” products and
obesity 9485 South America, 8 in North America, 4 in Africa, and 1 in Australasia (Table 1).Table 1List of anti- obesity drugs withdrawn from the market because of adverse drug reactionsMedicinal productPrimary mechanism
obesity 10459 VenezuelaCardiotoxicity4Cyclovalone + retinol + tiratricolBile acid secretionHyperlipidemia, dyspepsia, obesity 196419841988FranceLiver toxicity4DexfenfluramineSRIObesity199519951997WorldwideCardiotoxicity4FenbutrazateNDRAObesity195719631969EuropeDrug
obesity 11186 (methylphenethylamine)SNDRAObesity196619951999Europe, OmanDrug abuse, psychiatric4Methamphetamine (desoxyephedrine)cSNDRAADHD, obesity 194419711973USA, Turkey, Oman, NigeriaDrug abuse, drug dependence4PhendimetrazineNDRA196119791982TurkeyDrug
obesity 11538 Turkey, Oman, UK, VenezuelaDrug abuse4Phenylpropanolamine (norpseudoephedrine)NDRANasal decongestion, obesity 194719851987Germany, Brazil, Malaysia, Singapore, USA, Oman, Canada, Cuba, IndiaHemorrhagic stroke4PipradrolNDRIObesity,
obesity 15888 24 years).Table 2Summary comparison of post-marketing withdrawal patterns of centrally acting anti- obesity medicinal productsPrimary mode of action at receptor endingPrimary reason for withdrawalMedian interval
obesity 18367 The red boxes indicate products to which deaths were attributedDiscussionWe have identified 25 anti- obesity medications that were withdrawn after marketing between 1964 and 2009, 23 of which had centrally acting
obesity 19331 median interval to first reports of adverse reactions and first withdrawals was longer with the anti- obesity products (11 versus 3 years), but this is likely due to the smaller proportion of anti-obesity product
obesity 19427 anti-obesity products (11 versus 3 years), but this is likely due to the smaller proportion of anti- obesity product approvals after 1976 compared with the overall data (the median interval to withdrawal for the
obesity 20098 products were centrally acting anorectics suggests that use of this class of products in the treatment of obesity is associated with a negative benefit-to-harm balance over time (see Table 3 and Additional file 3).
obesity 20515 patterns of marketing authorizations of this class of products.Table 3Profile of centrally acting anti- obesity products withdrawn because of associated deaths over the last 50 yearsAminorex• First introduced
obesity 22281 Withdrawn from most countries where it was marketed in 1981• Still available for short-term management of obesity in the USARimonabant• Approved in Europe in 2006 for obesity treatment• Within 1 year of approval,
obesity 22344 available for short-term management of obesity in the USARimonabant• Approved in Europe in 2006 for obesity treatment• Within 1 year of approval, concerns were expressed about the risk of depression and suicide
obesity 24039 literatureOur findings are consistent with other published reports. A previous review reported that most anti- obesity treatments have been withdrawn from the market because of concerns about adverse reactions [[14]]. Two
obesity 24270 concluded that cardiovascular and psychiatric adverse reactions are major concerns with psychoactive anti- obesity drugs that have recently gained marketing approval from licensing authorities [[19], [20]]. A recent
obesity 24566 showed that cardiac and psychiatric disorders were the most common adverse reactions attributed to anti- obesity medicinal products [[21]]. The authors of another report concluded that lower doses of multiple chemical
obesity 24891 [[1]].Strengths and limitationsTo our knowledge, this is the first review that has systematically identified anti- obesity medicinal products withdrawn from the market because of adverse drug reactions. We comprehensively searched
obesity 25064 drug reactions. We comprehensively searched various sources of information in order to identify anti- obesity medicinal products that have been withdrawn, we accounted for the levels of evidence used in making
obesity 27213 note, several medicinal products with similar mechanisms of action to the withdrawn psychotropic anti- obesity medications have been successfully used for treating other medical conditions, and they have not been
obesity 27655 deficit hyperactivity disorder (ADHD) and narcolepsy [[25], [26]].There were no new approvals of anti- obesity medications during the 20 years from 1976 to 1995. It is unclear what caused this hiatus; however,
obesity 27842 this hiatus; however, we observed a steep increase in the number of scientific publications relating obesity prevalence and treatment after the hiatus (PubMed trend; Additional file 4). The resurgence of new approval
obesity 28281 1974. This is consistent with the fact that of the nine medicinal products currently available for obesity management, all six (78%) that exert their weight reducing actions through centrally acting mechanisms
obesity 28925 as major concerns of recently approved products with centrally acting mechanisms [[19]].Table 4Anti- obesity drugs currently approved for use in at least one countryBrand nameActive ingredientMechanism of actionYear
obesity 30398 short-term (≤1 year) cardiovascular profile [[27]]. However, whether the weight losses generated by anti- obesity medicinal products have beneficial effects on long-term cardiovascular outcome is unclear, largely because
obesity 31402 cardiovascular outcomes that are the health risks the use of the products were intended to reduce — an “ obesity treatment paradox”.Implications for future harms assessment and policyAlthough there have been revisions
obesity 31576 policyAlthough there have been revisions to regulatory guidance for the assessment of harms in anti- obesity drug trials [[31], [32]], there are uncertainties about the extent to which these guidelines are applied
obesity 35020 legislative action against the promoting and marketing of such products.ConclusionsWe have identified 25 anti- obesity medications withdrawn after marketing over the past 60 years, 23 of which were centrally acting anorectics.

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