Background
Methods
Search strategy
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WHO database of Consolidated List of Products whose consumption and/or sale have been banned, withdrawn, severely restricted, or not approved by governments (issues 6, 8, 12, and 14)
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Regulatory news sections of WHO Drug Information (volumes 1–29)
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WHO Pharmaceuticals Newsletter (1997–2015)
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UK Medicines and Healthcare products Regulatory Agency (MHRA) website
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US FDA website
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Database of withdrawn drugs of the European Medicines Agency (EMA)
Inclusion/exclusion criteria
Assessing the types of evidence
Data extraction
Statistical analyses
Results
Medicinal product | Primary mechanism of action | Therapeutic indication | Launch date | Year of first ADR report | Year first withdrawn | Countries withdrawn | Primary reason for withdrawal | Level of evidencea |
---|---|---|---|---|---|---|---|---|
Amfepramone (diethylpropion)b | SNDRA | Obesity | 1957 | 1974 | 1975 | Turkey, Sweden, Oman, UAE, Norway, Venezuela, EU, France, UK, Brazil | Cardiotoxicity | 4 |
Amphetamine | SNDRA | Obesity, narcolepsy | 1939 | 1957 | 1973 | USA, UAE, Turkey, Oman, Malaysia, Nigeria | Drug abuse and dependence | 4 |
Aminorex fumaratec | SRI | Obesity | 1962 | 1967 | 1967 | Germany, Venezuela, Switzerland, Austria | Cardiotoxicity | 4 |
Benfluorexc | SRI | Obesity, diabetes | 1976 | 2003 | 2009 | Europe | Cardiotoxicity | 3 |
Chlorphentermine | SRI | Obesity | 1962 | 1969 | Germany, Venezuela | Cardiotoxicity | 5 | |
Clobenzorex | SNDRA | Obesity | 1966 | 1986 | 2000 | Mauritius, USA, Oman | Drug abuse, psychiatric | 4 |
Cloforex | SRI | Obesity | 1965 | 1967 | 1967 | Germany, Sweden, Venezuela | Cardiotoxicity | 4 |
Cyclovalone + retinol + tiratricol | Bile acid secretion | Hyperlipidemia, dyspepsia, obesity | 1964 | 1984 | 1988 | France | Liver toxicity | 4 |
Dexfenfluramine | SRI | Obesity | 1995 | 1995 | 1997 | Worldwide | Cardiotoxicity | 4 |
Fenbutrazate | NDRA | Obesity | 1957 | 1963 | 1969 | Europe | Drug abuse, psychiatric | 2 |
Fenfluraminec | SRI | Obesity | 1973 | 1981 | 1997 | Worldwide | Cardiotoxicity | 3 |
Fenproporex (perphoxene) | NRA | Obesity, narcolepsy, ADHD | 1966 | 1997 | 1999 | Europe, Brazil | Drug abuse, psychiatric | 4 |
Iodinated casein strophanthin | Thyroxine analogue | Obesity | 1944 | 1964 | 1964 | USA | Endocrine, metabolism | 4 |
Levamphetamine | SNDRA | Obesity | 1944 | 1954 | 1973 | USA, Oman, UAE | Drug abuse and dependence | 4 |
Mazindol | NRDA | Obesity | 1970 | 1980 | 1987 | Oman, Brazil | Drug abuse, psychiatric (interaction with lithium) | 4 |
Mefenorex (methylphenethylamine) | SNDRA | Obesity | 1966 | 1995 | 1999 | Europe, Oman | Drug abuse, psychiatric | 4 |
Methamphetamine (desoxyephedrine)c | SNDRA | ADHD, obesity | 1944 | 1971 | 1973 | USA, Turkey, Oman, Nigeria | Drug abuse, drug dependence | 4 |
Phendimetrazine | NDRA | 1961 | 1979 | 1982 | Turkey | Drug abuse | 4 | |
Phenmetrazine | NDRA | Obesity | 1956 | 1959 | 1982 | Turkey, Oman, Nigeria | Drug abuse | 4 |
Phentermineb,c | NDRA | Obesity | 1959 | 1964 | 1981 | Sweden, UAE, Mauritius, Turkey, Oman, UK, Venezuela | Drug abuse | 4 |
Phenylpropanolamine (norpseudoephedrine) | NDRA | Nasal decongestion, obesity | 1947 | 1985 | 1987 | Germany, Brazil, Malaysia, Singapore, USA, Oman, Canada, Cuba, India | Hemorrhagic stroke | 4 |
Pipradrol | NDRI | Obesity, narcolepsy, ADHD | 1953 | 1968 | 1982 | USA, Turkey, Denmark, Venezuela | Drug abuse | 4 |
Pyrovalerone | NDRA | Obesity, chronic fatigue syndrome | 1974 | 1975 | 1979 | France | Drug abuse | 4 |
Rimonabantc | CB1 antagonist/inverse agonist | Obesity | 2006 | 2006 | 2007 | Europe, India | Psychiatric | 1 |
Sibutraminec | SNRI | Obesity | 2001 | 2002 | 2002 | EU; 4 Asian countries; Australia; Canada; Mexico; New Zealand; USA | Cardiotoxicity, psychiatric | 4 |
Primary mode of action at receptor ending | Primary reason for withdrawal | Median interval between launch and first ADR report | Median interval between first ADR report and withdrawal | Statistical comparisonsa |
---|---|---|---|---|
Neurotransmitter re-uptake inhibition (n = 8) | Cardiotoxicity: n = 7 Drug misuse: n = 1 | 5.5 years (IQR = 1.3 to 13.3 years | 1 year (IQR = 0 to 12 years) | Withdrawal due to cardiotoxicity significantly more likely vs neurotransmitter releasers (P = 0.0004) |
Neurotransmitter release (n = 14) | Cardiotoxicity: n = 1 Drug abuse or dependence: n = 12 Hemorrhagic stroke: n = 1 | 17.5 years (IQR = 5.8 to 28 years) | 5 years (IQR = 2 to 16.3 years) | Withdrawal due to drug misuse significantly more likely vs neurotransmitter re-uptake inhibitors (P = 0.002) |
Discussion
Aminorex • First introduced in 1962 • Became available within 3 years of introduction as an over-the-counter weight loss pill • Between 1965 and 1972, there was an alarming increase in the incidence of primary pulmonary hypertension [52] • The pulmonary hypertension epidemic ended in 1972 following the withdrawal of aminorex from the market | |
Benfluorex • 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 an epidemic of valvulopathy attributed to its use • Several deaths reported • To date, more than 3000 hospitalizations and at least 1300 deaths attributed to its use in France alone [53] | |
Fenfluramine • First approved in in 1973 • Reports of pulmonary hypertension first appeared in 1981 • Several other case reports subsequently published • Epidemiological studies showed an association between fenfluramine and pulmonary hypertension [54] • Withdrawn worldwide in 1997 | |
Methamphetamine (desoxyephedrine) • First introduced in 1944 • Within 10 years of its introduction, cases of its misuse had been reported • By the early 1970s, reports of its abuse as an anorectic were reported [55] • Was withdrawn in the USA and other countries in 1973 • Several cases of cardiac abnormalities related to its abuse have subsequently been reported | |
Phentermine • First approved in 1959 • Several cases of lung phospholipidosis in animals and humans reported thereafter • Reports of death began to appear in 1974 [56] • Withdrawn from most countries where it was marketed in 1981 • Still available for short-term management of obesity in the USA | |
Rimonabant • Approved in Europe in 2006 for obesity treatment • Within 1 year of approval, concerns were expressed about the risk of depression and suicide associated with its use [57] • Five deaths attributed to its use in the UK [58] • Was withdrawn in 2007 | |
Sibutramine • Approved in 1997 in the USA and Europe in 2001 • Within a year of its European approval, serious cardiovascular adverse reactions were reported, resulting in temporary withdrawal in Italy [59] • Several cases of severe cardiovascular adverse reactions, including deaths, were subsequently reported [60] • Withdrawn in Europe and USA in 2010 |
Comparison with existing literature
Strengths and limitations
Implications for drug therapy
Brand name | Active ingredient | Mechanism of action | Year approved |
---|---|---|---|
Adipex-P, Ionamin | Phentermine | Precise mechanism unknown: norepinephrine-dopamine releasing agent | 1959 |
Alli, Xenicala | Orlistat | Inhibits gastric and pancreatic lipases | 1999 |
Belviqa | Lorcaserin | Selective 5-HT2C receptor agonist | 2012 |
Contrave, Mysimbaa | Naltrexone + bupropion | Bupropion: re-uptake inhibitor and releasing agent of norepinephrine and a nicotinic acetylcholine receptor antagonist; naltrexone augments bupropion’s activation of proopiomelanocortin (POMC) | 2014 |
Didrex | Benzphetamine | Precise mechanism unknown: norepinephrine-dopamine releasing agent | 1960 |
Obezine | Phendimetrazine | Precise mechanism unknown: norepinephrine-dopamine releasing agent | 1961 |
Qsymia, Qnexaa | Phentermine + topiramate | The precise mechanism of action for both drugs is unknown: phentermine is a norepinephrine-dopamine releasing agent; topiramate augments gamma-aminobutyrate (GABA), inhibits α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate glutamate receptors, and inhibits carbonic anhydrase | 2012 |
Saxenda, Victozaa | Liraglutide | Glucagon-like peptide-1 receptor agonist | 2014 |
Tenuate Dospan | Diethylpropion | Precise mechanism unknown: norepinephrine-dopamine releasing agent | 1959 |