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

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          Abstract

          Background

          We identified anti-obesity medications withdrawn since 1950 because of adverse drug reactions after regulatory approval, and examined the evidence used to support such withdrawals, investigated the mechanisms of the adverse reactions, and explored the trends over time.

          Methods

          We conducted searches in PubMed, the World Health Organization database of drugs, the websites of drug regulatory 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 We included anti-obesity medications that were withdrawn between 1950 and December 2015 and assessed the levels of evidence used for making withdrawal decisions using the Oxford Centre for Evidence-Based Medicine criteria.

          Results

          We identified 25 anti-obesity medications withdrawn between 1964 and 2009; 23 of these were centrally acting, via monoamine neurotransmitters. Case reports were cited as evidence for withdrawal in 80% of instances. Psychiatric disturbances, cardiotoxicity (mainly attributable to re-uptake inhibitors), and drug abuse or dependence (mainly attributable to neurotransmitter releasing agents) together accounted for 83% of withdrawals. Deaths were reportedly associated with seven products (28%). In almost half of the cases, the withdrawals occurred within 2 years of the first report of an adverse reaction.

          Conclusions

          Most 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drugs that affect monoamine neurotransmitters licensed for the treatment of obesity over the past 65 years have been withdrawn because of adverse reactions.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 raise concerns 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 supplementary material

          The online version of this article (doi:10.1186/s12916-016-0735-y) contains supplementary material, which is available to authorized users.

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          Most cited references34

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          Multicenter, placebo-controlled trial of lorcaserin for weight management.

          Steven Smith, Neil Weissman, Christen Anderson … (2010)
          Lorcaserin is a selective serotonin 2C receptor agonist that could be useful in reducing body weight. In this double-blind clinical trial, we randomly assigned 3182 obese or overweight adults (mean body-mass index [the weight in kilograms divided by the square of the height in meters] of 36.2) to receive lorcaserin at a dose of 10 mg, or placebo, twice daily for 52 weeks. All patients also underwent diet and exercise counseling. At week 52, patients in the placebo group continued to receive placebo but patients in the lorcaserin group were randomly reassigned to receive either placebo or lorcaserin. Primary outcomes were weight loss at 1 year and maintenance of weight loss at 2 years. Serial echocardiography was used to identify patients in whom valvulopathy (as defined by the Food and Drug Administration) developed. At 1 year, 55.4% of patients (883 of 1595) receiving lorcaserin and 45.1% of patients (716 of 1587) receiving placebo remained in the trial; 1553 patients continued into year 2. At 1 year, 47.5% of patients in the lorcaserin group and 20.3% in the placebo group had lost 5% or more of their body weight (P<0.001), corresponding to an average loss of 5.8+/-0.2 kg with lorcaserin and 2.2+/-0.1 kg with placebo during year 1 (P<0.001). Among the patients who received lorcaserin during year 1 and who had lost 5% or more of their baseline weight at 1 year, the loss was maintained in more patients who continued to receive lorcaserin during year 2 (67.9%) than in patients who received placebo during year 2 (50.3%, P<0.001). Among 2472 patients evaluated at 1 year and 1127 evaluated at 2 years, the rate of cardiac valvulopathy was not increased with the use of lorcaserin. Among the most frequent adverse events reported with lorcaserin were headache, dizziness, and nausea. The rates of serious adverse events in the two groups were similar. In conjunction with behavioral modification, lorcaserin was associated with significant weight loss and improved maintenance of weight loss, as compared with placebo. (Funded by Arena Pharmaceuticals; ClinicalTrials.gov number, NCT00395135.) 2010 Massachusetts Medical Society
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            A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial.

            Meredith C. Fidler, Matilde Sanchez, Brian Raether … (2011)
            Lorcaserin is a novel selective agonist of the serotonin 2C receptor. Our objective was to evaluate the effects of lorcaserin on body weight, cardiovascular risk factors, and safety in obese and overweight patients. This randomized, placebo-controlled, double-blind, parallel arm trial took place at 97 U.S. research centers. Patients included 4008 patients, aged 18-65 yr, with a body mass index between 30 and 45 kg/m(2) or between 27 and 29.9 kg/m(2) with an obesity-related comorbid condition. Patients were randomly assigned in a 2:1:2 ratio to receive lorcaserin 10 mg twice daily (BID), lorcaserin 10 mg once daily (QD), or placebo. All patients received diet and exercise counseling. The ordered primary endpoints were proportion of patients achieving at least 5% reduction in body weight, mean change in body weight, and proportion of patients achieving at least 10% reduction in body weight at 1 yr. Serial echocardiograms monitored heart valve function. Significantly more patients treated with lorcaserin 10 mg BID and QD lost at least 5% of baseline body weight (47.2 and 40.2%, respectively) as compared with placebo (25.0%, P < 0.001 vs. lorcaserin BID). Least squares mean (95% confidence interval) weight loss with lorcaserin BID and QD was 5.8% (5.5-6.2%) and 4.7% (4.3-5.2%), respectively, compared with 2.8% (2.5-3.2%) with placebo (P < 0.001 vs. lorcaserin BID; least squares mean difference, 3.0%). Weight loss of at least 10% was achieved by 22.6 and 17.4% of patients receiving lorcaserin 10 mg BID and QD, respectively, and 9.7% of patients in the placebo group (P < 0.001 vs. lorcaserin BID). Headache, nausea, and dizziness were the most common lorcaserin-related adverse events. U.S. Food and Drug Administration-defined echocardiographic valvulopathy occurred in 2.0% of patients on placebo and 2.0% on lorcaserin 10 mg BID. Lorcaserin administered in conjunction with a lifestyle modification program was associated with dose-dependent weight loss that was significantly greater than with placebo.
            Article 0 comments Cited 142 times – based on 0 reviews     Review now
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              Management of obesity: improvement of health-care training and systems for prevention and care.

              William Dietz, Louise A. Baur, Kevin Hall … (2015)
              Although the caloric deficits achieved by increased awareness, policy, and environmental approaches have begun to achieve reductions in the prevalence of obesity in some countries, these approaches are insufficient to achieve weight loss in patients with severe obesity. Because the prevalence of obesity poses an enormous clinical burden, innovative treatment and care-delivery strategies are needed. Nonetheless, health professionals are poorly prepared to address obesity. In addition to biases and unfounded assumptions about patients with obesity, absence of training in behaviour-change strategies and scarce experience working within interprofessional teams impairs care of patients with obesity. Modalities available for the treatment of adult obesity include clinical counselling focused on diet, physical activity, and behaviour change, pharmacotherapy, and bariatric surgery. Few options, few published reports of treatment, and no large randomised trials are available for paediatric patients. Improved care for patients with obesity will need alignment of the intensity of therapy with the severity of disease and integration of therapy with environmental changes that reinforce clinical strategies. New treatment strategies, such as the use of technology and innovative means of health-care delivery that rely on health professionals other than physicians, represent promising options, particularly for patients with overweight and patients with mild to moderate obesity. The co-occurrence of undernutrition and obesity in low-income and middle-income countries poses unique challenges that might not be amenable to the same strategies as those that can be used in high-income countries.
              Article 0 comments Cited 140 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Igho J. Onakpoya: +44 (0) 1865289672 , igho.onakpoya@kellogg.ox.ac.uk
                Journal
                Journal ID (nlm-ta): BMC Med
                Journal ID (iso-abbrev): BMC Med
                Title: BMC Medicine
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1741-7015
                Publication date (Electronic): 29 November 2016
                Publication date PMC-release: 29 November 2016
                Publication date Collection: 2016
                Volume: 14
                Electronic Location Identifier: 191
                Affiliations
                [1 ]Nuffield Department of Primary Care Health Sciences, University of Oxford, Centre for Evidence-Based Medicine, Gibson Building, Radcliffe Observatory Quarter, Oxford, OX2 6GG UK
                [2 ]Nuffield Department of Primary Care Health Sciences, University of Oxford, Centre for Evidence-Based Medicine, Radcliffe Primary Care Building, Radcliffe Observatory Quarter, Oxford, UK
                Article
                Publisher ID: 735
                DOI: 10.1186/s12916-016-0735-y
                PMC ID: 5126837
                PubMed ID: 27894343
                SO-VID: 513be958-9e79-4d71-b315-a032c22d1d40
                Copyright © © The Author(s). 2016
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 13 August 2016
                Date accepted : 27 October 2016
                Categories
                Subject: Research Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2016

                ScienceOpen disciplines: Medicine
                Keywords: obesity,drug withdrawal,adverse drug reaction,systematic review
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: obesity, drug withdrawal, adverse drug reaction, systematic review

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