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Safety Profile of Benznidazole in the Treatment of Chronic Chagas Disease: Experience of a Referral Centre and Systematic Literature Review with Meta-Analysis

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Abstract

Introduction

Benznidazole is the preferred drug for treatment of Chagas disease. However, it is toxic and of limited value in chronic infection.

Objective

We aimed to estimate the rates of and factors related to adverse reactions (ARs) to benznidazole and treatment discontinuations (TDs).

Methods

A meta-analysis was performed using an electronic search of the published literature with no language restrictions until June 2017. Prospective studies were included of chronically infected patients in which at least one treatment arm included benznidazole. Data were added from a prospective cohort of patients with Chagas disease at our centre (January 2007–June 2017). Weighted rates of ARs and TDs were estimated, and potentially related factors were analysed.

Results

Some 413 studies were found, from which we chose 42 (nine clinical trials and 33 observational studies, including ours), comprising data for 7822 patients. The weighted rate of ARs to benznidazole was 44.1% (95% confidence interval [CI] 37.2–51.2). ARs were more frequent in adults than in children (51.6 vs. 24.5%), with the most common being skin reactions (34%), gastrointestinal complaints (12.6%) and neurological symptoms (11.5%). Grade 4 ARs were recorded in 3% of cases. The weighted rate of TDs was 11.4% (95% CI 8.5–14.5); TDs were more frequent in adults than in children (14.2 vs. 3.8%). In our cohort, only female sex was related to an increased rate of ARs but not to TDs.

Conclusion

Benznidazole had a poor tolerability profile, with a high incidence of TDs, especially in adult patients and women. Optimised dosing schedules and/or new drugs are urgently needed.

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References

  1. World Health Organization. Chagas disease in Latin America: an epidemiological update based on 2010 estimates. Wkly Epidemiol Rec. 2015;90:33–43.

    Google Scholar 

  2. World Health Organization. Control of Chagas disease: second report of the WHO Expert Committee. WHO technical report series, vol. 905. Geneva: World Health Organization; 2002.

    Google Scholar 

  3. Pérez-Molina JA, Molina I. Chagas disease. Lancet. 2018;391(10115):82–94.

    Article  PubMed  Google Scholar 

  4. Bern C. Chagas’ disease. N Engl J Med. 2015;373:456–66.

    Article  CAS  PubMed  Google Scholar 

  5. Angheben A, Boix L, Buonfrate D, et al. Chagas disease and transfusion medicine: a perspective from non-endemic countries. Blood Transfus. 2015;13:540–50.

    PubMed  PubMed Central  Google Scholar 

  6. Howard EJ, Xiong X, Carlier Y, Sosa Estani S, Buekens P. Frequency of the congenital transmission of Trypanosoma cruzi: a systematic review and meta-analysis. BJOG. 2014;121:22–33.

    Article  CAS  PubMed  Google Scholar 

  7. Martin-Davila P, Fortun J, Lopez-Velez R, et al. Transmission of tropical and geographically restricted infections during solid-organ transplantation. Clin Microbiol Rev. 2008;21:60–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Shikanai-Yasuda MA, Carvalho NB. Oral transmission of Chagas disease. Clin Infect Dis. 2012;54:845–52.

    Article  PubMed  Google Scholar 

  9. Schmunis GA, Yadon ZE. Chagas disease: a Latin American health problem becoming a world health problem. Acta Trop. 2010;115:14–21.

    Article  PubMed  Google Scholar 

  10. Perez-Molina JA, Perez AM, Norman FF, Monge-Maillo B, Lopez-Velez R. Old and new challenges in Chagas disease. Lancet Infect Dis. 2015;15:1347–56.

    Article  PubMed  Google Scholar 

  11. Manne-Goehler J, Umeh CA, Montgomery SP, Wirtz VJ. Estimating the burden of Chagas disease in the United States. PLoS Negl Trop Dis. 2016;10:e0005033.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Requena-Méndez A, Aldasoro E, de Lazzari E, et al. Prevalence of Chagas disease in Latin-American migrants living in Europe: a systematic review and meta-analysis. PLoS Negl Trop Dis. 2015;9:e0003540.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Laranja FS, Dias E, Nobrega G, Miranda A. Chagas’ disease. A clinical, epidemiologic, and pathologic study. Circulation. 1956;14:1035–60.

    Article  PubMed  Google Scholar 

  14. Coura JR, de Abreu LL, Pereira JB, Willcox HP. Morbidity in Chagas’ disease. IV. Longitudinal study of 10 years in Pains and Iguatama, Minas Gerais, Brazil [in Portuguese]. Mem Inst Oswaldo Cruz. 1985;80:73–80.

    Article  CAS  PubMed  Google Scholar 

  15. Dias JC. The indeterminate form of human chronic Chagas’ disease: a clinical epidemiological review. Rev Soc Bras Med Trop. 1989;22:147–56.

    Article  CAS  PubMed  Google Scholar 

  16. Sgambatti de Andrade ALS, Zicker F, de Oliveira RM, et al. Randomised trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection. Lancet. 1996;348:1407–13.

    Article  Google Scholar 

  17. Sosa Estani S, Segura EL, Ruiz AM, Velazquez E, Porcel BM, Yampotis C. Efficacy of chemotherapy with benznidazole in children in the indeterminate phase of Chagas’ disease. Am J Trop Med Hyg. 1998;59:526–9.

    Article  CAS  PubMed  Google Scholar 

  18. Viotti R, Vigliano C, Lococo B, et al. Long-term cardiac outcomes of treating chronic Chagas disease with benznidazole versus no treatment: a nonrandomized trial. Ann Intern Med. 2006;144:724–34.

    Article  CAS  PubMed  Google Scholar 

  19. Murcia L, Carrilero B, Munoz-Davila MJ, Thomas MC, López MC, Segovia M. Risk factors and primary prevention of congenital Chagas disease in a nonendemic country. Clin Infect Dis. 2013;56:496–502.

    Article  CAS  PubMed  Google Scholar 

  20. Pérez-Molina JA. Management of Trypanosoma cruzi coinfection in HIV-positive individuals outside endemic areas. Curr Opin Infect Dis. 2014;27:9–15.

    Article  PubMed  Google Scholar 

  21. Fabbro DL, Streiger ML, Arias ED, Bizai ML, del Barco M, Amicone NA. Trypanocide treatment among adults with chronic Chagas disease living in Santa Fe city (Argentina), over a mean follow-up of 21 years: parasitological, serological and clinical evolution. Rev Soc Bras Med Trop. 2007;40:1–10.

    Article  PubMed  Google Scholar 

  22. Pérez-Molina JA, Pérez-Ayala A, Moreno S, Fernández-González MC, Zamora J, López-Vélez R. Use of benznidazole to treat chronic Chagas’ disease: a systematic review with a meta-analysis. J Antimicrob Chemother. 2009;64:1139–47.

    Article  CAS  PubMed  Google Scholar 

  23. Morillo CA, Marin-Neto JA, Avezum A, et al. Randomized trial of benznidazole for chronic Chagas’ cardiomyopathy. N Engl J Med. 2015;373:1295–306.

    Article  CAS  PubMed  Google Scholar 

  24. Dias JCP, Ramos AN, Gontijo ED, et al. Brazilian consensus on Chagas disease, 2015 [in Portuguese]. Epidemiol Serv Saude. 2016;25:7–86.

    PubMed  Google Scholar 

  25. Coura JR, de Abreu LL, Willcox HP, Petana W. Comparative controlled study on the use of benznidazole, nifurtimox and placebo, in the chronic form of Chagas’ disease, in a field area with interrupted transmission. I. Preliminary evaluation [in Portuguese]. Rev Soc Bras Med Trop. 1997;30:139–44.

    Article  CAS  PubMed  Google Scholar 

  26. Escribà JM, Ponce E, de Dios Romero A, et al. Treatment and seroconversion in a cohort of children suffering from recent chronic Chagas infection in Yoro, Honduras. Mem Inst Oswaldo Cruz. 2009;104:986–91.

    Article  PubMed  Google Scholar 

  27. Perez-Ayala A, Perez-Molina JA, Norman F, et al. Chagas disease in Latin American migrants: a Spanish challenge. Clin Microbiol Infect. 2011;17:1108–13.

    Article  CAS  PubMed  Google Scholar 

  28. Pinazo M-J, Muñoz J, Posada E, et al. Tolerance of benznidazole in treatment of Chagas’ disease in adults. Antimicrob Agents Chemother. 2010;54:4896–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Molina I, Salvador F, Sánchez-Montalvá A, et al. Toxic profile of benznidazole in patients with chronic Chagas disease: risk factors and comparison of the product from two different manufacturers. Antimicrob Agents Chemother. 2015;59:6125–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Jackson Y, Alirol E, Getaz L, Wolff H, Combescure C, Chappuis F. Tolerance and safety of nifurtimox in patients with chronic Chagas disease. Clin Infect Dis. 2010;51:e69–75.

    Article  CAS  PubMed  Google Scholar 

  31. Pinazo M-J, Guerrero L, Posada E, Rodríguez E, Soy D, Gascon J. Benznidazole-related adverse drug reactions and their relationship to serum drug concentrations in patients with chronic Chagas disease. Antimicrob Agents Chemother. 2013;57:390–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hasslocher-Moreno AM, do Brasil PEAA, de Sousa AS, Xavier SS, Chambela MC, Sperandio da Silva GM. Safety of benznidazole use in the treatment of chronic Chagas’ disease. J Antimicrob Chemother. 2012;67:1261–6.

    Article  CAS  PubMed  Google Scholar 

  33. Cancer Therapy Evaluation Program. Common toxicity criteria (CTC). Version 5.0. 2017. Available at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_50. Accessed 12 Feb 2018.

  34. Barclay CA, Cerisola JA, Lugones H, et al. Aspectos farmacológicos y resultados terapéuticos del benznidazol en el tratamiento de la infección chagásica. Prensa Med Argent. 1978;65:239–44.

    Google Scholar 

  35. Nyaga VN, Arbyn M, Aerts M. Metaprop: a Stata command to perform meta-analysis of binomial data. Arch Public Health. 2014;72:39.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Molina I, Gómez i Prat J, Salvador F, et al. Randomized trial of posaconazole and benznidazole for chronic Chagas’ disease. N Engl J Med. 2014;370:1899–908.

    Article  CAS  PubMed  Google Scholar 

  37. Levi GC, Lobo IM, Kallás EG, Amato Neto V. Etiological drug treatment of human infection by Trypanosoma cruzi. Rev Inst Med Trop Sao Paulo. 1996;38:35–8.

    Article  CAS  PubMed  Google Scholar 

  38. de Castro AM, Luquetti AO, Rassi A, Chiari E, Galvão LMDC. Detection of parasitemia profiles by blood culture after treatment of human chronic Trypanosoma cruzi infection. Parasitol Res. 2006;99:379–83.

    Article  PubMed  Google Scholar 

  39. Streiger ML, Barco MLD, Fabbro DL, Arias ED, Amicone NA. Estudo longitudinal e quimioterapia específica em crianças, com doença de Chagas crônica, residentes em área de baixa endemicidade da República Argentina. Rev Soc Bras Med Trop. 2004;37:365–75.

    Article  PubMed  Google Scholar 

  40. Gallerano RH, Marr JJ, Sosa RR. Therapeutic efficacy of allopurinol in patients with chronic Chagas’ disease. Am J Trop Med Hyg. 1990;43:159–66.

    Article  CAS  PubMed  Google Scholar 

  41. Salvador F, Molina I, Sulleiro E, et al. Tropical diseases screening in immigrant patients with human immunodeficiency virus infection in Spain. Am J Trop Med Hyg. 2013;88:1196–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Rodriques Coura J, de Castro SL. A critical review on Chagas disease chemotherapy. Mem Inst Oswaldo Cruz. 2002;97:3–24.

    Article  PubMed  Google Scholar 

  43. Morillo CA, Waskin H, Sosa-Estani S, et al. Benznidazole and posaconazole in eliminating parasites in asymptomatic T. cruzi carriers: the STOP-CHAGAS Trial. J Am Coll Cardiol. 2017;69:939–47.

    Article  CAS  PubMed  Google Scholar 

  44. Torrico F, Gascon J, Ortiz L, Alonso-Vega C, Pinazo M-J, Schijman A, et al. Treatment of adult chronic indeterminate Chagas disease with benznidazole and three E1224 dosing regimens: a proof-of-concept, randomised, placebo-controlled trial. Lancet Infect Dis. 2018;18(4):419–30.

    Article  CAS  PubMed  Google Scholar 

  45. Aldasoro E, Pinazo MJ, Oliveira I, et al. Arthritis and benznidazole: more closely related than we thought. Antimicrob Agents Chemother. 2015;59:727–9.

    Article  CAS  PubMed  Google Scholar 

  46. Dias JCP, Coura JR.  Clínica e terapêutica da doença de Chagas: uma abordagem prática para o clínico geral. SciELO Books. Rio de Janeiro: Ed. FIOCRUZ, 1997. p. 486. ISBN 85-85676-31-0.

    Book  Google Scholar 

  47. Wilkinson SR, Kelly JM. Trypanocidal drugs: mechanisms, resistance and new targets. Expert Rev Mol Med. 2009;11:e31.

    Article  PubMed  Google Scholar 

  48. Castro JA, de Mecca MM, Bartel LC. Toxic side effects of drugs used to treat Chagas’ disease (American trypanosomiasis). Hum Exp Toxicol. 2006;25:471–9.

    Article  CAS  PubMed  Google Scholar 

  49. Rajão MA, Furtado C, Alves CL, et al. Unveiling benznidazole’s mechanism of action through overexpression of DNA repair proteins in Trypanosoma cruzi. Environ Mol Mutagen. 2014;55:309–21.

    Article  CAS  PubMed  Google Scholar 

  50. Salvador F, Sánchez-Montalvá A, Martínez-Gallo M, et al. Evaluation of cytokine profile and HLA association in benznidazole related cutaneous reactions in patients with Chagas disease. Clin Infect Dis. 2015;61:1688–94.

    CAS  PubMed  Google Scholar 

  51. Tornheim JA, Lozano Beltran DF, Gilman RH, et al. Improved completion rates and characterization of drug reactions with an intensive Chagas disease treatment program in rural Bolivia. PLoS Negl Trop Dis. 2013;7:e2407.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Sperandio da Silva GM, Mediano MFF, Americano Alvarenga, do Brasil PE, et al. A clinical adverse drug reaction prediction model for patients with Chagas disease treated with benznidazole. Antimicrob Agents Chemother. 2014;58:6371–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Molina I, Salvador F, Sánchez-Montalvá A, et al. Pharmacokinetics of benznidazole in healthy volunteers and implications in future clinical trials. Antimicrob Agents Chemother. 2017;61:e01912–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Wiens MO, Kanters S, Mills E, et al. Systematic review and meta-analysis of the pharmacokinetics of benznidazole in the treatment of Chagas disease. Antimicrob Agents Chemother. 2016;60:7035–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Altcheh J, Moscatelli G, Mastrantonio G, et al. Population pharmacokinetic study of benznidazole in pediatric Chagas disease suggests efficacy despite lower plasma concentrations than in adults. PLoS Negl Trop Dis. 2014;8:e2907.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Hines RN. The ontogeny of drug metabolism enzymes and implications for adverse drug events. Pharmacol Ther. 2008;118:250–67.

    Article  CAS  PubMed  Google Scholar 

  57. Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology–drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349:1157–67.

    Article  CAS  PubMed  Google Scholar 

  58. Carrilero B, Murcia L, Martínez-Lage L, Segovia M. Side effects of benznidazole treatment in a cohort of patients with Chagas disease in non-endemic country. Rev Esp Quimioter. 2011;24:123–6.

    CAS  PubMed  Google Scholar 

  59. Górgolas M, Robles I, Cabello A, et al. The use of steroids to prevent cutaneous reactions to benznidazole in patients with Chagas disease. Pathog Glob Health. 2013;107:157–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Soy D, Aldasoro E, Guerrero L, et al. Population pharmacokinetics of benznidazole in adult patients with Chagas disease. Antimicrob Agents Chemother. 2015;59:3342–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Raaflaub J. Multiple-dose kinetics of the trypanosomicide benznidazole in man. Arzneimittel-Forschung. 1980;30(12):2191–4.

    Google Scholar 

  62. Pérez-Molina JA, Sojo-Dorado J, Norman F, et al. Nifurtimox therapy for Chagas disease does not cause hypersensitivity reactions in patients with such previous adverse reactions during benznidazole treatment. Acta Trop. 2013;127:101–4.

    Article  CAS  PubMed  Google Scholar 

  63. World Health Organization. The WHO adverse reaction terminology—WHO-ART. Uppsala: WHO Collaborating Centre for International Drug Monitoring; 2009.

    Google Scholar 

  64. Laplumé H, Barousse AP, Cabrera H. Efectos indeseables de Nifurtimox y Benznidazol. Medicina (B Aires). 1982;42(2):223.

    PubMed  Google Scholar 

  65. Carpintero DJ. Use of thioctic acid for prevention of the adverse effects induced by benznidazole in patients with chronic Chagas’ infection [in Spanish]. Medicina (B Aires). 1983;43:285–90.

    CAS  Google Scholar 

  66. Sosa-Estani S, Armenti A, Araujo G, et al. Treatment of Chagas disease with benznidazole and thioctic acid [in Spanish]. Medicina (B Aires). 2004;64:1–6.

    PubMed  Google Scholar 

  67. Levi GC, Amato Neto V, de Araújo Bezerra Sant’anna IF. Side-effects of Ro 7-1051, a nitroimidazole used tentatively as a specific treatment for Chagas’ disease [in Portuguese]. Rev Inst Med Trop Sao Paulo. 1975;17:49–52.

    CAS  PubMed  Google Scholar 

  68. Ferreira HD. Clinico-therapeutic trial with benzonidazole in Chagas’ disease in Portuguese]. Rev Inst Med Trop Sao Paulo. 1976;18:357–64.

    CAS  PubMed  Google Scholar 

  69. Meirovich CI, Montrull HL, Gallerano RH, Sosa RR. Allopurinol in the treatment of chronic Chagas’ disease [in Spanish]. Arq Bras Cardiol. 1985;45:217–23.

    CAS  PubMed  Google Scholar 

  70. de Arruda J. Tolerance to benzonidazole during the etiological treatment of Chagas’ disease. Arquivos brasileiros de cardiologia. 1987;48(6):395–7.

    Google Scholar 

  71. Viotti R, Vigliano C, Armenti H, Segura E. Treatment of chronic Chagas’ disease with benznidazole: clinical and serologic evolution of patients with long-term follow-up. Am Heart J. 1994;127:151–62.

    Article  CAS  PubMed  Google Scholar 

  72. Riarte A, Luna C, Sabatiello R, et al. Chagas’ disease in patients with kidney transplants: 7 years of experience 1989–1996. Clin Infect Dis. 1999;29:561–7.

    Article  CAS  PubMed  Google Scholar 

  73. Gallerano RR, Sosa RR. Interventional study in the natural evolution of Chagas disease. Evaluation of specific antiparasitic treatment. Retrospective-prospective study of antiparasitic therapy. Rev Fac Cien Med Univ Nac Cordoba. 2000;57(2):135–62.

    CAS  PubMed  Google Scholar 

  74. Anselmi M, Angheben A, Degani M, Tais S. Imported Chagas disease in Italy: the tip of the iceberg. Description of the first 10 cases treated at the Centre for Tropical Diseases [abstract]. Trop Med Int Health. 2009;14(Suppl 2):240.

    Google Scholar 

  75. de Pontes V, Souza Júnior AS, Cruz F, et al. Adverse reactions in Chagas disease patients treated with benznidazole, in the State of Ceara. Rev Soc Bras Med Trop. 2010;43:182–7.

    Article  PubMed  Google Scholar 

  76. Salvador F, Treviño B, Sulleiro E, et al. Trypanosoma cruzi infection in a non-endemic country: epidemiological and clinical profile. Clin Microbiol Infect. 2014;20:706–12.

    Article  CAS  PubMed  Google Scholar 

  77. Antinori S, Grande R, Bianco R. High frequency of adverse reactions and discontinuation with benznidazole treatment for chronic Chagas disease in Milan, Italy. Clin Infect Dis. 2015;60:1873–5.

    Article  PubMed  Google Scholar 

  78. Moreira CH. Benznidazole-related adverse drug reactions in Brazilian patients with Chagas disease [abstract]. Am J Trop Med Hyg. 2015;93(4 Suppl):336.

    Google Scholar 

  79. Alvarez MG, Hernández Y, Bertocchi G, et al. New scheme of intermittent benznidazole administration in patients chronically infected with Trypanosoma cruzi: a pilot short-term follow-up study with adult patients. Antimicrob Agents Chemother. 2016;60:833–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Diniz Marques R, da Silva Marques R, Marques RD, et al. Efficacy of benznidazole in the treatment of young people in the indeterminate phase of Chagas disease. Rev Bras Med. 2003;60(10):755–64.

    Google Scholar 

  81. Yun O, Lima MA, Ellman T, et al. Feasibility, drug safety, and effectiveness of etiological treatment programs for Chagas disease in Honduras, Guatemala, and Bolivia: 10-year experience of Médecins Sans Frontières. PLoS Negl Trop Dis. 2009;3:e488.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Altcheh J, Moscatelli G, Moroni S, Garcia-Bournissen F, Freilij H. Adverse events after the use of benznidazole in infants and children with Chagas disease. Pediatrics. 2011;127:e212–8.

    Article  PubMed  Google Scholar 

  83. Monje Rumi MM, Pérez Brandán C, Gil JF, et al. Benznidazole treatment in chronic children infected with Trypanosoma cruzi: serological and molecular follow-up of patients and identification of Discrete Typing Units. Acta Trop. 2013;128:130–6.

    Article  CAS  Google Scholar 

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Correspondence to José A. Pérez-Molina.

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Funding was provided by ISCIII (Instituto de Salud Carlos III), project “RD16/0027/0020 and RD16/0027/0002” Red de Enfermedades Tropicales, Subprograma RETICS del Plan Estatal de I + D + I 2013–2016 and by FEDER (Fondo Europeo de Desarrollo Regional).

Conflict of interest

Clara Crespillo-Andújar, Emmanuele Venanzi-Rullo, Rogelio López-Vélez, Begoña Monge-Maillo, Francesca Norman, Ana López-Polín and José A. Pérez-Molina declare that they have no conflict of interest.

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Crespillo-Andújar, C., Venanzi-Rullo, E., López-Vélez, R. et al. Safety Profile of Benznidazole in the Treatment of Chronic Chagas Disease: Experience of a Referral Centre and Systematic Literature Review with Meta-Analysis. Drug Saf 41, 1035–1048 (2018). https://doi.org/10.1007/s40264-018-0696-5

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