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Mirabegron: A Review in Overactive Bladder Syndrome

Drugs volume 78, pages 833–844 (2018)Cite this article

Abstract

The first-in-class β3-adrenoceptor agonist mirabegron is indicated in the EU (Betmiga™), Japan (Betanis™) and several other countries for the management of overactive bladder (OAB) syndrome. Evidence for its use in this setting includes several large phase 3 trials. Compared with placebo, oral mirabegron for 12 weeks reduced the frequency of micturition and generally also that of incontinence, with other benefits including reduced urgency, increased void volume and improved health related quality-of-life (HR-QOL). Mirabegron comparisons versus tolterodine are descriptive; however, in a 12-week powered comparison versus solifenacin in patients dissatisfied with antimuscarinic efficacy, mirabegron did not demonstrate noninferiority in reducing micturition frequency or significantly differ in terms of improving other urinary symptoms. Urinary and HR-QOL benefits of mirabegron were sustained over up to 52 weeks of treatment and the drug was generally well tolerated, with a numerically lower incidence of dry mouth than antimuscarinics. Real-world data support the trial findings and indicate possible persistence and adherence benefits for mirabegron over antimuscarinics. Mirabegron use is not generally restricted by patient age, sex or antimuscarinic treatment status, although data in men (from a phase 4 study and phase 3 trial subanalyses) are variable; additional studies in older and male OAB patients are awaited with interest. Although further longer-term efficacy and tolerability data would be beneficial, current clinical evidence indicates that mirabegron provides an alternative to antimuscarinics for the management of OAB in adults, including those for whom antimuscarinics have proven unsuitable.

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References

  1. Gormley EA, Lightner DJ, Faraday M, et al. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline amendment. J Urol. 2015;193(5):1572–80.

    Article  PubMed  Google Scholar 

  2. International Continence Society. Terminology: overactive bladder (OAB, urgency) syndrome. 2010. http://www.ics.org/terminology/23. Accessed 18 May 2018.

  3. Thiagamoorthy G, Cardozo L, Robinson D. Current and future pharmacotherapy for treating overactive bladder. Expert Opin Pharmacother. 2016;17(10):1317–25.

    Article  PubMed  CAS  Google Scholar 

  4. Palmer CJ, Choi JM. Pathophysiology of overactive bladder: current understanding. Curr Bladder Dysfunct Rep. 2017;12:74–9.

    Article  Google Scholar 

  5. Mayo Clinic. Overactive bladder. 2018. http://www.mayoclinic.org. Accessed 18 May 2018.

  6. Wagg A, Nitti VW, Kelleher C, et al. Oral pharmacotherapy for overactive bladder in older patients: mirabegron as a potential alternative to antimuscarinics. Curr Med Res Opin. 2016;32(4):621–38.

    Article  PubMed  CAS  Google Scholar 

  7. European Medicines Agency. Betmiga prolonged-release tablets: summary of product characteristics. 2017. http://www.ema.europa.eu/. Accessed 18 May 2018.

  8. Astellas Pharma Inc. Betanis tablet: Japanese prescribing information. Tokyo: Astellas Pharma Inc.; 2015.

    Google Scholar 

  9. Takasu T, Ukai M, Sato S, et al. Effect of (R)-2-(2-aminothiazol-4-yl)-4’-{2-[(2-hydroxy-2-phenylethyl)amino]ethyl} acetanilide (YM178), a novel selective β3-adrenoceptor agonist, on bladder function. J Pharmacol Exp Ther. 2007;321(2):642–7.

    Article  PubMed  CAS  Google Scholar 

  10. European Medicines Agency. Assessment report: Betmiga. 2012. http://www.ema.europa.eu. Accessed 19 May 2018.

  11. European Medicines Agency. EPAR summary for the public: Betmiga. 2015. http://www.ema.europa.eu. Accessed 18 May 2018.

  12. Nitti VW, Rosenberg S, Mitcheson DH, et al. Urodynamics and safety of the β3-adrenoceptor agonist mirabegron in males with lower urinary tract symptoms and bladder outlet obstruction. J Urol. 2013;190(4):1320–7.

    Article  PubMed  CAS  Google Scholar 

  13. Matsukawa Y, Takai S, Funahashi Y, et al. Urodynamic evaluation of the efficacy of mirabegron on storage and voiding functions in women with overactive bladder. Urology. 2015;85(4):786–90.

    Article  PubMed  Google Scholar 

  14. Sawada N, Nomiya M, Hood B, et al. Protective effect of a β3-adrenoceptor agonist on bladder function in a rat model of chronic bladder ischemia. Eur Urol. 2013;64(4):664–71.

    Article  PubMed  CAS  Google Scholar 

  15. Sacco E, Bientinesi R, Tienforti D, et al. Discovery history and clinical development of mirabegron for the treatment of overactive bladder and urinary incontinence. Exp Opin Drug Discov. 2014;9(4):433–48.

    Article  CAS  Google Scholar 

  16. Alexandre EC, Kiguti LR, Calmasini FB, et al. Mirabegron relaxes urethral smooth muscle by a dual mechanism involving β3-adrenoceptor activation and α1-adrenoceptor blockade. Br J Pharmacol. 2016;173(3):415–28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Malik M, van Gelderen EM, Lee JH, et al. Proarrhythmic safety of repeat doses of mirabegron in healthy subjects: a randomized, double-blind, placebo-, and active-controlled thorough QT study. Clin Pharmacol Ther. 2012;92(6):696–706.

    Article  PubMed  CAS  Google Scholar 

  18. Mo W, Michel M, Kaumann A, et al. Cardiostimulant effects of mirabegron in human atrium and ventricle in vitro [abstract no. 571]. Heart Lung Circ. 2017;26(Suppl 2):S291.

    Article  Google Scholar 

  19. van Gelderen M, Stolzel M, Meijer J, et al. An exploratory study in healthy male subjects of the mechanism of mirabegron-induced cardiovascular effects. J Clin Pharmacol. 2017;57(12):1534–44.

    Article  PubMed  CAS  Google Scholar 

  20. Nitti VW, Chapple CR, Walters C, et al. Safety and tolerability of the β3-adrenoceptor agonist mirabegron, for the treatment of overactive bladder: results of a prospective pooled analysis of three 12-week randomised phase III trials and of a 1-year randomised phase III trial. Int J Clin Pract. 2014;68(8):972–85.

    Article  PubMed  CAS  Google Scholar 

  21. Batista JE, Kolbl H, Herschorn S, et al. The efficacy and safety of mirabegron compared with solifenacin in overactive bladder patients dissatisfied with previous antimuscarinic treatment due to lack of efficacy: results of a noninferiority, randomized, phase IIIb trial. Ther Adv Urol. 2015;7(4):167–79.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Chapple CR, Kaplan SA, Mitcheson D, et al. Randomized double-blind, active-controlled phase 3 study to assess 12-month safety and efficacy of mirabegron, a β3-adrenoceptor agonist, in overactive bladder. Eur Urol. 2013;63(2):296–305.

    Article  PubMed  CAS  Google Scholar 

  23. Novack GD, Lewis RA, Vogel R, et al. Randomized, double-masked, placebo-controlled study to assess the ocular safety of mirabegron in healthy volunteers. J Ocul Pharmacol Ther. 2013;29(7):674–80.

    Article  PubMed  CAS  Google Scholar 

  24. Iitsuka H, Tokuno T, Amada Y, et al. Pharmacokinetics of mirabegron, a β3-adrenoceptor agonist for treatment of overactive bladder, in healthy Japanese male subjects: results from single- and multiple-dose studies. Clin Drug Investig. 2014;34(1):27–35.

    Article  PubMed  CAS  Google Scholar 

  25. Eltink C, Lee J, Schaddelee M, et al. Single dose pharmacokinetics and absolute bioavailability of mirabegron, a β3-adrenoceptor agonist for treatment of overactive bladder. Int J Clin Pharmacol Ther. 2012;50(11):838–50.

    Article  PubMed  CAS  Google Scholar 

  26. Krauwinkel W, van Dijk J, Schaddelee M, et al. Pharmacokinetic properties of mirabegron, a β3-adrenoceptor agonist: results from two phase I, randomized, multiple-dose studies in healthy young and elderly men and women. Clin Ther. 2012;34(10):2144–60.

    Article  PubMed  CAS  Google Scholar 

  27. Iitsuka H, van Gelderen M, Katashima M, et al. Pharmacokinetics of mirabegron, a β3-adrenoceptor agonist for treatment of overactive bladder, in healthy East Asian subjects. Clin Ther. 2015;37(5):1031–44.

    Article  PubMed  CAS  Google Scholar 

  28. Lee J, Zhang W, Moy S, et al. Effects of food intake on the pharmacokinetic properties of mirabegron oral controlled-absorption system: a single-dose, randomized, crossover study in healthy adults. Clin Ther. 2013;35(3):333–41.

    Article  PubMed  CAS  Google Scholar 

  29. Takusagawa S, van Lier JJ, Suzuki K, et al. Absorption, metabolism and excretion of [14C]mirabegron (YM178), a potent and selective β3-adrenoceptor agonist, after oral administration to healthy male volunteers. Drug Metab Dispos. 2012;40(4):815–24.

    Article  PubMed  CAS  Google Scholar 

  30. Konishi K, Tenmizu D, Takusagawa S. Identification of uridine 5′-diphosphate-glucuronosyltransferases responsible for the glucuronidation of mirabegron, a potent and selective β3-adrenoceptor agonist, in human liver microsomes. Eur J Drug Metab Pharmacokinet. 2017. https://doi.org/10.1007/s13318-017-0450-x.

    Article  Google Scholar 

  31. Lee J, Moy S, Meijer J, et al. Role of cytochrome p450 isoenzymes 3A and 2D6 in the in vivo metabolism of mirabegron, a β3-adrenoceptor agonist. Clin Drug Investig. 2013;33(6):429–40.

    Article  PubMed  CAS  Google Scholar 

  32. Dickinson J, Lewand M, Sawamoto T, et al. Effect of renal or hepatic impairment on the pharmacokinetics of mirabegron. Clin Drug Investig. 2013;33(1):11–23.

    Article  PubMed  CAS  Google Scholar 

  33. Yamaguchi O, Ikeda Y, Ohkawa S. Phase III study to assess long-term (52-week) safety and efficacy of mirabegron, a β3-adrenoceptor agonist, in Japanese patients with overactive bladder. Low Urin Tract Symptoms. 2017;9(1):38–45.

    Article  PubMed  CAS  Google Scholar 

  34. Khullar V, Amarenco G, Angulo JC, et al. Efficacy and tolerability of mirabegron, a β3-adrenoceptor agonist, in patients with overactive bladder: results from a randomised European-Australian phase 3 trial. Eur Urol. 2013;63(2):283–95.

    Article  PubMed  CAS  Google Scholar 

  35. Herschorn S, Barkin J, Castro-Diaz D, et al. A phase III, randomized, double-blind, parallel-group, placebo-controlled, multicentre study to assess the efficacy and safety of the β3 adrenoceptor agonist, mirabegron, in patients with symptoms of overactive bladder. Urology. 2013;82(2):313–20.

    Article  PubMed  Google Scholar 

  36. Kuo HC, Lee KS, Na Y, et al. Results of a randomized, double-blind, parallel-group, placebo- and active-controlled, multicenter study of mirabegron, a β3-adrenoceptor agonist, in patients with overactive bladder in Asia. Neurourol Urodyn. 2015;34(7):685–92.

    Article  PubMed  CAS  Google Scholar 

  37. Nitti VW, Auerbach S, Martin N, et al. Results of a randomized phase III trial of mirabegron in patients with overactive bladder. J Urol. 2013;189(4):1388–95.

    Article  PubMed  CAS  Google Scholar 

  38. Yamaguchi O, Marui E, Kakizaki H, et al. Phase III, randomised, double-blind, placebo-controlled study of the β3-adrenoceptor agonist mirabegron, 50 mg once daily, in Japanese patients with overactive bladder. BJU Int. 2014;113(6):951–60.

    Article  PubMed  CAS  Google Scholar 

  39. Kim HW, Shin DG, Yoon SJ, et al. Mirabegron as a treatment for overactive bladder symptoms in men: efficacy and safety results from a multicenter, randomized, double-blind, placebo-controlled, parallel comparison phase IV study (MIRACLE study) [abstract no. 273]. Neurourol Urodyn. 2017;36(Suppl. 3):S247–9.

    Google Scholar 

  40. Nitti VW, Khullar V, van Kerrebroeck P, et al. Mirabegron for the treatment of overactive bladder: a prespecified pooled efficacy analysis and pooled safety analysis of three randomised, double-blind, placebo-controlled, phase III studies. Int J Clin Pract. 2013;67(7):619–32.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Chapple CR, Nitti VW, Khullar V, et al. Onset of action of the β3-adrenoceptor agonist, mirabegron, in phase II and III clinical trials in patients with overactive bladder. World J Urol. 2014;32(6):1565–72.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Chapple C, Khullar V, Nitti VW, et al. Efficacy of the β3-adrenoceptor agonist mirabegron for the treatment of overactive bladder by severity of incontinence at baseline: a post hoc analysis of pooled data from three randomised phase 3 trials. Eur Urol. 2015;67(1):11–4.

    Article  PubMed  CAS  Google Scholar 

  43. Khullar V, Amarenco G, Angulo JC, et al. Patient-reported outcomes with the β3-adrenoceptor agonist mirabegron in a phase III trial in patients with overactive bladder. Neurourol Urodyn. 2016;35(8):987–94.

    Article  PubMed  CAS  Google Scholar 

  44. Castro-Diaz D, Chapple CR, Hakimi Z, et al. The effect of mirabegron on patient-related outcomes in patients with overactive bladder: the results of post hoc correlation and responder analyses using pooled data from three randomized phase III trials. Qual Life Res. 2015;24(7):1719–27.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Khullar V, Cambronero J, Angulo JC, et al. Efficacy of mirabegron in patients with and without prior antimuscarinic therapy for overactive bladder: a post hoc analysis of a randomized European-Australian phase 3 trial. BMC Urol. 2013;13(45):1–9.

    Google Scholar 

  46. Wagg A, Cardozo L, Nitti VW, et al. The efficacy and tolerability of the β3-adrenoceptor agonist mirabegron for the treatment of symptoms of overactive bladder in older patients. Age Ageing. 2014;43(5):666–75.

    Article  PubMed  Google Scholar 

  47. Tubaro A, Batista JE, Nitti VW, et al. Efficacy and safety of daily mirabegron 50 mg in male patients with overactive bladder: a critical analysis of five phase III studies. Ther Adv Urol. 2017;9(6):137–54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Nozawa Y, Kato D, Tabuchi H, et al. Safety and effectiveness of mirabegron in patients with overactive bladder in a real-world clinical setting: a Japanese post-marketing study. Low Urin Tract Symptoms. 2016. https://doi.org/10.1111/luts.12148.

    Article  PubMed  Google Scholar 

  49. Kato D, Tabuchi H, Uno S. Safety, efficacy, and persistence of long-term mirabegron treatment for overactive bladder in the daily clinical setting: interim (1-year) report from a Japanese post-marketing surveillance study. Low Urin Tract Symptoms. 2017. https://doi.org/10.1111/luts.12188.

    Article  PubMed  Google Scholar 

  50. Yoshida M, Nozawa Y, Kato D, et al. Safety and effectiveness of mirabegron in patients with overactive bladder aged ≥ 75 years: analysis of a Japanese post-marketing study. Low Urin Tract Symptoms. 2017. https://doi.org/10.1111/luts.12190.

    Article  PubMed  Google Scholar 

  51. Kato D, Uno S, Van Schyndle J, et al. Persistence and adherence to overactive bladder medications in Japan: a large nationwide real-world analysis. Int J Urol. 2017;24(10):757–64.

    Article  PubMed  CAS  Google Scholar 

  52. Wagg A, Franks B, Ramos B, et al. Persistence and adherence with the new β3 receptor agonist, mirabegron, versus antimuscarinics in overactive bladder: early experience in Canada. Can Urol Assoc J. 2015;9(9–10):343–50.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Sussman D, Yehoshua A, Kowalski J, et al. Adherence and persistence of mirabegron and anticholinergic therapies in patients with overactive bladder: a real-world claims data analysis. Int J Clin Pract. 2017. https://doi.org/10.1111/ijcp.12824.

    PubMed  Article  Google Scholar 

  54. Chapple CR, Nazir J, Hakimi Z, et al. Persistence and adherence with mirabegron versus antimuscarinic agents in patients with overactive bladder: a retrospective observational study in UK clinical practice. Eur Urol. 2017;72(3):389–99.

    Article  PubMed  CAS  Google Scholar 

  55. Astellas Pharma Ltd. Mirabegron (Betmiga)—new recommendations about the risk of increase in blood pressure [media release]. Sep 2015. http://assets.publishing.service.gov.uk.

  56. Corcos J, Przydacz M, Campeau L, et al. CUA guideline on adult overactive bladder. Can Urol Assoc J. 2017;11(5):E142–73.

    Article  PubMed  PubMed Central  Google Scholar 

  57. National Institute for Health and Care Excellence. Urinary incontinence in women: management. Clinical guideline. 2013. http://www.nice.org.uk/guidance/cg171. Accessed 18 May 2018.

  58. Kim TH, Lee KS. Persistence and compliance with medication management in the treatment of overactive bladder. Investig Clin Urol. 2016;57(2):84–93.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Benner JS, Nichol MB, Rovner ES, et al. Patient-reported reasons for discontinuing overactive bladder medication. BJU Int. 2010;105(9):1276–82.

    Article  PubMed  Google Scholar 

  60. Sharaf AA, Hashim H. Profile of mirabegron in the treatment of overactive bladder: place in therapy. Drug Des Dev Ther. 2017;11:463–7.

    Article  CAS  Google Scholar 

  61. Wallace KM, Drake MJ. Overactive bladder. F1000Res. 2016. https://doi.org/10.12688/f1000research.7131.1. Accessed 18 May 2018.

    Article  Google Scholar 

  62. Athanasopoulos A, Giannitsas K. An overview of the clinical use of antimuscarinics in the treatment of overactive bladder. Adv Urol. 2011;2011:820816.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Andersson KE, Sarawate C, Kahler KH, et al. Cardiovascular morbidity, heart rates and use of antimuscarinics in patients with overactive bladder. BJU Int. 2010;106(2):268–74.

    Article  PubMed  Google Scholar 

  64. Rosa GM, Ferrero S, Nitti VW, et al. Cardiovascular safety of β3-adrenoceptor agonists for the treatment of patients with overactive bladder syndrome. Eur Urol. 2016;69(2):311–23.

    Article  PubMed  CAS  Google Scholar 

  65. Chapple CR, Siddiqui E. Mirabegron for the treatment of overactive bladder: a review of efficacy, safety and tolerability with a focus on male, elderly and antimuscarinic poor-responder populations, and patients with OAB in Asia. Expert Rev Clin Pharmacol. 2017;10(2):131–51.

    Article  PubMed  CAS  Google Scholar 

  66. Leonard CE, Reichman ME, Toh D, et al. Mini-Sentinel Prospective Surveillance Plan: prospective routine observational monitoring of mirabegron. 2016. http://www.sentinelinitiative.org. Accessed 18 May 2018.

  67. Simeone JC, Nordstrom BL, Appenteng K, et al. Replication of Mini-Sentinel study assessing mirabegron and cardiovascular risk in non-Mini-Sentinel databases. Drugs Real World Outcomes. 2018;5(1):25–34.

    Article  PubMed  Google Scholar 

  68. Kakizaki H, Lee KS, Yamamoto O, et al. Efficacy and safety of add-on mirabegron vs. placebo to tamsulosin in men with overactive bladder symptoms (MATCH study) [abstract no. LBA13]. J Urol. 2018;199(4S Suppl.):e988.

    Article  Google Scholar 

  69. Maman K, Aballea S, Nazir J, et al. Comparative efficacy and safety of medical treatments for the management of overactive bladder: a systematic literature review and mixed treatment comparison. Eur Urol. 2014;65(4):755–65.

    Article  PubMed  CAS  Google Scholar 

  70. European Association of Urology. Guidelines on urinary incontinence. 2015. https://uroweb.org/wp-content/uploads/20-Urinary-Incontinence_LR.pdf. Accessed 21 Mar 2018.

  71. National Institute for Health and Care Excellence. Mirabegron for treating symptoms of overactive bladder. Technology appraisal guidance. 2013. http://www.nice.org.uk. Accessed 18 May 2018.

  72. Nazir J, Berling M, McCrea C, et al. Economic impact of mirabegron versus antimuscarinics for the treatment of overactive bladder in the UK. Pharmacoecon Open. 2017;1(1):25–36.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Nazir J, Maman K, Neine ME, et al. Cost-effectiveness of mirabegron compared with antimuscarinic agents for the treatment of adults with overactive bladder in the United Kingdom. Value Health. 2015;18(6):783–90.

    Article  PubMed  Google Scholar 

  74. Aballea S, Maman K, Thokagevistk K, et al. Cost effectiveness of mirabegron compared with tolterodine extended release for the treatment of adults with overactive bladder in the United Kingdom. Clin Drug Investig. 2015;35(2):83–93.

    Article  PubMed  Google Scholar 

  75. Angulo JC, Sanchez-Ballester F, Peral C, et al. Cost effectiveness analysis of fesoterodine compared to mirabegron in first-line therapy setting for overactive bladder with urge urinary incontinence, from the Spanish National Health System perspective. Actas Urol Esp. 2016;40(8):513–22.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

During the peer review process, the manufacturer of mirabegron was also offered the opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

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    Emma D. Deeks

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The preparation of this review was not supported by any external funding.

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Emma D. Deeks is a salaried employee of Adis/Springer, is responsible for the article content and declares no relevant conflicts of interest.

Additional information

The manuscript was reviewed by: K. E. Andersson, Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA; H. Kuo, Department of Urology, Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien, Taiwan; E. Sacco, Department of Urology, Agostino Gemelli Hospital, Catholic University Medical School, Rome, Italy; A. Wagg, Division of Geriatric Medicine, University of Alberta, Edmonton, AB, Canada.

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Deeks, E.D. Mirabegron: A Review in Overactive Bladder Syndrome. Drugs 78, 833–844 (2018). https://doi.org/10.1007/s40265-018-0924-4

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