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Bladder sedatives mirabegron vs antimuscarinics in overactive bladder

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Initial management of overactive bladder includes behavioural modifications, urge inhibition and pharmacotherapy. until recently, antimuscarinics have been cornerstone pharmacotherapeutic agents. their long term usage has been limited due to side effects particularly, but not limited to, constipation, dry mouth, cognitive impairment and tachycardia. Mirabegron, a beta3 agonist, is new kid on the block been available in India since mid 2018. The potential benefits over antimuscarics are significantly less side effects and equivalent efficacy. the potential side effect of hypertension has not been found significant over placebo. Already found a place as second line therapy and comination therapy, it is increasingly being accepted as first line alternative.

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Bladder sedatives mirabegron vs antimuscarinics in overactive bladder

  1. 1. MIRABEGRON: NEW KID ON THE BLOCK ​Dr Mayank Mohan Agarwal MBBS, MS, MRCS(Ed), ​DNB, M.Ch (PGIMER, Chandigarh) VMMF and IAUA Fellowships Uro-Oncology, Pelvic Floor Reconstruction (MSKCC, NY; UCLA, LA; WFUBMC, NC)​ Ex-Associate Professor of Urology (PGIMER, Chandigarh) Consultant and Head of Urology (Aster) Dr. Ramesh Cardiac and Multispecialty Hospitals Pvt. Ltd. Guntur (AP), India
  2. 2. INTRODUCTION • Physiology of lower urinary tract • Receptors in lower urinary tract • Pathophysiology of overactive bladder • Shortcomings of current medications • Mirabegron – efficacy • Mirabegron – safety • Guideline statement
  3. 3. FILLING PHASE + SY + SO - PSY - SY + - BLADDER ↔ URETHRA REFLEXES
  4. 4. VOIDING PHASE - SY - SO + PSY - + BLADDER ↔ URETHRA REFLEXES
  5. 5. OAB: definition • urinary urgency, with or without urgency incontinence, usually with increased daytime frequency and nocturia, if there is no proven infection or other obvious pathology
  6. 6. OAB: pathogenesis
  7. 7. Patchy denervation is a common observation in DO, regardless of etiology (German et al, 1995; Charlton et al, 1999; Drake et al, 2000; Mills et al, 2000). A smooth muscle cell deprived of its innervation shows an upregulation of surface membrane receptors and may have altered membrane potential, which increases the likelihood of spontaneous contraction in that cell.
  8. 8. Antimuscarinics
  9. 9. Adverse effects
  10. 10. Adverse effects • QT prolongation - Not related to blockade of muscarinic receptors - linked to inhibition of the hERG potassium channel in the heart • CNS side effects - cognitive dysfunction - memory impairment - Dizziness - Fatigue - headache
  11. 11. Mirabegron • Beta 3 receptor agonist • Mild alpha 1a and 1d blocker • Mild M2 antagonist Alexandre et al. Mirabegron relaxes urethral smooth muscle by a dual mechanism involving β3- adrenoceptor activation and α1-adrenoceptor blockade. British Journal of Pharmacology (2016) 173 415–428 415
  12. 12. Efficacy of Mirabegron: vs placebo • Meta-analysis (1) • 4 phase III RCT’s • SCORPIO • ARIES • CAPRICORN • 178-CL-048 • N (Mirabegron) = 1759 N (placebo) = 1765 • Duration 50w (~1yr) Cui et al. The efficacy and safety of mirabegron in treating OAB: a systematic review and meta-analysis of phase III trials. Int Urol Nephrol (2014) 46:275–284
  13. 13. Efficacy of Mirabegron: vs placebo • Meta-analysis (1) • 4 phase III RCT’s • SCORPIO • ARIES • CAPRICORN • 178-CL-048 • N (Mirabegron) = 1759 N (placebo) = 1765 Cui et al. The efficacy and safety of mirabegron in treating OAB: a systematic review and meta-analysis of phase III trials. Int Urol Nephrol (2014) 46:275–284 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 D incontinence episodes D no. of voids D no. of urgency episodes D. no. of nocturia efficacy
  14. 14. Efficacy of Mirabegron: vs placebo • Meta-analysis (1) • 4 phase III RCT’s • SCORPIO • ARIES • CAPRICORN • 178-CL-048 • N (Mirabegron) = 1759 N (placebo) = 1765 • Duration 50w (~1yr) Cui et al. The efficacy and safety of mirabegron in treating OAB: a systematic review and meta-analysis of phase III trials. Int Urol Nephrol (2014) 46:275–284 -1 -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 Adverse effects p = NS
  15. 15. Efficacy of Mirabegron: vs placebo • Meta-analysis (2) • 5 phase III RCT’s • N (placebo) = 1610 • N (Mirabegron 25) = 597 • N (Mirabegron 50) = 2354 • N (Mirabegron 100) = 1982 Wu et al. The Role of Mirabegron in Overactive Bladder: A Systematic Review and Meta-Analysis. Urol Int 2014;93:326–337
  16. 16. Efficacy of Mirabegron: vs placebo • Meta-analysis (2) • 5 phase III RCT’s • N (placebo) = 1610 • N (Mirabegron 25) = 597 • N (Mirabegron 50) = 2354 • N (Mirabegron 100) = 1982 Wu et al. The Role of Mirabegron in Overactive Bladder: A Systematic Review and Meta-Analysis. Urol Int 2014;93:326–337 INCONTINENCE EPISODES IN 24H
  17. 17. Efficacy of Mirabegron: vs placebo • Meta-analysis (2) • 5 phase III RCT’s • N (placebo) = 1610 • N (Mirabegron 25) = 597 • N (Mirabegron 50) = 2354 • N (Mirabegron 100) = 1982 Wu et al. The Role of Mirabegron in Overactive Bladder: A Systematic Review and Meta-Analysis. Urol Int 2014;93:326–337 NO. OF MICTURITIONS IN 24H
  18. 18. Efficacy of Mirabegron: vs placebo • Meta-analysis (2) • 5 phase III RCT’s • N (placebo) = 1610 • N (Mirabegron 25) = 597 • N (Mirabegron 50) = 2354 • N (Mirabegron 100) = 1982 Wu et al. The Role of Mirabegron in Overactive Bladder: A Systematic Review and Meta-Analysis. Urol Int 2014;93:326–337 ADVERSE EFFECTS
  19. 19. Efficacy of Mirabegron: vs tolterodine • Meta-analysis (2) • 4 phase III RCT’s • N (placebo) = 724 • N (Mirabegron 25) = 167 • N (Mirabegron 50) = 1472 • N (Mirabegron 100) = 1549 • N (tolterodine 4) = 1455 Wu et al. The Role of Mirabegron in Overactive Bladder: A Systematic Review and Meta-Analysis. Urol Int 2014;93:326–337
  20. 20. Efficacy of Mirabegron: vs tolterodine • Meta-analysis (2) • 4 phase III RCT’s • N (placebo) = 724 • N (Mirabegron 25) = 167 • N (Mirabegron 50) = 1472 • N (Mirabegron 100) = 1549 • N (tolterodine 4) = 1455 Wu et al. The Role of Mirabegron in Overactive Bladder: A Systematic Review and Meta-Analysis. Urol Int 2014;93:326–337INCONTINENCE EPISODES IN 24H
  21. 21. Efficacy of Mirabegron: vs tolterodine • Meta-analysis (2) • 4 phase III RCT’s • N (placebo) = 724 • N (Mirabegron 25) = 167 • N (Mirabegron 50) = 1472 • N (Mirabegron 100) = 1549 • N (tolterodine 4) = 1455 Wu et al. The Role of Mirabegron in Overactive Bladder: A Systematic Review and Meta-Analysis. Urol Int 2014;93:326–337 NO. OF MICTURITIONS IN 24H
  22. 22. Efficacy of Mirabegron: vs tolterodine • Meta-analysis (2) • 4 phase III RCT’s • N (placebo) = 724 • N (Mirabegron 25) = 167 • N (Mirabegron 50) = 1472 • N (Mirabegron 100) = 1549 • N (tolterodine 4) = 1455 Wu et al. The Role of Mirabegron in Overactive Bladder: A Systematic Review and Meta-Analysis. Urol Int 2014;93:326–337ADVERSE EFFECTS
  23. 23. Adverse effects antimuscarinics AUA 2014
  24. 24. Mirabegron add on to Solifenacin • N = 223 Yamaguchi et al. Safety and efficacy of mirabegron as ‘add-on’ therapy in patients with overactive bladder treated with solifenacin: a post-marketing, open-label study in Japan (MILAI study). BJU Int 2015; 116: 612–622
  25. 25. Mirabegron add on to Solifenacin • N = 223 Yamaguchi et al. Safety and efficacy of mirabegron as ‘add-on’ therapy in patients with overactive bladder treated with solifenacin: a post-marketing, open-label study in Japan (MILAI study). BJU Int 2015; 116: 612–622
  26. 26. Mirabegron add on to Solifenacin • N = 223 Yamaguchi et al. Safety and efficacy of mirabegron as ‘add-on’ therapy in patients with overactive bladder treated with solifenacin: a post-marketing, open-label study in Japan (MILAI study). BJU Int 2015; 116: 612–622
  27. 27. Mirabegron add on to Solifenacin • N = 223 Yamaguchi et al. Safety and efficacy of mirabegron as ‘add-on’ therapy in patients with overactive bladder treated with solifenacin: a post-marketing, open-label study in Japan (MILAI study). BJU Int 2015; 116: 612–622
  28. 28. Mirabegron add on to Solifenacin • N = 2174 • Combination = 727 • Solifenacin 5 = 728 • Solifenacin 10 =719 Drake et al. Efficacy and Safety of Mirabegron Add-on Therapy to Solifenacin in Incontinent Overactive Bladder Patients with an Inadequate Response to Initial 4-Week Solifenacin Monotherapy: A Randomised Double-blind Multicentre Phase 3B Study (BESIDE). EUROPEAN UROLOGY 7 0 ( 2 0 1 6 ) 1 3 6 – 1 4 5
  29. 29. Mirabegron add on to Solifenacin
  30. 30. Mirabegron add on to Solifenacin • N = 2174 • Combination = 727 • Solifenacin 5 = 728 • Solifenacin 10 =719 Drake et al. Efficacy and Safety of Mirabegron Add-on Therapy to Solifenacin in Incontinent Overactive Bladder Patients with an Inadequate Response to Initial 4-Week Solifenacin Monotherapy: A Randomised Double-blind Multicentre Phase 3B Study (BESIDE). EUROPEAN UROLOGY 7 0 ( 2 0 1 6 ) 1 3 6 – 1 4 5
  31. 31. Mirabegron add on to Solifenacin • N = 2174 • Combination = 727 • Solifenacin 5 = 728 • Solifenacin 10 =719 Drake et al. Efficacy and Safety of Mirabegron Add-on Therapy to Solifenacin in Incontinent Overactive Bladder Patients with an Inadequate Response to Initial 4-Week Solifenacin Monotherapy: A Randomised Double-blind Multicentre Phase 3B Study (BESIDE). EUROPEAN UROLOGY 7 0 ( 2 0 1 6 ) 1 3 6 – 1 4 5 INCONTINENCE EPISODES IN 24H
  32. 32. Mirabegron add on to Solifenacin • N = 2174 • Combination = 727 • Solifenacin 5 = 728 • Solifenacin 10 =719 Drake et al. Efficacy and Safety of Mirabegron Add-on Therapy to Solifenacin in Incontinent Overactive Bladder Patients with an Inadequate Response to Initial 4-Week Solifenacin Monotherapy: A Randomised Double-blind Multicentre Phase 3B Study (BESIDE). EUROPEAN UROLOGY 7 0 ( 2 0 1 6 ) 1 3 6 – 1 4 5 NO. OF MICTURITIONS IN 24H
  33. 33. Mirabegron add on to Solifenacin • N = 2174 • Combination = 727 • Solifenacin 5 = 728 • Solifenacin 10 =719 Drake et al. Efficacy and Safety of Mirabegron Add-on Therapy to Solifenacin in Incontinent Overactive Bladder Patients with an Inadequate Response to Initial 4-Week Solifenacin Monotherapy: A Randomised Double-blind Multicentre Phase 3B Study (BESIDE). EUROPEAN UROLOGY 7 0 ( 2 0 1 6 ) 1 3 6 – 1 4 5
  34. 34. Possibility of continuing medication • N = 380 (mirabegron) • N = 2248 (tolterodine)
  35. 35. Possibility of continuing medication • N = 380 (mirabegron) • N = 2248 (tolterodine) 0 10 20 30 40 50 60 70 80 30 d 90 d 180 d Probability of remaining on treatment mirabegron tolterodine
  36. 36. What do guidelines say • EUROPEAN ASSOCIATON OF UROLOGY 2018
  37. 37. What do guidelines say • AMERICAN UROLOGICAL ASSOCIATION 2014
  38. 38. PHARMACOLOGY • ABSORPTION - 25% 25MG - 35% 50MG • TMAX – 3-4 HOURS • T1/2 – 40HOURS • 71% PLASMA PROTEIN BOUND • METABOLIZED IN LIVER WITH CYTP450 SYSTEM REDUCED WITH FOOD HIGHER IN WOMEN 55% IN URINE 34% IN FECES UNCHANGED
  39. 39. CAUTIONS • PREGNANCY CATEGORY C • DOSE ADJUSTMENT IN • SEVERE RENAL DISEASE (AUC ↑ 118% AND CMAX ↑ 92%) • MODERATE LIVER DISEASE (AUC ↑ 65% AND CMAX ↑ 175%) • Caution with CYP2D6/3A4 substrates with a narrow therapeutic index • Anticoagulants • Antidepressants • antiepileptics
  40. 40. CONCLUSION • Mirabegron is safe with side effect profile similar to placebo • Mirabegron is as effective as antimuscarinics in OAB • Mirabegron can be considered as first line therapy alternative to antimuscarinics • Mirabegron added on to solifenacin is more effective than increasing dose
  41. 41. THANK YOU

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