TREATMENT OF OVERACTIVE BLADDER IN ADULTS FUGA 2016 KGH

TREATMENT OF OVERACTIVE BLADDER IN ADULTS FUGA 2016 KGH

CONTENTS Overactive bladder (OAB) Treatment of OAB Beta-3 adrenoceptor agonist (Betmiga ) - Panacea? LASER treatment - a flash in the pan or the real future?

Overactive bladder (OAB)

OVERLAP BETWEEN OAB

TYPE OF OAB OAB Dry +

TREATMENT OF OVERACTIVE BLADDER IN ADULTS AUA/SUFU Guideline (2012); Amended (2014) Diagnosis & Treatment Algorithm: AUA/SUFU Guideline on Non-Neurogenic Overactive Bladder in Adults History and Physical; Urinalysis Diagnosis unclear or additional information needed Consider urine culture, post-void residual, bladder diary, and/or symptom questionnaires Not OAB or Complicated OAB; treat or refer Signs/symptoms of OAB, (-) urine microscopy Signs/symptoms of OAB Patient education: - Normal urinary tract function - Benefits/risks of treatment alternatives - Agree on treatment goals Patient desires treatment, is willing to engage in treatment, and/or treatment is in patient s best interests Follow-up for efficacy and adverse events Behavioral Treatments Standard (consider adding pharmacologic management if partially effective) Treatment goals not met after appropriate duration*; Patient desires further treatment, is willing to engage in treatment, and/or further treatment in patient s best interests Treatment goals met In extremely rare cases, consider urinary diversion or augmentation cystoplasty Pharmacologic management Standard With active management of adverse events; consider dose modification or alternate medication if initial treatment is effective but adverse events or other considerations preclude continuation Treatment goals not met after appropriate duration*; Patient desires further treatment, is willing to engage in treatment, and/or further treatment in patient s best interests Reassess and/or refer; consider urine culture, post-void residual, bladder diary, symptom questionnaires, other diagnostic procedures as necessary for differentiation Signs/symptoms consistent with OAB diagnosis; Treatment goals not met after appropriate duration*; Patient desires further treatment, is willing to engage in treatment, and/or further treatment in patient s best interests Consider in carefully-selected and thoroughly-counseled patients with moderate to severe symptoms Intradetrusor onabotulinumtoxina Standard (patients must be willing to perform CISC) OR Peripheral tibial nerve stimulation (PTNS) Recommendation (patients must be willing and able to make frequent office visits) OR Sacral neuromodulation (SNS) Recommendation The complete OAB Guideline is available at www.auanet.org/guidelines. Copyright 2014 American Urological Association Education and Research, Inc. *Appropriate duration is 8 to 12 weeks for behavioral therapies and 4 to 8 weeks for pharmacologic therapies

DIAGNOSIS OF OAB The clinician should engage in a diagnostic process to document symptoms and signs that characterize OAB and exclude other disorders that could be the cause of the patient s symptoms; the minimum requirements for this process are a careful history, physical exam, and urinalysis. OAB is not a disease; it is a symptom complex that generally is not a life-threatening condition. After assessment has been performed to exclude conditions requiring treatment and counseling, no treatment is an acceptable choice made by some patients and caregivers. Clinicians should provide education to patients regarding normal lower urinary tract function, what is known about OAB, the benefits vs. risks/burdens of the available treatment alternatives and the fact that acceptable symptom control may require trials of multiple therapeutic options before it is achieved.

Treatment of OAB

TREATMENT OF OAB First-Line Treatments: 1. Clinicians should offer behavioral therapies (e.g., bladder training, bladder control strategies, pelvic floor muscle training, fluid management) as first line therapy to all patients with OAB. 2. Behavioral therapies may be combined with pharmacologic management.

TREATMENT OF OAB Second-Line Treatments: 1. Clinicians should offer oral anti-muscarinics or oral ß3-adrenoceptor agonists as second-line therapy. 2. If an immediate release (IR) and an extended release (ER) formulation are available, then ER formulations should preferentially be prescribed over IR formulations because of lower rates of dry mouth. 3. Transdermal (TDS) oxybutynin (patch [now available to women ages 18 years and older without a prescription] or gel) may be offered.

TREATMENT OF OAB Second-Line Treatments: 4. If a patient experiences inadequate symptom control and/or unacceptable adverse drug events with one anti-muscarinic medication, then a dose modification or a different anti-muscarinic medication or b3-adrenoceptor agonist may be tried. 5. Clinicians should not use anti-muscarinics in patients with narrow angle glaucoma unless approved by the treating ophthalmologist and should use anti-muscarinics with extreme caution in patients with impaired gastric emptying or a history of urinary retention.

TREATMENT OF OAB Second-Line Treatments: 6. Clinicians should manage constipation and dry mouth before abandoning effective anti-muscarinic therapy. Management may include bowel management, fluid management, dose modification or alternative anti-muscarinics. 7. Clinicians must use caution in prescribing anti-muscarinics in patients who are using other medications with anti-cholinergic properties. 8. Clinicians should use caution in prescribing anti-muscarinics or ß3- adrenoceptor agonists in the frail OAB patient. 9. Patients who are refractory to behavioral and pharmacologic therapy should be evaluated by an appropriate specialist if they desire additional therapy.

TREATMENT OF OAB Third-Line Treatments: 1. Specialists may offer intradetrusor onabotulinumtoxina (100U) as third-line treatment in the carefully-selected and thoroughlycounseled patient who has been refractory to first- and second-line OAB treatments. The patient must be able and willing to return for frequent post-void residual evaluation and able and willing to perform self-catheterization if necessary. 2. Specialists may offer peripheral tibial nerve stimulation (PTNS) as third line treatment in a carefully selected patient population.

TREATMENT OF OAB Third-Line Treatments: 3. Specialists may offer sacral neuromodulation (SNS) as third-line treatment in a carefully-selected patient population characterized by severe refractory OAB symptoms or patients who are not candidates for second-line therapy and are willing to undergo a surgical procedure. 4. Practitioners and patients should persist with new treatments for an adequate trial in order to determine whether the therapy is efficacious and tolerable.

TREATMENT OF OAB Additional Treatments: 1. Indwelling catheters (including transurethral, suprapubic, etc.) are not recommended as a management strategy for OAB because of the adverse risk/benefit balance except as a last resort in selected patients. 2. In rare cases, augmentation cystoplasty or urinary diversion for severe, refractory, complicated OAB patients may be considered.

TREATMENT OF OAB Treatments follow-up: Combination therapeutic approaches should be assembled methodically, with the addition of new therapies occurring only when the relative efficacy of the preceding therapy is known. Therapies that do not demonstrate efficacy after an adequate trial should be ceased. The clinician should offer follow up with the patient to assess compliance, efficacy, side effects, and possible alternative treatments.

PERSISTENCE WITH ANTIMUSCARINICS CAN BE A CHALLENGE 100 90 80 70 Solifenacin (n=1,381) Tolterodine ER (n=1,758) Tolterodine IR (n=482) Oxybutynin ER (n=590) Oxybutynin IR (n=1371) Propiverine (n=97) Trospium (n=352) Darifenacin (n=23) Flavoxate (n=89) Patients (%) 60 50 40 30 20 10 0 1 2 3 4 5 6 7 8 9 10 11 12 Months ER, extended release; IR, immediate release Adapted from Wagg et al. BJU Int 2012;110(11):1767-74.

Beta-3 adrenoceptor agonist (Betmiga ) - Panacea?

BETMIGA MODE OF ACTION Nerve pathways in normal bladder control Mode of action of OAB treatments Adapted from Chu FM, Dmochowski R. Am J Med 2006;119(3 Suppl 1):3 8.

Beta-3 adrenoceptor agonist BETMIGA PHASE 3 CLINICAL TRIAL PROGRAMME

CO-PRIMARY ENDPOINTS 24 (FAS-I) 24 (FAS) 11.55 FAS, Full Analysis Set FAS-I, FAS Incontinence *Statistically significantly superior compared with placebo at the 0.05 level with multiplicity adjustments Adapted from Khullar V, et al. Eur Urol 2013;63(2):283 95.

CO-PRIMARY ENDPOINTS Mean change from baseline in mean number of incontinence episodes per 24 hrs Baseline Week 4 Week 8 Week 12 0-0.6-1.3-1.9-2.5 * * Placebo Mirabegron 50 mg Mirabegron 100 mg Tolterodine ER 4 mg (n = 291) (n = 293) (n = 300) NS * NS * FAS Incontinence Set NS, No statistically significant improvement versus placebo *Statistically significantly superior compared with placebo at the 0.05 level with multiplicity adjustments Adapted from Khullar V, et al. Eur Urol 2013;63(2):283 95.

CO-PRIMARY ENDPOINTS Mean change from baseline in mean number of micturitions per 24 hrs Baseline Week 4 Week 8 Week 12 0-0.6-1.3-1.9-2.5 * * NS NS * * Placebo Mirabegron 50 mg Mirabegron 100 mg Tolterodine ER 4 mg (n=480) (n=473) (n=475) FAS Full Ananlysis Set NS, No statistically significant improvement versus placebo *Statistically significantly superior compared with placebo at the 0.05 level with multiplicity adjustments Adapted from Khullar V, et al. Eur Urol 2013;63(2):283 95.

CO-PRIMARY ENDPOINTS 24 (FAS-I) 24 (FAS) FAS, Full Analysis Set FAS-I, FAS Incontinence *Statistically significantly superior compared with placebo at the 0.05 level with multiplicity adjustments Adapted from Herschorn S, et al. Urology. 2013 Aug;82(2):313-20.

MIRABEGRON SIGNIFICANTLY IMPROVED SYMPTOM BOTHER (OAB-Q) AT EACH VISIT (FAS) Improvement Mean change from baseline to final visit in symptom bother 0-5.0-10.0 * -15.0-20.0 * * * -25.0 * Baseline Week 4 Week 8 Week 12 Final Visit Placebo Mirabegron 50 mg Tolterodine ER 4 mg * * * (n=475) (n=465) (n=469) FAS, Full Analysis Set OAB-q, overactive bladder questionnaire 1. Adapted from Khullar V, et al. Eur Urol 2013;63(2):283 95. * Statistically significant improvement versus placebo at 0.05 level

MIRABEGRON SIGNIFICANTLY IMPROVED TREATMENT SATISFACTION AT FINAL VISIT Improvement Mean change from baseline to final visit in TS-VAS 3.0 2.5 2.0 1.5 1.0 0.5 0 Placebo (n=428) Mirabegron 50 mg (n=414) * Tolterodine ER 4 mg (n=425) * * Statistically significant improvement versus placebo at 0.05 level FAS, Full Analysis Set; TS-VAS, Treatment Satisfaction Visual Analog Scale 1. Adapted from Khullar V, et al. Eur Urol 2013;63(2):283 95.

MIRABEGRON SIGNIFICANTLY IMPROVED TOTAL HRQOL SCORE AT FINAL VISIT COMPARED WITH PLACEBO Improvement Mean change from baseline to final visit in total HRQoL 20.0 15.0 10.0 5.0 * * 0 Baseline Week 4 Week 8 Week 12 Final Visit Placebo Mirabegron 50 mg Tolterodine ER 4 mg (n = 428) (n = 414) (n = 425) * Statistically significant improvement versus placebo at 0.05 level *Data are least squares mean adjusted for baseline, gender and geographical region; Statistically significantly superior compared with placebo at the 0.05 level; HRQoL=health-related quality of life; OAB-q=Overactive Bladder Questionnaire; FAS=full analysis set 1. Adapted from Khullar V, et al. Eur Urol 2013;63(2):283 95.

Mean change from baseline to final visit in micturitions per 24 hrs 0-0.24-0.48-0.72-0.96-1.20-1.44-1.68-1.92-2.16-2.40 Pre-specified subgroup analysis by prior OAB therapy Pooled data ISE (046/047/074): micturition frequency (FAS) (n=704) -0.93 FAS, Full Analysis Set ISE, Integrated Summary of Effectiveness OAB Baseline 11.53 11.78 11.62 11.61-0.74 (CI -1.01, -0.47) Placebo (n=688) (n=624) -1.67-1.51 Mirabegron 50 mg 1. Adapted from Nitti VW, et al. Int J Clin Pract. 2013 Jul;67(7):619-32. OAB -0.33 (CI -0.62, -0.05) (n=636) -1.84 OAB

Post-hoc subgroup analysis : Previous OAB therapy discontinued due to insufficient efficacy: micturitions (FAS) Mean change from baseline to final visit in micturitions per 24 hrs Baseline 0-0.20-0.40-0.60-0.80-1.00-1.20-1.40-1.60-1.80-2.00 FAS, Full Analysis Set -1.03 Placebo Mirabegron 50 mg Tolterodine ER 4 mg 11.89 11.49 11.99 (n=159) -0.59 (CI -1.15, -0.04) (n=160) -1.62 1. Adapted from Khullar et al. BMC Urology 2013, 13:45-0.08 (CI -0.64, 0.47) OAB (n=155) -1.11

Once daily mirabegron in a 50 or 100 mg dose is an effective treatment for overactive bladder symptoms with a low occurrence of side effects. Nitti VW, et al. Results of a randomized phase III trial of Mirabegron in patients with overactive bladder. J Urol. 2013;189(4):1388 95

The evidence described would suggest that mirabegron is not a cure for OAB, but is as efficacious as most antimuscarinics including tolterodine ER 4 mg compared with placebo regarding: objective measures such as reduction in number of voids per 24 hours, mean volume per void, mean number of episodes of general urinary incontinence, urgency urinary incontinence and urgency per 24 hours. subjective measures such as severity of urgency, PPBC, ICIQ-OAB and KHQ. It is important to note however that urgency, the pathognomonic symptom of OAB, was never the primary outcome measure. With regard to tolerability, the data would suggest that patients taking mirabegron suffer a similar rate of TEAEs as those taking placebo alone, whereas the rate in those on antimuscarinics is greater.

Mirabegron, the first and only licensed β3-ar agonist for the treatment of OAB, offers an efficacious and safe alternative to first-line treatment in adult patients poorly controlled with or intolerant to antimuscarinics. Future studies are required to provide more information regarding potential benefits of combined therapy with antimuscarinics or α-blockers and also longer term effects of β3- AR agonists.

LASER treatment on OAB WET - a flash in the pan or the real future?

This clinical evaluation of a new non-invasive Er:YAG laser treatment for stress and mixed urinary incontinence showed high efficacy in improvement of UI with no adverse effects noted. Patients discomfort during the treatment was minimal and satisfaction very high. For evaluation of the duration of the treatment effects, longer follow-ups are necessary and we are looking forward to seeing our patients at 12 and 24 months postop.

We included 175 women (aged 49.7 ± 10 years) with newly diagnosed SUI (66% of women) and MUI (34%), respectively. Patients were clinically examined and classified by incontinence types (SUI and MUI) and grades (mild, moderate, severe, and very severe) using International Consultation on Incontinence Modular Questionnaire (ICIQ) and assessing Incontinence Severity Index (ISI). The results of our study, have shown that new non-invasive Er:YAG laser could be regarded as a promising additional treatment strategy for SUI with at least one year lasting positive effects. On the other hand, it does not seem appropriate for treating MUI.

CLINICAL EXPERIENCE LASER or HIFU Efficacy and effect and cost single or combination therapy specialist and certificate

TAKE HOME MESSAGE Overactive bladder (OAB) -precise diagnosis Treatment of OAB -combination therapies Beta-3 adrenoceptor agonist (Betmiga ) - may first-line medication but no panacea LASER treatment - the real changing future

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