Over active bladder
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The document discusses overactive bladder (OAB) and its prevalence, symptoms, diagnosis, and treatment. It provides the following key points: - OAB symptoms like urgency, frequency, and nocturia are common, affecting over half of men and women aged 40-59. - Diagnosis is usually based on patient history and symptoms. A bladder diary can help assess frequency and episodes. Physical exam and urinalysis rule out other causes. - Conservative treatments include behavioral changes, pelvic floor therapy, and medications. Anticholinergic drugs and beta-3 agonists like mirabegron and solifenacin are commonly used oral pharmacologic options. - More invasive treatments for refract
![Study Design
The study duration was 18 weeks, comprising a single‐blind, 4‐week placebo run‐in, a 12‐week double‐blind treatment
period, and a 2‐week, single‐blind, placebo run‐out period. Patients aged ≥18 years who had had symptoms of wet OAB
(urgency, urinary frequency and UI) for ≥3 months were eligible for screening. In patients with mixed stress UI/UUI, UUI
had to be the predominant factor as evidenced by diary data and determined by the investigator. Those who recorded on
average ≥8 micturitions/24 h, ≥1 urgency episode/24 h (grade 3 or 4 on the Patient Perception of Intensity of Urgency
Scale [PPIUS]/24 h , and ≥3 UI episodes over the 7‐day micturition diary were eligible for randomisation to double‐blind
treatment in a 2:2:1:1:1:1 ratio to daily:
Solifenacin 5 mg + mirabegron 25 mg (combined S5 + M25) once daily
Solifenacin 5 mg + mirabegron 50 mg (combined S5 + M50) once daily
Placebo
Mirabegron 25 mg OD
Mirabegron 50 mg OD
Solifenacin 5 mg OD](https://image.slidesharecdn.com/overactivebladder-190514045604/85/Over-active-bladder-47-320.jpg)
Over active bladder
- 3. Prevalence of OAB 51% of men and 56% of women age between 40 to 59 experienced the symptoms of OAB…. Can Urol Assoc J. 2017 May; 11(5): E142–E173.
- 4. Prevalence of OAB 64% of Women with bladder issues still struggle in SILENCE… Can Urol Assoc J. 2017 May; 11(5): E142–E173.
- 5. Impact of Urinary Incontinence on Quality of Life… Psychological • Guilt/depression. • Loss of self respect & dignity. • Fear of being a burden/Lack of bladder control. Physical • Limitations or cessation of physical activities. QOL Social • Reduction in social interaction • Alteration of travel plans • Increased risk of institutionalization of frail older persons Sexual • Avoidance of sexual contact and intimacy. Occupational • Absence from work. • Decreased productivity. Domestic • Requirements for Specialized underwear, Bedding. • Special precautions with clothing.
- 6. Overactive bladder - Definition “Urgency, with or without urge incontinenence, usually with frequency and nocturia… If there is no infection or proven pathology. Abrams et al . Neurourol Urodyn 2002:21; 167- 78
- 7. Overactive bladder Nocturia is the complaint that the individual has to wake at night one or more times to void. Urgency is the complaint of a sudden compelling desire to pass urine which is difficult to defer. Increased daytime frequency is the complaint by the patient who considers that he/she voids too often by day. Urinary incontinence is the complaint of any involuntary leakage of urine.
- 9. Diagnosis of Overactive Bladder Most cases of overactive bladder can be diagnosed based on: Patient history, symptomassessment. Physical examination. Urinalysis. Initiation of noninvasive treatment does not require an extensive further workup. Bladder diary.
- 10. History How long? How old when started? How much (volume)? Degree of bother? Characteristics of leakage? Activity related? D a y and night, wet pads at night = instability Urgency? Suppressible = probably SUI not suppressible (urge incontinence) = instability Other: fluid intake, UTI’s, pain, hematuria, LE swelling, medications.
- 11. Differential Diagnosis: Overactive Bladder, Stress Incontinence, and Mixed Symptoms Abrams P, Wein AJ. The Overactive Bladder—A Widespread and Treatable Condition. 1998. Medical History and Physical Examination Symptom Assessment Symptoms OAB SUI Mixed symptoms Urgency (strong,sudden desire to void) YES NO YES Frequency with urgency (> 8 times/24 h) YES NO YES Leaking during physical activity (eg, coughing, sneezing, lifting) NO YES YES Amount of urinary leakage with each episode of incontinence Large (if present) small Variable Ability to reach the toilet in time following an urge to void Often no YES Variable Waking to pass urine at night Usually Seldom Maybe
- 12. Bladder diary What is a Bladder Diary? A bladder diary is a tool used by you and your healthcare professional to better understand your OAB symptoms. It helps you track and know how much and when you drink liquids, how much and when you urinate, when you have that “gotta go” feeling, and how much and when you leak urine. When is a Bladder Diary used? You can use a Bladder Diary before or after visiting with your healthcare professional. You may choose to complete a Bladder Diary before you see your healthcare professional for the first time. Having a Bladder Diary during your first visit can be helpful. You may find it easier to explain your symptoms and how they are affecting your life. If you don’t keep a Bladder Diary before your first office visit, your healthcare professional may ask you to start one. It can help them understand your daily habits and how your bladder is working during a 24-hour period.
- 13. Bladder diary How to complete the diary: Begin your diary when you wake up each day. Take notes throughout the day, and continue until you complete 24 hours. For example, if you wake up at 7 a.m. on the first day of your diary, take notes until 7 a.m. the next day. During the day, write down how much liquid you drink. If you do not know exactly how much liquid you are drinking, it’s important to take a good guess about the number of ounces every time. Most containers will list the number of ounces they contain. Use these listings to help you make an estimate—for example, an 500ml of juice, 250ml can of soda, or 1L bottle of water. Take note of how much urine you make during the day. If your healthcare professional asks you to keep a Bladder Diary, you will probably get a special collection device to use. It sits under your toilet seat. It is marked with measurements to let you know how much urine you make. If you are keeping the diary on your own before visiting a healthcare professional, you may want to collect your urine in a paper cup. Choose a cup that you know holds a certain amount of liquid, such as 500ml. It’s best to keep a diary for at least three days.. Copy as many pages of the Bladder Diary you need to complete the three days or visit UrologyHealth.org/OAB to print out more. Don’t forget to bring your completed diary with you to your first office visit.
- 14. Bladder diary
- 15. Physical Examination Abdomen Masses: palpable bladder, etc. Pelvis/perineum External genitalia: atrophic vaginitis vaginal Strenght of PFM Prolapse (assoc. 50% of SUI patients GYN malignancy, fistula Rectal: tone, masses, teach Kegels during exam prostate Neurological (reflexes, LE’s, sensory, motor)
- 16. Physical Examination Rule out possible causes of LUTS. Atrophic vaginitis Estrogen deficiency Pelvic floor dysfunction Pelvic organ prolapse Potentially serious pathologic conditions Signs of Hypoestrogenation Prominent caruncle • Cystocele • Rectocele • Enterocele • Uterine prolapse
- 17. Fantl JA, et al. Agency for Healthcare Policy and Research; 1996. AHCPR publication 96-0686. Laboratory Tests Urinalysis Routine µscopy Culture Look for hematuria (Blood in urine) , pyuria (Urine with white blood cells or Pus), bacteriuria (Urine with Bacteria) , glucosuria (Urine with Glucose), proteinuria (Urine with Protein) Appropriate blood work up Glucose Electrolytes Prostate specific antigen (PSA) inmen
- 18. Laboratory Tests Rule out possible causes of LUTS ( Lower Urinary Tract symptoms) Urinary tract infection (UTI) or sexuallytransmitted disease (STD) Diabetes mellitus (T2DM & T1DM) L U T tumor or kidneystones Potentially serious pathologicconditions
- 20. Urodynamics Urodynamics : The diagnostic study of pressure in the bladder, in treating incontinence. ‘A Urodyanamic observation characterized by involuntary detrusor contractions during the filling phase which may be spontaneous or provoked Abrams et al, 2002
- 21. Urodynamics Urodynamic evaluation is recommended: prior to invasive (Fast progression) treatments. after treatment failure. Urodynamic studies should only be performed after a full basic urological assessment.
- 22. Urodynamic classification of OAB (Flisser et al) Based on – Presence of Detrusar Overactivity Patients Awareness Ability to abort Type 1- 4.
- 23. OAB – 1: The patient complains of OAB symptoms, but no involuntary detrusor contractions are demonstrated.
- 24. OAB - 2 There are involuntary detrusor contractions, but the patient is aware of them and can voluntarily contract the sphincter, prevent incontinence, and abort the detrusor contraction.
- 25. OAB - 3 •Involuntary detrusor contractionspresent , the patient is aware of them and can voluntarily contract the sphincter and momentarily prevent incontinence, but the patient is unable to abort the detrusor contraction and when the sphincter fatigues, incontinence ensues .
- 26. OAB - 4 Involuntary detrusor contractions present , but the patient is not able to contract the sphincter voluntarily or abort the detrusor contraction and simply voids involuntarily
- 27. Overactive bladder and detrusor over activity UI increases
- 28. Therapy for OAB 1) Behavioral modification/ lifestyle changes 2) Pelvic floor muscle therapy 3) Oral pharmacologic agent 4) Intravesical agent - 1) Capsaicin 2) Resiniferatoxin 3) Botulinum toxin -A 5) Sacral Neuromodulation 6) surgical therapy
- 29. Conservative management Behavioral modification Dietary modification Bladder training Fluid management Pelvic floor muscle therapy (PFMT))
- 30. Management OAB – often can not be cured Sympathetic approach Reasonable expectation Goal – minimize effect on quality of life
- 31. Medications for OAB Anticholinergic drugs for OAB Beta-3 adrenergic drugs for OAB
- 32. Anticholinergic drugs for OAB The largest class of drugs used to treat OAB is anticholinergic drugs. They work by blocking a chemical in your body called acetylcholine. This chemical sends a message to your bladder to contract. By blocking this chemical, these drugs reduce the contractions that cause you to release urine. In studies that compared the drugs, all anticholinergics worked equally as well in treating OAB. Anticholinergics drugs used in OAB management: Oxybutynin. Tolterodine. Trospium. Darifenacin. Solifenacin. Fesoterodine.
- 33. Beta-3 adrenergic drugs for OAB The only drug in this class is mirabegron. It works by relaxing the smooth muscle in the walls of your bladder. This effect helps your bladder hold more urine. This drug is available as a tablet that you take by mouth once per day. It interacts with several other drugs. Make sure you tell your doctor about all medications you’re taking.
- 34. Antispasmodic drugs for OAB | Antispasmodic drugs Flavoxate is the only drug in this class. It’s an oral drug that reduces bladder spasms. This is an older drug. Some studies show that it doesn’t work as well as newer drugs to treat symptoms of OAB.
- 35. The new combination approved by USFDA
- 37. Mirabegron - brief Mirabegron is a new drug approved by USFDA in 2012 Mirabegron is the only OAB treatment in its class that targets the beta-3 pathway to increase bladder capacity Help relax the smooth muscle that surrounds the bladder Help the bladder to fill more completely and increase urine storage Available strengths are 25mg & 50mg with Once Daily Dosage
- 38. Overactive Bladder Monotherapy Indicated for overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency 25 mg PO qDay 25 mg dose is typically effective within 8 weeks May increase to 50 mg PO qDay based on individual efficacy and tolerability Combination with muscarinic antagonist Indicated in combination with the muscarinic antagonist solifenacin succinate for treatment of OAB with symptoms of urge urinary incontinence, urgency, and urinary frequency Combination regimen: 25 mg PO qDay plus solifenacin succinate 5 mg PO qDay May increase mirabegron to 50 mg PO qDay after 4-8 weeks based on individual efficacy and tolerability Mirabegron - brief
- 39. Mechanism of Action Beta-3 adrenergic receptor agonist which causes relaxation of the detrusor smooth muscle of the urinary bladder and increases bladder capacity Absorption : Bioavailability: 29% (25-mg), 35% (50-mg), Peak Plasma Time: 3.5 hr Peak Plasma Concentration: ~3-fold increase from 50 mg dose to 100 mg dose AUC: ~2.5-fold increase from 50 mg dose to 100 mg dose, Steady state: 7 days Distribution, Protein Bound: 71%, Vd, steady state: 1670 L Metabolism: Via multiple pathways including dealkylation, (direct) glucuronidation, amide hydrolysis, and minimal oxidative metabolism in vivo by CYP2D6 and CYP3A4, Possible involvement of butylcholinesterase, uridine diphospho-glucuronosyltransferases (UGT) and alcohol dehydrogenase, Moderate CYP2D6 inhibitor Elimination: Half-Life: 50 hr, Total body clearance: 57 L/hr (following IV administration), Excretion: Urine (55%); feces (34%), Excretion, unchanged: Urine (~25%); feces (0%). Mirabegron – brief (PKPD)
- 40. Mirabegron – Administration Oral Administration May take with or without food Swallow whole with water, do not chew, divide, or crush tablet Storage Extended-release tablets: Store at 25°C (77°F) with excursions permitted from 15-30°C (59-86°F)
- 41. Solifenacin - brief Solifenacin is a new drug approved by USFDA in 2004. Solifenacin is the only OAB treatment in its class that targets the Competitive muscarinic-receptor antagonist. Available strengths are 5mg & 10mg with Once Daily Dosage.
- 42. Solifenacin - Dosing & Uses Dosage Forms & Strengths tablet: (5mg &10mg) Overactive Bladder Indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency Monotherapy: 5 mg PO qDay; may be increased to 10 mg PO qDay Combination with beta3 agonists Indicated in combination with mirabegron for treatment of OAB with symptoms of urge urinary incontinence, urgency, and urinary frequency Combination regimen: 5 mg PO qDay in combination with mirabegron 25 mg PO qDay Dosing Modifications Renal impairment: CrCl <30 mL/min: Not to exceed 5 mg/day Hepatic impairment : Moderate: Not to exceed 5 mg/day, Severe (Child-Pugh class C): Not recommended, CYP3A4 inhibitors, Strong CYP3A4 (eg, ketoconazole): Not to exceed 5 mg/day
- 43. Solifenacin - PKPD Pharmacology Mechanism of Action : Competitive muscarinic-receptor antagonist Absorption Bioavailability: 90% Peak plasma time: 3-8 hr Distribution Protein bound: 98% Metabolism Metabolized in liver, primarily by CYP3A4 Elimination Half-life: 45-68 hr Excretion: Urine (69.2%), feces (22.5%)
- 44. SYNERGY I:- (No. Patients = 6991, Duration:- 12 weeks) compared mirabegron/solifenacin combination therapy to solifenacin monotherapies. Conclusions :- Combined therapy with solifenacin 5 mg + mirabegron 25 mg and solifenacin 5 mg + mirabegron 50 mg provided consistent improvements in efficacy compared with the respective monotherapies across most of the outcome parameters. Efficacy and safety of combinations of mirabegron and solifenacin compared with monotherapy and placebo in patients with overactive bladder (SYNERGY study). BJU Int. 2017 Oct;120(4):562-575
- 45. Study Design This was a multinational, multicentre, randomised, double‐blind, parallel‐group, placebo‐ and active‐controlled Phase III study (NCT01972841), performed in accordance with the International Conference on Harmonization, Good Clinical Practice and the Declaration of Helsinki. Independent Review Board/Independent Ethics Committee‐approved written informed consent was obtained from each patient before the study. Patients enrolled at sites in the USA also signed a Health Insurance Portability and Accountability Act (HIPAA) authorisation form.
- 46. Study Design
- 47. Study Design The study duration was 18 weeks, comprising a single‐blind, 4‐week placebo run‐in, a 12‐week double‐blind treatment period, and a 2‐week, single‐blind, placebo run‐out period. Patients aged ≥18 years who had had symptoms of wet OAB (urgency, urinary frequency and UI) for ≥3 months were eligible for screening. In patients with mixed stress UI/UUI, UUI had to be the predominant factor as evidenced by diary data and determined by the investigator. Those who recorded on average ≥8 micturitions/24 h, ≥1 urgency episode/24 h (grade 3 or 4 on the Patient Perception of Intensity of Urgency Scale [PPIUS]/24 h , and ≥3 UI episodes over the 7‐day micturition diary were eligible for randomisation to double‐blind treatment in a 2:2:1:1:1:1 ratio to daily: Solifenacin 5 mg + mirabegron 25 mg (combined S5 + M25) once daily Solifenacin 5 mg + mirabegron 50 mg (combined S5 + M50) once daily Placebo Mirabegron 25 mg OD Mirabegron 50 mg OD Solifenacin 5 mg OD
- 48. SYNERGY II :- (No. Patients = 2084, Duration:- 12 months) compared mirabegron/solifenacin combination therapy to solifenacin monotherapies. Patient summary This study investigated the effectiveness and safety of a combination of two different treatments (mirabegron 50 mg and solifenacin 5 mg) or solifenacin (5 mg or 10 mg) alone in patients aged <65 yr or ≥65 yr, and <75 yr or ≥75 yr with overactive bladder. Symptoms of overactive bladder, such as the urgent need to visit the toilet, incontinence, and frequent urination, were improved with all treatments regardless of the patient’s age, but combination treatment demonstrated the greatest benefit, and was well tolerated. Conclusions :- Mirabegron and solifenacin combination treatment for OAB symptoms was well tolerated over 12 months and led to efficacy improvements over each monotherapy. This innovative combination is a treatment option that could become widely used in the clinic. Long-term Safety and Efficacy of Mirabegron and Solifenacin in Combination Compared with Monotherapy in Patients with Overactive Bladder: A Randomized, Multicenter Phase 3 Study (SYNERGY II). Eur Urol Focus. 2017 Dec;3(6):629-638.
- 49. Design, setting, and participants & Outcome Design, setting, and participants Patients remaining incontinent (≥1 episode during 3-d diary) following 4-wk single-blind daily solifenacin 5 mg were randomized 1:1:1 to a daily double-blind combination (solifenacin 5 mg and mirabegron 25 mg, increased to 50 mg at wk 4), solifenacin 5 mg or 10 mg for 12 wk. Four cohorts stratified by age (<65 yr, ≥65 yr and < 75 yr, ≥75 yr) were investigated. Outcome measurements and statistical analysis Efficacy assessments: change from baseline to end of treatment in average daily incontinence (primary) and micturition frequency (key secondary), number of incontinence episodes during the 3-d diary (key secondary), and change from baseline in average daily urgency and urgency incontinence episodes. Safety included treatment-emergent adverse events and vital signs.
- 50. BESIDE :- (No. Patients = 2174, Duration:- 12 weeks), mirabegron 50 mg in combination with solifenacin 5 mg was superior to solifenacin 5 mg alone for relieving symptoms of incontinence and frequent urination. PATIENT SUMMARY: This study investigated the effectiveness and safety of a combination of two different treatments (mirabegron 50mg and solifenacin 5mg) or solifenacin (5mg or 10mg) alone in patients aged <65 yr or ≥65 yr, and <75 yr or ≥75 yr with overactive bladder. Symptoms of overactive bladder, such as the urgent need to visit the toilet, incontinence, and frequent urination, were improved with all treatments regardless of the patient's age, but combination treatment demonstrated the greatest benefit, and was well tolerated. Conclusions: Efficacy and safety in the overall population is maintained in older (65 yr) and elderly (75 yr) patients treated with a combination of solifenacin and mirabegron, or solifenacin monotherapy; irrespective of age, combination was associated with the greatest improvement in overactive bladder symptoms Treating Overactive Bladder in Older Patients with a Combination of Mirabegron and Solifenacin: A Prespecified Analysis from the BESIDE Study. Eur Urol Focus. 2017 Dec;3(6):629-638.
- 51. DESIGN, SETTING,PARTICIPANTS, OUTCOME & RESULTS DESIGN, SETTING, AND PARTICIPANTS: Patients remaining incontinent (≥1 episode during 3-d diary) following 4-wk single-blind daily solifenacin 5mg were randomized 1:1:1 to a daily double-blind combination (solifenacin 5mg and mirabegron 25mg, increased to 50mg at wk 4), solifenacin 5mg or 10mg for 12 wk. Four cohorts stratified by age (<65 yr, ≥65 yr and < 75 yr, ≥75 yr) were investigated. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Efficacy assessments: change from baseline to end of treatment in average daily incontinence (primary) and micturition frequency (key secondary), number of incontinence episodes during the 3-d diary (key secondary), and change from baseline in average daily urgency and urgency incontinence episodes. Safety included treatment-emergent adverse events and vital signs. RESULTS AND LIMITATIONS: Full analysis set included 2110 patients: 30.9% aged ≥65 yr and 8.9% aged ≥75 yr. At the end of treatment, daily, and 3- d incontinence daily micturitions, urgency, and urgency incontinence, were improved in each treatment group and age group; the largest reductions were observed with combination in each age cohort. There were no notable differences in vital signs or the incidence of treatment-emergent adverse events between treatment and age groups, with the exception of dry mouth, which was highest with solifenacin10mg.
- 52. Thank You