DISCLOSURES

 Currently Michael Feloney, MD FACS  Speaker for Astellas Pharma Associate Professor Chairman  Formerly Department of Urology  Speaker for Pfizer  Instructor for Allergan FEMALE

OBJECTIVES OF DISCUSSION BUT FIRST AN ABMS/ABU/ABOG UPDATE

 To discuss types of female urinary incontinence  To discuss the workup of female urinary incontinence  To discuss past treatments and what’s happened in the treatment of urinary incontinence in the last 3 years

DEFINITION OF URINARY INCONTINENCE EPIDEMIOLOGY

 Urinary incontinence is the involuntary loss of  22 million people are affected in U.S. urine that represents a social or hygienic  17 million have overactive bladder syndrome (OAB) problem and is objectively demonstrable  85% of people w/ urinary incontinence are women  The urinary leakage may be through:  50% of nursing home residents are affected  the  15-30% of women over age 65 are affected  an extra-urethral route  1 in 4 women will experience during their lifetime

1 MANY WOMEN DO NOT SEEK TREATMENT FOR INCONTINENCE ANATOMY OF THE LOWER URINARY TRACT Over 40% of women believe that incontinence is a normal part of aging  Reservoir (bladder) Studies have shown that less than half of incontinent women have ever talked to a physician about  detrusor 1,2 incontinence  Trigone Even among middle-aged women with daily symptoms, only 54% had talked to a physician 1 Reasons for not seeking treatment (middle-aged women): 3  Outlet  Do not consider incontinence to be a problem  bladder neck (proximal or internal sphincter)  Feel able to manage incontinence on their own  Too embarrassed to seek help  urethra  Afraid that surgery will be recommended

1 Burgio et al, 1991 2 Burgio et al, 1994 3 Miller et al, 2003

NORMAL BLADDER FUNCTION

 2 principle modes of operation  Filling/Storage  Elimination/Voiding  Coordinated by different neurologic centers  Pontine reticular formation  Sacral spinal micturition center  Under both autonomic and voluntary control

FILLING/STORAGE VOLITIONAL ELIMINATION/VOIDING

1. Accommodate  volume with low pressure  Coordinated contraction of detrusor until empty 2. Outlet that remains closed with  abdominal   resistance at bladder neck and urethral pressure sphincter 3. Absence of involuntary bladder contractions  Absence of anatomic obstruction  Normal sensation of fullness

2 NEUROANATOMY OF THE LOWER TRACT

 Sacral parasympathetic system (S2 - S4)  pelvic splanchnic in the pelvic plexus  muscarinic cholinergic receptors (M2&M3)  efferent and afferent supply to bladder  Thoracaolumbar or sympathetic system (T11-L2)  superior hypogastric and pelvic plexus

 α and β adrenergic receptors (α1 & β1-3 )  efferent and afferent supply to bladder, prostate  Sacral somatic outflow (S3 & S4)  pudendal nerve (perineal branch)  nicotinic cholinergic  efferent and afferent supply to external sphincter

NORMAL URINARY TRACT STATS

 Bladder Capacity 400-600 ml  Bladder Filling Pressure 10 cm H20  Ureteral Pressure 20 cm H20  First desire to void at 150-250 cc  Female Voiding Pressure 30-50 cm H20  Male Voiding Pressure 50-75 cm H20  Female Urine Flow 30-35 ml/s  Male Urine Flow 15-25 ml/s

CLASSIFICATION OF INCONTINENCE (SUI)  Sudden loss of urine with Ab pressure  Stress incontinence  coughing, sneezing, lifting, physical exertion  Urge incontinence  Causes  Total incontinence  decreased pelvic floor support  hypermobility of bladder neck and urethra  Overflow (paradoxical) incontinence  intrinsic sphincter deficiency  loss of urethral mucosal coaptation  Risk Factors  Female, childbirth, obesity

3 URGE INCONTINENCE (UUI) OVERFLOW INCONTINENCE

 Involuntary detrusor contractions which result in loss of urine  False or Paradoxical incontinence  Spontaneous  Secondary to:  Provoked  running water, door knobs, heel bounce, cough etc.  urethral stricture  Causes  bladder neck contracture  idiopathic (majority)  dysfunctional voiding  neurogenic  detrusor sphincter dysnergia  intravesical irritation (CA, IC, FB, infection)  bladder outlet obstruction  poor detrusor contractility  behavioral Neurogenic/myogenic bladder

(SCI, MS, CVA, DM)

TOTAL INCONTINENCE MIXED URINARY INCONTINENCE (MUI)

 Unconscious loss of urine  First sensation is usually wetness  Mixture of Stress and Urge Incontinence  Causes  In my practice   profound intrinsic sphincter deficiency 60% of women with incontinence have MUI   fistulous communication (ureteral, vesical or 30% of women have UUI alone urethral (proximal to the external sphincter)  congenital incontinence (ectopic )

STRESS URINARY INCONTINENCE IS THE MOST COMMON TYPE IN WOMEN BASED PREVALENCE OF INCONTINENCE ON LITERATURE REVIEW Stress Is the Most Common Type Women >60 Years Old in Women <60 Years Old

Urge Mixed Urge Stress 20% Stress 29% Stress 35% 30% 49% 55% Mixed Urge Mixed 25% 22% 35%

Adapted from: Thom D. J Am Geriatr Soc. 1998;46(4):473-480. Hampel C, et al. Urology. 1997;50(suppl 6A):4-14.

4 URINARY INCONTINENCE: URINARY INCONTINENCE: BURDEN OF ILLNESS BURDEN OF ILLNESS

Impact on physical activity Lower quality of life 1,2  Avoidance of physical activities 1,2  Emotional Impact  Reason for discontinuing exercise 3

“[It’s] a cause of shame, a sign of weakness” Workplace impact “It’s embarrassing; it’s depressing”  Main site of leakage for many women 1  Use of pads; restriction of fluid intake 4  “I have had to modify my whole life over it”

1 Lagro-Janssen T, Smits A, Van Weel C. Urinary incontinence in women and the effects on their lives. Scan J Prim Health 1 Maclennan 2000 Care 1992; 10:211-6. 2 Hunskaar S, Visnes A. The quality of life in women with urinary incontinence as measured by the 2 Brown et al, 2000 Sickness Impact Profile JAGS 1991; 39:378-382 3 Nygaard I, DeLancey JO, Arnsdorf L et al. Exercise and incontinence. Obstet Gynecol 1990; 75:848-851 4 Fitzgerald ST et al. Urinary Incontinence. Impact on Working Women. AAOHN Journal. 2000; 48: 112-118

BURDEN OF ILLNESS: IMPACT OF SUI ON INDIRECT MEASURE OF BURDEN OF ILLNESS WOMEN MODERATELY TO EXTREMELY BOTHERED

60  $1 Billion market size for adult absorbent pads 50  $4 Billion market size or OAB pharmacotherapy 40 Physical Activity  $26 Billion market size for all incontinence Daily Activities 30 Social Activities related products or services 20 Confidence

to extreme to impact 10  Note only $10 million so far spent by NIH on Proportionreporting moderate 0 Type of activity incontinence research

Fultz et al, Burden of Stress Urinary Incontinence, American Journal of Obstetrics and Gynecology, In press

TRANSIENT CAUSES OF INCONTINENCE THINK DIAPERS

 Delirium  Infection OUTPATIENT INCONTINENCE WORK UP  Atrophic Vaginitis  Pharmacology  Endocrine  Restraint  Stool Impaction

5 HISTORY OF INCONTINENCE PHYSICAL EXAM  Duration and Acuteness of symptoms  General Function (Can she get to the bathroom?)  Dribbling, Flowing, Feels as if voiding  Abdomen  When and Where incontinence occurs  Surgical scars, distended bladder, tenderness, masses  What provokes it (cough, exercise, H20, door knobs)  Neurologic  Degree (how many pads per day)  Sensation, motor strength, reflexes  Urgency, Day and Night frequency, Dysuria, blood  Rectal: tone, tenderness, mass, stool, thin ant. wall  UTI’s, Vaginitis, Stone, CA, radiation Hx  External and Internal genitalia (Pelvic Exam)  Obstetric, Surgical, and Trauma Hx  mucosa (Atrophic Vaginitis), discharge  Hx of DM, Neurologic Dz (CVA, PD, MS, SC)  urethral mobility, patulousness, urethral caruncle  Sensation of vaginal fullness  bulges (cystocele, rectocele, enterocele)  Hx of pelvic organ prolapse  leakage with provocation (cough etc.)

DIAGNOSTIC EVALUATION BLADDERSCANTM BVI 3000  Post void residual (US or Straight cath)  UA with culture and sensitivity  Voiding Diary (UO, Fluid intake, leak, urgency, activity)  24 hour pad test  (especially when RBC found on UA)  Urine Cytology  Simple uroflometry  Simple Cystometrogram/Poor man’s UDS  Complex Urodynamics (CUDS)  Voiding Cystourethragram (VCUG)

BARDSCAN BME 150-A

6 URINE VOIDING DIARY

Amount Leakage* Urge Present Fluid Intake Time Voided Activity (0-3 Scale) (Yes/No) Amount/ Type 16 oz. coffee 6:50AM 425 mL Getting up/breakfast 0 No 6 oz. orange juice

8:00AM – – – – 8 oz. coffee

9:10AM 200 mL Cough 2 No –

12:25PM 400 mL Working/at lunch 0 No 8 oz. water

4:30PM 350 mL Leaving work 0 No –

6:30PM 125 mL Exercise class 2 No 12 oz. water

8:20PM 200 mL Laugh during dinner 2 No 4 oz. water

10:50PM 250 mL Getting ready for bed 0 No –

*Leakage: 0=no leakage; 1=drops; 2=wet underwear or light pad; 3=soaked pad or clothing. Schick

COMPLEX URODYNAMICS --HOTTEDAHL

 Improves diagnostic capability and formulates treatment  May not be indicated in women with pure SUI  Particular indications for incontinence include  Failed therapy and surgery  MUI  Large PVR  Hx of Neurological dz  Measures:  Intra-abdominal pressures and Intravesical pressures  calculates detrusor pressure (ves pres - ab pres)  urine flow  external sphincter activity with EMG  Done with simultaneous fluoro makes it Videourodynamics

7 CONSERVATIVE TREATMENT OF SUI  Diapers and/or absorbent pads  Pelvic floor or “Kegel” exercises with biofeedback and weighted cones  Urethral plugs  Electrical stimulation of pelvic floor muscle  Topical estrogen  Alpha adrenergic agonists <>  ornade spansules (off label) (off market)  Pseudophedrine (off label)  Catheterization if all else fails

SURGICAL TREATMENT OF SUI FEMSOFT URETHRAL PLUGS OLD GOLD STANDARD

 Abdominal Retropubic Urethropexy also called a retropubic colposuspension  Marshall Marchetti Krantz-1949  Burch-1961  Long Term Follow up cure rates  43%-90%  Open procedure with Pfannenstiel incision  Laparoscopic approach-1991  Overnight hospital stay  Increased risk of pelvic organ prolapse (7.5- 32%) Ward KL, et al. Tension free vaginal tape versus colposuspension for primary urodynamic stress incontinence: 5 year follow up. BJOG 2007: 226-233.

SURGICAL TREATMENT OF SUI NEW GOLD STANDARD RETROPUBIC APROACH (IN TO OUT)  Midurethral Slings first described in 1996 as a macropore polypropylene mesh placed under the  TVT- first to market (Gynecare) midurethra  Has 5-20 year follow up cure rates  Advantage (Boston Scientific)  52%-100%  Align (Bard)  Less invasive and faster then urethropexy  Aris (Coloplast)  Much more cost effective then urethropexy  Can perforate the bladder, urethra, and even bowel  Complication rates  Organ perforation 12.2%  Voiding dysfunction 18%  Vaginal erosion 6% Culligan P, et al. A randomized controlled trial comparing a modified Burch procedure and a suburethral sling: long term follow up. Int urogynecol J (2003) 14: 229-233. Ward KL, et al. Tension free vaginal tape versus colposuspension for primary urodynamic stress incontinence: 5 year follow up. BJOG 2007: 226-233.

8 MIDURETHRAL SLING

SUPRAPUBIC RETROPUBIC APPROACH (OUT TO IN)

 Sparc second sling to market (AMS)  Lynx (Boston Scientific)  Align (Bard)  Aris (Coloplast)

TRANS OBTURATOR TRANS-OBTURATOR SLING ANATOMY

 Monarc (AMS) first w/ this approach (2004) Retropubic Midurethral Sling  TVT-O (Gynecare)

 Obtyrx (Boston Scientific) Inferior Pubic Ramus Obturator Canal  Aris (Coloplast) with Vessels

Delivery Needle Point of Entry

Obturator Foramen Urethra Transobturator Midurethral Sling

9 TRANS-OBTURATOR APPROACH

TRANS OBTURATOR TAPE INFRAPUBIC APPROACH  Less invasive than retropubic tapes  Very difficult to perforate bladder and bowel  Prefyx by Boston Scientific is the only one  5 year cure rates and satisfaction rates are similar  No long term data to retropubic tapes  And not being used in the Omaha area  15+ year data is still pending  Fewer complications than retropubic  perforation 0.8%, voiding problems 11%, erosion 3%  May not be adequate for patients w/ ISD type SUI  Is as cost effective as retropubic tapes Angioli R, et al. Tension-free Vaginal Tape Versus Transobturator Suburethral Tape: Five Year Follow up Results of a Prospective Randomised Trial. J. Eururo 2010 (8): 671-677. Lier D, et al. Trans-oburator tape compared with tension-free vaginal tape in the surgical treatment of stress urinary incontinence: a cost utility analysis. BJOG 2011. Sung V, et al. Comparison of Retropubic versus Transobturator approach to Midurethral Slings: A Systematic Review and Meta-Analysis. Am J Obstet Gynecol. 2007 July; 197(1): 3-11.

WHAT’S COMING UP IN TX OF SUI

 Mini Midurethral slings/Single-Incision Slings MINI MIDURETHRAL SLING  MiniArc (AMS)  Solyx (Boston Scientific)  Less invasive  No external incisions  Being performed in offices with local analgesia  Less mesh (no mesh lateral to the obturator)  So far, short term efficacy no better then traditional midurethral slings  No long term data available  Two mini slings (TVT-secur and adjust) have been taken off the market  Secondary to demonstrated inferiority with decreased efficacy and complications (mesh erosion)

10 MINI MIDURETHRAL SLING ANYTHING ELSE FOR SUI

 Renessa by Novasys Medical  Radiofreqency energy to heat and denature collagen in the urethra  In office procedure  No good long term data yet. Does have some positive short term data.  Duloxetine (Cymbalta) (off label)  Trials stopped secondary to unwanted side effect

TREATMENT OF UUI CONSERVATIVE

 Bladder training:voiding interval by 15 min / week   fluid intake  Avoid: caffeine, EtOH, acidic food  Dietary additives: Prelief  Physical Therapy of the Pelvic Floor  Percutaneous Peripheral Nerve Stimulation

11 PHYSICAL THERAPY FOR PELVIC FLOOR PERCUTANEOUS NEUROMODULATION

Uroplasty

EARLY ANTICHOLINERGICS FOR UUI PHARMACOLOGIC TREATMENTS FOR UUI  belladonna (pan muscarinic alkaloid)  Belladonna powdered extract (16.2mg PR)  hyoscyamine sulfate (pan muscarinic alkaloid)  Anticholinergics  Levsin (0.125 mg SL qid)  Antidepressants  Cystospaz-M (0.375 mg PO bid)  Muscle Relaxants  flavoxate hydrochloride(M1 & M2 selective)  Urispas (100-200mg PO tid-qid)  Urinary Alkalinization Agents  oxybutynin chloride (M1,M2,M3 selective)  Vasopressin Analogs  Ditropan (2.5-5mg PO qid)  Ditropan XR (5-30mg PO qd)  trospium chloride (M2 and M3 selective)  Sanctura 20 mg PO bid

PDR 58th Ed. 2004

NEW ANTICHOLINERGICS ALTERNATIVE PHARMACOTHERAPY  tolterodine tartrate (M2 and M3 selective)  Detrol LA 4mg PO qd FOR UUI (OFF LABEL USE)  fesoteridine fumarate (M2 and M# selective)  Antidepressant  Toviaz 4-8 mg qd imipramine (Tofranil) 25 mg - 100mg qhs  solifenacin succinate (M3 selective)   Vesicare 5-10 mg PO qd imipramine-PM (Tofranil-PM) 75mg PO qd  darifenacin hydrobromide (M3 highly selective)  Urinary Alkalinization agent  Enablex 7.5-15 mg PO qd Urocit K (1080 mg bid, 540 mg tid)  trospium chloride (M2 and M3 selective)  Vasopressin Analogue  Sanctura XR 60 mg qd  oxybutynin chloride (M1, M2, and M3 selective) Desmopressin 20 -40 microgram  Oxytrol 3.9 mg transdermal patch q4 days intranasally qhs  Gelnique 3% or 10% gel applied daily  General muscle relaxants

Diazapam Baclofen

12 LATEST PHARMACOTHERPEAUTICS ONABOTULINUM TOXIN A BOTOX FDA APPROVAL JUNE 2013  Botulinum Toxin  Blocks release of Acetylcholine  β Adrenoreceptor Agonists  Actively relax bladder

Hicks A, et al. GW427353 (Solabegron), a Novel, Selective B3-Adrenergic Receptor Agonist, Evokes Bladder Relaxation and Increases Micturition Reflex Threshold in the Dog. JPET Oct 2007 vol 323 no 1 202-209. Takasu T, et al. Effect of (R)-2-(2-Aminothiazol-4-yl)-4’-<2-((2-hydroxy-2-phenylethyl) amino)ethyl> acetanilide (YM178), a Novel Selective B3-adrenoceptor Agonist, on Bladder Function. JPET May 2007 vol. 321 no 2 642-647.

BOTULINUM TOXIN

 Botulinum Toxin-A (Botox® by Allergan)  Intravesical Injection (detrusor muscle)  Rigid or flexible cystoscope  100-200 Units  Diluted in 10-20 cc  Approx 6.8 units per mL  Average duration of response is 6-8 months  Neurogenic Detrusor Overactivity and OAB

Lie K. et al. Botulinum Toxin A for Idiopathic Detrusor Overactivity. Ann Acad Med Singapore. 2010; 39: 714-718.

BETA ADRENERGIC RECEPTORS OF BLADDER HUMAN ΒETA 3-ADRENERGIC AGONISTS

 β3 receptors found in the human bladder  Mirabegron (Astellas) – (YM178)¹ smooth muscle  Solabegron (GlaxoSmithKline) – (GW427353)

 Also found in myocardium, skeletal, gall  TRK-380 (Toray Industries)2 bladder, prostate, uterus, adipose tissue, brain  Activation leads to Detrusor muscle relaxation  Other subtypes in the bladder are β1 and β2 but they are presumed to account for only 3%

of the β adrenergic receptors. In other species

β1 and β2 predominate in the bladder. 1.Igawa Y, et al. Beta3-Adrenoceptor Agonists: Possible Role in the Treatment of Overactive Bladder. Korean J Urol. 2010 Dec; 51(12): 811-818. 2. Kanie S, et al. Pharmacological Effect of TRK-380, a Novel Selective Human B3- Adrenoceptor Agonist, on Mammalian Detrusor Strips. 23 Dec 2011, In Press. 3. Tyagi P, et al. Investigations into the Presence of Functional B1, B2, and B3 Adrenoceptors in Urothelium and Destrusor of Human Bladder. Int Braz J Urol. 2009; 35: 76-83.

13 HUMAN ΒETA 3-ADRENERGIC AGONISTS MIRABEGRON FDA APPROVAL JUNE 2012  Muscle relaxation occurs via stimulation of the Gs protein, which increases cAMP by activating  First to come on the market adenyle cyclase which activates protein kinase A  Marketed as Myrbetriq® (PKA) to mediate the biologic effects of relaxation  2 doses (25mg and 50mg) by supressing the calcium-calmodulin-dependent interaction of myosin with actin  Demonstrated dose-dependent reduction of micturition frequency of OAB patients  Stimulation of large conductance Ca2+ activated K+ channels have also been implicated  Potentially can be combined with Solifenacin (Vesicare)  Note: They do not affect strength of bladder contraction Kullmann, F et al. Effects of B3-Adrenergic Receptor Activation on Rat Hyperactivity Induced by Ovariectomy. J Pharmacol Exp Ther. 2009 Sept; 330 (3): 704-717.

TREATMENT OF UUI SURGICAL SAFETY PROFILE  Sacral Neuromodulation (Interstim®)  Metabolized by CYP2D6  Bladder augmentation  Well tolerated  autoaugmentation  Less dry mouth then anti-muscarinics  enterocystoplasty  Ileocystoplasty  GI events were 12.1% (most common)  Cecocystoplasty  Increase in HR 1.6 to 4.1 beats per minute  Sigmoid cystoplasty  At the 100-200mg doses  gastrocystoplasty   Long term safety data to predict the risk of drug related cardiac & vascular events not available  ilial conduit and  May have lower CNS side effects

Tyagi P et al. Mirabegron: a safety review. Expert Opin. Drug Saf. (2011) 10(2): 287-294.

Overview How InterStim Components Work Together

1. Tined lead is placed parallel the S3 3 nerve.

2. Implantable neurostimulator generates mild electrical pulses that are delivered through the lead electrodes. 2 3. Clinician and patient programmers 1 set the parameters of the electrical pulses.

14 TREATMENT OF TOTAL INCONTINENCE Durasphere/Coaptite/Zuidex

 For ISD Consists of:  Urethral submucosa injections w/ bulking agents • Pyrolytic Carbon Coated Micro-beads  Durasphere, Coaptite, Zuidex • Polysaccharide Carrier Gel  Placement of a pubovaginal sling in women  Adjustable Continence Therapy (ACT system) Designed to be:  Placement of an artificial urinary sphincter (AUS) • Biocompatible  For fistulas, ectopic ureters • Non-migratory  Surgical correction • Permanent

BULKING AGENTS URETHRAL BULKING AGENTS (INJECTION THERAPY)

Injection therapy is the injection of a material into the tissue surrounding the urethra. This procedure, done on an outpatient basis, tightens the seal of the sphincter by adding bulk to the surrounding tissue resulting in an increase in resistance to the flow of urine.

Adjustable Continence Therapy (ACT)* System

Periurethral Silicone-Balloon Application with postoperative adjustability

Components of the ACT-Device:

Titanium port

Conduit with guide wire

Balloon

*Designed & manufactured by Uromedica, Inc., MN U.S.A. AMS

15 TREATMENT OF OVERFLOW INCONTINENCE

 For urethral stricture or bladder neck contracture  CIC (clean intermittent catheterization)  Surgical repair (endoscopic incision)  For dysfunctional voiders/DSD  Tamsulosin (Flomax) (off label)  Botox injection of the urethral sphincter (off label)  For kinked from prolapse  Pessary fitting/placement  Surgical correction of the prolapse

WHAT CAN YOU TELL MOST OF YOUR TREATMENT OF OVERFLOW INCONTINENCE FEMALE PATIENTS? CONTINUED  Bladder Hygiene  For flaccid distended neurogenic type bladder  Urinate every 3-4 hours (Don’t abuse bladder)  manual decompression of bladder crede maneuver  Urinate in a relaxed environment  CIC  Double voiding can improve emptying  Bethanechol (cholinergic agonist)  Stay away from irritating foods and ®  Interstim beverages  Practice “Kegel” exercises daily  Topical estrogen for introitus/vagina

SUMMARY

 Urinary Incontinence is prevalent  4 types (stress, urge, total, overflow)  Treatable/Curable  May be a symptom of more life threatening disease  Look for transient causes that are easily treated  Newest treatments: Botox® intravesical

injections, oral β3 agonists, mini midurethral slings

16