Urinary Incontinence: What Can You Do to Improve Control? Nicole J. Brandt, PharmD, MBA, CGP, BCPP, FASCP Professor, Geriatric Pharmacotherapy, Pharmacy Practice and Science UMB School of Pharmacy Director, Clinical and Educational Programs of Peter Lamy Center Drug Therapy and Aging Email: nbrandt@rx.umaryland.edu Learning Objectives 1. Describe the different types of UI 2. List at least 4 different pharmacologic classes that treat UI 3. Identify common clinical adverse effects when utilizing these medications 4. Apply the concepts above to a case discussion 2 1
Evaluation of UI Goals of Evaluation Confirm the presence of UI Identify conditions, including potentially reversible ones that may be contributing to UI Identify patients who require further evaluation before any therapeutic interventions are attempted and those who may receive initial treatment without further testing Identify a presumptive diagnosis 2
Work up History: Neurological, medical and genitourinary. Evaluate for bowel incontinence Medication History Functional assessment Voiding Dairy Physical Examination: General appearance: degree of mobility, visual impairment, obesity, odor (urine, smoke or alcohol) Neurological examination: focusing on diseases, mental status, gait, dexterity, motor strength, deep tendon reflexes and sensation of the lower extremities Female: pelvic examination and gynecologic examination Male: abdominal examination, rectal examination Baseline Information: Laboratory Studies: Chem 12, urinalysis and urine culture Post void residual Bladder Diary 3
Goals of Urinary Incontinence Management Reduce wetting episodes Improve activities of daily living and quality of life Reduce complications Reduce caregiver burden Should be individualized based on the patient s underlying disease states and disabilities Types of Urinary Incontinence Transient Acute Functional Chronic Urge Stress Mixed Overflow 4
Transient (Acute) UI Sudden worsening of UI usually due to a reversible etiology D elirium I nfection A trophic Urethritis P harmacologic (i.e diuretics) P sychological E xcess urine output (polyuria in DM) R estricted mobility S tool impaction Neurotransmitter Involvement Ref: Rahn DD. Pathophysiology of Urinary Incontinence, Voiding Dysfunction, and Overactive Bladder. Obstet Gynecol Clin N Am 36:3 (2009) 463-474 5
https://www.uspharmacist.com/article/pharmacists role in managing male urinary incontinence 11 Common Drug Offenders Medication Class Effects Diuretics (e.g. furosemide) Caffeine Anticholinergic agents (e.g. oxybutynin) Antidepressants (e.g. amitriptyline) Antipsychotics (e.g. olanzapine) Sedatives/hypnotics (e.g. lorazepam) Opioid analgesics (e.g. oxycodone) Alpha adrenergic agonists (e.g. pseudoephedrine), beta adrenergic agonists (e.g. albuterol), calcium channel blockers (e.g. nimlodipine) Alcohol Nicotine Polyuria, frequency, urgency Aggravation or precipitation of incontinence due to diuretic effect Urinary Retention, overflow incont, stool impaction Anticholinergic properties, sedation Anticholinergic properties, sedation Sedation, delirium, immobility, muscle relaxation Urinary retention, fecal impaction, sedation, delirium Urinary Retention Polyuria, frequency, urgency, sedation, delirium, immobility Bladder irritability, smoker s cough Drug Induced Urinary Incontinence US Pharmacist. 2014;39(8):24 29. 6
Functional Incontinence: Not due to urinary tract problem Occurs when otherwise continent people with difficulty getting to bathroom Patients with physical or cognitive impairment Signs: Accident on the way to the bathroom Generally loose large volume of urine at one time 14 Ann Intern Med. 2014;161(6):429-440. doi:10.7326/m13-2410 7
Overactive Bladder/Urge Incontinence 15 AUA Overactive Bladder Guideline Recommendations (2012) First Line Behavioral therapies Bladder training Bladder control strategies Pelvic floor muscle training Fluid management Second Line Anti muscarinic agents e.g Oxybutynin Tolterodine Beta 3 Agonists e.g. mirabegron Third Line Onabotulinum toxin A Sacral neuromodulation Peripheral tibial nerve stimulation 16 8
Treatments for UI/OAB 17 Anticholinergic Medications Increased sensitivity in the elderly, leading to: Confusion/Delerium Xerostomia Constipation Urinary Retention Can t see Can t spit Can t pee Can t sh**! S - alivation L - acrimation U - rination D - efecation 9
Role of Drug Therapy in OAB Mirabegron is FDA approved for the treatment of overactive bladder (with symptoms of urge urinary incontinence, urgency and urinary frequency) Only non anti muscarinic agent approved for the treatment of OAB Three multinational phase III studies assessed the safety and efficacy of Mirabegron in the treatment of OAB (Nitti et al., Khullar et al., Herschorn et al.) http://www.myrbetriq.com/what is myrbetriq oab medication 19 Mirabegron MOA: selective 3 agonist Kinetics: Can be taken with or without food Moderate CYP2D6 inhibition Dosing: 25 50mg once a day (available as 25mg & 50mg tablets) Max 25mg if: CrCl < 30ml/min, moderate hepatic insufficiency No contraindications http://2.bp.blogspot.com/ Epdhl5uhryQ/T_Rnjlfh2II/AAAAAAAAAqw/_QzU4YF 2hw/s1600/mirabegron.png 20 10
Randomization Eligibility: >18 yo with OAB symptoms > 3 mo. Average micturition freq. >8 per 24h >3 episodes of urgency +/ incontinence Study Design Khullar et al. (2012) 21 Post Hoc Prior Anti Muscarinic Treatment Failure Khullar et al. (2012) No Prior Anti muscarinic therapy Prior Anti muscarinic therapy 960 (50.4%) 946 (49.6%) Reason for Discontinuation Insufficient effect Poor tolerability Both 633 (33.2%) 253 (13.3%) 86 (4.5%) Khullar V,et al (2012). Eur Urol. 2013 Feb;63(2):283 95. doi: 10.1016/j.eururo.2012.10.016 22 11
Mean Reduction in Micturition Episodes per 24 hours Nitti et al. Pooled Analysis (2013) Mirabregon 50mg (SD) Placebo (SD) Participants 1324 1328 Baseline Endpoint 11.7(0.09) 9.9 (0.09) 11.6 (0.09) 10.4 (0.09) Change from Baseline 1.8 (0.08) 1.2 (0.08) Change vs. Placebo 0.55 (0.10) 95% CI, p value ( 0.75, 0.36), <0.001 Nitti VW,et al. J Urol. 2013 Apr;189(4):1388 95. doi: 10.1016/j.juro.2012.10.017. Epub 2012 Oct 16. 23 Mean Reduction in Incontinence Episodes per 24 hours Nitti et al. Pooled Analysis (2013) Mirabregon 50mg (SD) Placebo (SD) Participants 862 878 Baseline Endpoint 2.7(0.09) 1.2 (0.09) 2.7 (0.09) 1.6(0.09) Change from Baseline 1.5 (0.08) 1.1 (0.08) Change vs. Placebo 0.40 (0.09) 95% CI, p value ( 0.75, 0.36), <0.001 24 12
Primary Endpoints including Tolterodine ER Khullar et al. (2012) 25 12 Month Safety Study Design Chapple et al. (2012) 2 week placebo run in 12 month randomized treatment phase Mirabegron 50mg (n = 812) Mirabegron 100mg (n = 820) Tolterodine ER 4mg (n = 812) Single blind Randomized Double blind, Active controlled Phase III study 3 6 9 Randomization Eligibility: >18 yo with OAB symptoms > 3 mo. Average micturition freq. >8 per 24h and >3 episodes of urgency +/ incontinence Screening for TEAEs continued until 30 days after last study drug intake 26 13
Baseline Demographics Chapple et al. (2012) n (%) Mirabegron 50mg Mirabegron 100mg Tolterodine ER 4mg Male 210 (25.9) 212 (25.9) 212 (26.1) Female 602 (74.1) 608 (74.1) 600 (73.9) > 65 yo 289 (35.6) 316 (38.5) 303 (37.3) > 75 yo 75 (9.2) 75 (9.9) 83 (10.2) Prior OAB drug use 446 (54.9) 419 (51.1) 447 (55.0) OAB Mean Duration 87.4 87.9 83.8 (mo.) Previous Study Treatment Naïve* 139 (17.1) 161 (19.6) 156 (19.2) * 81.3% of participants had been treated with mirabegron, tolterodine ER, or placebo in previous Phase II studies, but had a 30 day washout period before enrollment. Chapple CR, Eur Urol. 2013 Feb;63(2):296 305. 27 Treatment Emergent Adverse Effects Chapple et al. (2012) 12 Frequent (>2%) TEAEs of Interest Percentage of subjects 10 8 6 4 2 9.2 9.8 9.6 2.8 2.4 8.6 4.1 3.2 2.8 3 2.5 2.7 0 Hypertension Dry Mouth Headache Constipation TEAE Mirabegron 50mg Mirabegron 100mg Tolterodine ER 4mg 28 14
Cardiovascular Adverse Effects of Interest Chapple et al. (2012) Cardiovascular TEAEs of Interest 12 10 11 10.1 10.6 Percentage of subjects 8 6 4 3.9 4.1 6 2 0 0.4 0.2 0.4 Corrected QT Interval Prolongation Hypertension Cardiac Arrhythmia Cardiovascular TEAE Mirabegron 50mg Mirabegron 100mg Tolterodine ER 4mg 29 Discontinuations due to TEAEs Chapple et al. (2012) 12 Discontinuations due to TEAEs 10 Percentage of subjects 8 6 4 6.4 5.9 6 4.2 3 5.5 2 0 Any AE Lack of Efficacy Reason for Discontinuation Mirabegron 50mg Mirabegron 100mg Tolterodine ER 4mg 30 15
Any symptom in an elderly patient should be considered a drug side effect until proved otherwise. J Gurwitz, M Monane, S Monane, J Avorn Brown University Long-term Care Quality Letter 1995 Onabotulinum toxina (BOTOX ) Role in Therapy: 3 rd line treatment MOA: Inhibition of acetylcholine release from presynaptic nerve terminals Prevents stimulation of muscarinic receptors Indicated for: Symptoms of urge urinary incontinence, urgency, and frequency in adults who have an inadequate response to or are intolerant of an anticholinergic/b3 agoinist Box Warning: Spread of toxin effect 16
OnabotulinumtoxinA (BOTOX ) Contraindications: Urinary retention Current UTI PVR > 200mL, unable to perform clean intermittent selfcatheterization Drug Drug Interactions: Aminoglycosides Muscle relaxants Anticholinergics Other botulinum products Stress Incontinence 17
Behavioral Interventions 1) Pelvic floor muscle exercises (Kegal) contract muscles used to stop stream of urine abdominal muscles concurrently relaxed hold for 4 seconds, work up to 10 seconds repeat several times a day improvement takes 6 8 weeks cure rates 30 70% 2)Vaginal weight training active retention of increasing vaginal weights increase pelvic floor muscle strength Kegel Exercises 18
Drug Therapy Estrogen 0.625 Conjugated estrogens mg po qd 0.5 1 gm topically three times a week 1 (2mg) estradiol vaginal ring/insert placed for 90 days Decongestants Pseudoephedrine 15 60 mg tid Ephedrine 25mg bid Other Options Surgical Procedures: Pure sphincter weakness > periurethral injections of collagen Bladder hypermobility > bladder is resuspended Pelvic Organ Support Devices: Pessaries are recommended for women who have symptomatic pelvic organ prolapse in two circumstances 1) as a temporary measure for women awaiting surgical correction 2) or women who are unable to undergo surgical correction Complications when misused or neglected: ulceration of the vagina and rectovaginal and vesicovaginal fistula 19
Pessaries Mixed Incontinence 20
Mixed Incontinence A combination of urge and stress incontinence Common in older women One symptom urge or stress usually predominates Drug Therapy Imipramine 10 50 mg TID or HS Weak anticholinergic on detrusor muscle Alpha agonist on the urethral smooth muscle due to inhibition of norepinephrine reuptake Duloxetine (off label and FDA indicated) Enhances external urethral sphincter activity through serotonergic and α1 adrenergic mechanisms Causes a centrally mediated increase in bladder capacity through a serotonergic mechanism Norton et al, Journ Obst Gynecol, 2002 21
Overflow Incontinence Treatment Approaches Pharmacologic: 1. In Men, manage the Benign Prostatic Hyperplasia Non Pharmacologic: 1. Bladder compression 2. Surgery 3. Catheters 22
Catheters Indwelling Catheters: Indicated for: Bladder outlet obstruction that cannot be otherwise managed Sever pain in a terminal situation in which the patient cannot stand or be changed Severe pressure ulcers or other wounds that must be kept dry Patient prefers this method Complications: Long term use is significant cause of bacteriuria and UTI. Obstruction secondary to encrustation Leakage Unprescribed removal Pain, bladder spasms, urethral erosion, stones,, urethritis, periurethral abscess Sepsis and death Principles of Using an Indwelling Catheter Use Use only when indicated Maintain sterile closed gravity drainage system Do not routinely irrigate Prevention Wash entry site with warm soapy water daily Change catheter every 4 8 wks Avoid routine Abx use Avoid surveillance cultures Dealing with Infections complications: only tx when symptomatic and change the catheter first before collection 23
Examples Texas (Condom) Catheters Suprapubic Catheters: Indicated for short term use following gynecologic, urologic and other surgery or as an alternative to long term catheter use. (Contraindication: in persons with chronic unstable bladder). This catherization involves percutaneous or surgical introduction of a catheter into the bladder through the anterior abdominal wall. Complications include: leakage around the catheter, bladder stone formation, symptomatic UTI and recurrent blocked catheter. 24
Urinary Protective Garments 49 Case Application An elderly man approaches the pharmacy counter asking for help with his bladder: he states he was diagnosed with overactive bladder several months ago, and that his provider recently discontinued a trial of oxybutynin 5mg TID prn due to the patient experiencing sedation and dizziness. He states he is independent with all ADLs (such as toileting and dressing). Medical Conditions: Overactive bladder, diabetes with hx complications (diabetic retinopathy, neuropathy, nephropathy), dyslipidemia, hypertension Prescription Medications: Metformin XR 500mg daily, last refill 6 months ago Atorvastatin 80mg daily, no missed doses, refill history consistent Lisinopril 20mg daily, no missed doses, refill history consistent Nonprescription Medications: Aspirin 81mg daily for heart health Allergies/ADR s: No known allergies and no known adverse reactions to medications Wants to know if there is anything else he can do? Wondering about the Oxybutynin patch and if tolerability may be better? 50 25
Questions??? Nicole J. Brandt, PharmD, MBA, CGP, BCPP,FASCP Email: nbrandt@rx.umaryland.edu 51 26