OVERACTIVE BLADDER IN THE ELDERLY PATIENT

Transcription

1 Program Name: OVERACTIVE BLADDER IN THE ELDERLY PATIENT Planning Committee: John Papastergiou, BScPhm Denise Gélinas, B.Pharm, MBA Surinder Gill, BScPhm Accrediation Information: This version of the program is unaccredited and intended for informational purposes only. An accredited version is available online at until September 1, Sponsor: This case study is supported by an educational grant from Pfizer Canada Inc. 1

2 Learning Objectives At completion of the program, the participant will be able to: Explain the importance of managing overactive bladder (OAB) symptoms in the older patient Describe the beneficial and adverse effects of OAB therapies in older patients Tailor treatment strategy to the needs of the older patient Abbreviations: OAB = overactive bladder BPH = benign prostatic hyperplasia Pre/Post-Course Survey [Scale: 1 5; 1 = low; 5 = high] 1. How prepared do you feel to effectively support the older patient with their OAB management? 2. How prepared do you feel to make recommendations for safe management of OAB in the older patient? 3. How confident are you in your understanding of optimal management of older OAB patients with multiple comorbidities? 4. Do you feel you can confidently differentiate the available treatment options for OAB? 5. To what extent do you feel prepared to educate older OAB patients to ensure complete adherence to treatment? 6. Do you feel you have adequate tools to support patients with their overall daily management of OAB? Introduction As the prevalence of overactive bladder (OAB) increases with the advancing age of the population, it is important to recognize and manage this bothersome condition which has a significant impact on quality of life. Overactive bladder and its management present special concerns for pharmacists managing elderly patients. To support optimal OAB management in the older patient population, this program will review the evidence regarding some of these concerns, specifically: acute urinary retention (AUR) treating complex patients who have multiple comorbidities and who receive polypharmacy optimizing OAB medication dose preserving cognitive function 2

3 Role of the Pharmacist Many elderly patients suffer with OAB needlessly; the older patient is more likely to be untreated or under-treated. 1 5 Barriers to treatment include patient and practitioner perceptions that OAB is just part of aging, or that elderly patients are too frail or too complex for treatment if multiple conditions are present, or that cognitive side effects are too high a risk in this group. Older patients are also less likely to discuss their OAB symptoms with their physician. There is an opportunity for pharmacists to help address this gap by identifying patients who should be screened, and encouraging communication with the physician. 1 3,5,6 Supporting elderly patients with OAB includes ensuring they are properly screened, that a diagnosis is made when OAB is present, and that the condition is addressed and addressed optimally. Supporting patients with managing side effects and with adherence to treatment is also important since attrition rates are high. 6 OAB in the Elderly Overactive bladder (OAB) is a prevalent and bothersome condition that has a significant impact on quality of life. Overactive bladder affects ~ 12 to 18% of Canadians, and is under-diagnosed and undertreated. Diagnosis and management are important to minimize OAB s impact on daily functioning and quality of life The prevalence and burden of OAB is even heavier in the older patient population: The incidence of OAB symptoms increases with age, and rises to over 23% in those older than 60 years. 9,11 14 Overactive bladder (OAB) will become an increasingly prevalent problem as the population ages. 11,12,15 OAB is associated with additional health risks in older patients, particularly falls and fractures, and is associated with increased mortality and is a predictor of institutionalization. 1,11,12 Older patients are less likely to discuss their OAB symptoms with their physician, and are more likely to be untreated or under-treated. 1 3,5,6 OAB symptoms should not be tolerated as an inevitable part of aging. They are manageable, even in the frail elderly person and the importance of treatment is high in this population. 11,12 3

4 Definition Overactive bladder is defined by the International Continence Society (ICS) and the Canadian Urological Association (CUA) as Urgency, with or without urgency incontinence, usually associated with frequency and nocturia. Physicians diagnose OAB based on the presence of 3 key symptoms, using a combination of history, physical exam, and urinalysis. Key symptoms: 7,8 Urgency: Sudden, compelling desire to void that is difficult to defer Frequency: The need to frequently urinate ( 8 micturitions/24 hrs) Nocturia: Waking up 2 times at night to void Urgency Incontinence, which is defined as urgency, followed by involuntary urination, may be present in OAB but is not necessary for a diagnosis of OAB. 8 Prevalence The Canadian Bladder Survey used a cross-canada telephone survey to ascertain the prevalence of lower urinary tract symptoms (LUTS) and urinary incontinence (UI) in Canada (see Figure 1). 9 The Canadian Bladder Survey found: OAB symptoms were reported in 13.9% of respondents. Prevalence increased with age and rose to over 23% in those older than 60 years. The prevalence of OAB symptoms was similar in both sexes; (13.1% of men and 14.7% of women). In the 75+ years age group, OAB was more prominent in men. OAB with urgency urinary incontinence is more common in women (7.1% vs. 3.3%). Figure 1. Prevalence of OAB in Canada 9 Herschorn et al. BJU Int (1):

5 Quality of Life Quality of life is significantly affected by OAB, especially when incontinence is present. Quality of life is affected with OAB due to: 16,17 Interference with social and occupational activities (the 2006 estimated total direct cost burden for OAB in Canada was over $300 million 14 ) Psychological and social consequences (especially with incontinence). It is quite common for patients with wet-oab to avoid sexual activity and other activities due to the fear of loss of bladder control Restricting activities to environments with washroom access fear of leaving the house for extended periods The impact of OAB on a patient s quality of life is estimated to be the same or even greater than that of diabetes. 16 In addition to the bothersome symptoms of OAB, patients commonly experience: 16 embarrassment frustration anxiety annoyance depression fear of odour Refer to the Canadian Urological Association for additional information. Incontinence Roughly 10% of Canadians have some form of urinary incontinence. Stress incontinence is not a diagnostic feature of OAB. 8,18 There are 3 main types of urinary incontinence. See CanadianContinence.ca for a tool to help patients differentiate between basic types of urinary incontinence: Urgency Urinary Incontinence (UUI; bladder incontinence associated with urgency) Stress Urinary Incontinence (SUI; bladder incontinence due to increased abdominal pressure during exertion) Mixed Urinary Incontinence (MUI; the combination of UUI and SUI) Urgency incontinence may be present in OAB, however, in many cases it is not. 5

6 Differential Diagnosis Common conditions that can share symptoms with OAB, and that are usually included in the differential diagnosis include: 18 Interstitial cystitis (IC) Acute urinary tract infection* (UTI) Prostatic enlargement in men * not asymptomatic bacteriuria, which is common in the elderly Practice Tip! Potential causes of reversible urinary incontinence: Remember DIPPERS 19 Delirium Infection Pharmaceuticals Psychological problems Excess urine output Reduced mobility Stool impaction Factors to Consider Certain factors or conditions can create signs or symptoms that may mimic or contribute to OAB symptoms (see Table 1). 20 Table 1. Factors that Affect Symptoms 20 Conditions, Medications, Dietary Habits that Could Contribute to OAB Symptoms Neurological Conditions Multiple sclerosis, spinal cord injury, stroke, Alzheimer s disease, dementia, Parkinson s disease Systemic conditions Congestive heart failure, diabetes mellitus, constipation Medications Diuretics, anticholinergics, opioids, calcium channel blockers, cholinesterase inhibitors, alpha-agonists, antihistamines Dietary and lifestyle concerns Excessive intake of caffeine and/or alcohol Impaired mobility can interfere with ability to reach toileting facilities Excessive fluid intake 6

7 Importance of Treatment Despite its prevalence and burden, OAB remains largely untreated, especially in men. 21 Barriers to optimal treatment in the elderly population can include concerns about: 1,11,21,22 acute urinary retention (AUR) treating complex patients who have multiple comorbidities patients with polypharmacy the safety of dose increases effects on cognitive function Case Study 1: The Patient with Enlarged Prostate Jim is a 76-year-old healthy man with enlarged prostate who is currently receiving alpha blocker and 5-alpha reductase treatment. History: Jim had been having symptoms that came on gradually over several months and included frequency, urgency, and nocturia. His prostate exam revealed diffuse enlargement with no nodules. He agreed to a prostate-specific antigen (PSA) test, the result of which was a value of 3.5 ng/ml and an ultrasound, which shows a post-voiding residual (PVR) volume of 125 cc. After 6 weeks on alpha blocker treatment, Jim agreed to begin alpha blocker and 5-alpha reductase inhibitor (5-ARI) therapy, and has now been on the combined treatment for 7 weeks. Terms at a Glance Storage symptoms refer to the bladder s ability to hold urine. Storage symptoms are often referred to as being irritative in nature, and consist of urgency and frequency, including nighttime frequency (nocturia). Voiding symptoms are generally considered to be obstructive symptoms associated with enlarged prostate. A PSA > 1.5ng/ml correlates with enlarged prostate >30g Post-void residual (PVR) is the volume of urine remaining in the bladder after micturition. Incomplete bladder emptying is a voiding symptom. PVR is measured either by ultrasound or by draining the remaining volume with a catheter. His voiding diary shows reduced overall frequency and nocturia but persistent urgency. For the past 6 weeks, he has normalized his fluid intake and avoided caffeine, with no change in urgency symptoms. He has a current post-void residual volume of 90 cc. 7

8 Case Challenge Jim is experiencing both voiding and storage symptoms. According to the available evidence, what is the risk of acute urinary retention if Jim is initiated on antimuscarinic therapy? a) Less than 3% b) From 9 to 21% c) From 25 to 48% d) More than 56% Risk of AUR Jim s decline in frequency, nocturia, and PVR suggest that his prostate treatment is reducing his voiding symptoms. However, his persistent urgency is diagnostic of overactive bladder. Behavioural approaches are not reducing his urgency and antimuscarinic treatment is indicated. A major barrier to optimal treatment of OAB in men is the concern that acute urinary retention may develop as an effect of antimuscarinic treatment when voiding symptoms are present. However, published placebo-controlled, open-label and active-comparator studies show that the risk of acute urinary retention with antimuscarinics is less than 3%. 23 Additionally, clinical trial evidence has shown that adding antimuscarinic treatment to alpha blocker therapy in men with bothersome OAB symptoms can significantly improve frequency and urgency episodes. 23,24 Post void residual volume should be monitored in patients complaining of voiding symptoms. The combination of an alpha-blocker and an antimuscarinic agent is an appropriate and valid option for male patients with voiding symptoms and persistent storage symptoms, providing their post-voiding residual is 200 ml. Chapple C. Can Urol Assoc J. 2011; 5 (5 Supple2): S

9 Voiding and Storage Symptoms Voiding and storage symptoms commonly overlap in men with enlarged prostate (see Figure 2). Importantly, the storage symptoms characteristic of OAB are the more bothersome symptoms. 2,23,25 Figure 2: Voiding and Storage Symptoms Commonly Overlap in Men (the EpiLUTS study) 23,25 Chapple C. Can Urol Assoc J. 2011;5(5 Suppl 2):S143. Republished with permission from Canadian Urological Association Journal; adapted with permission from British Journal of Urology Treating Storage Symptoms Concurrent with BPH Despite a high prevalence of storage symptoms in men, they are usually treated with benign prostatic hyperplasia (BPH) therapies instead of OAB therapies. When storage symptoms persist after treatment for benign prostatic hyperplasia (BPH), patients can benefit from OAB treatment (see Figure 3). 2,23,25 Clinical trial evidence has shown that adding antimuscarinic treatment to alpha blocker therapy in men with bothersome OAB symptoms can significantly improve frequency and urgency episodes. 23,24 Figure 3: Simplified Treatment Algorithm for Male Lower Urinary Tract Symptoms 23 LUTS = lower urinary tract symptoms Chapple C. Can Urol Assoc J. 2011;5(5 Suppl 2):S143. Republished with permission from Canadian Urological Association Journal 9

10 Non-pharmacological Treatment The Canadian Urological Association recommends conservative measures as the first approach to management, to increase bladder capacity, reduce urinary frequency, and allow the patient to suppress urgency. These might include: 8,16,17,20,26 Limiting fluid consumption to ~ L/day Limiting consumption of caffeine and alcohol Limiting fluid intake 2 hours before going to bed Bladder training Pelvic floor muscle training Maintaining regular bowel movements Smoking cessation Weight loss if necessary Pelvic floor muscle training (PFMT) The sling of muscles and connective tissue that extend across the base of the pelvis supports the pelvic organs and bladder. Pelvic floor muscle training employs exercise protocols designed to strengthen the pelvic floor muscles and improve function. 27 PMFT is available to patients in the form of: PFMT/Kegel exercises 27 Pilates classes 28 These approaches have been shown to be similarly effective in improving pelvic floor muscle function. Tools: Click here to access a pamphlet about pelvic floor exercises for female patients Click here to access a bladder training guide If conservative measures alone are ineffective, adding pharmacotherapy may improve symptoms. 10

11 Pharmacological Treatment First-Line Pharmacotherapy Clinical guidelines recommend first-line pharmacotherapy with antimuscarinic agents, which have been in use for 30 years. 8,29 A novel treatment option, which is now available is a selective beta 3 adrenoceptor antagonist, mirabegron. Mirabegron has a first-line indication in the treatment of OAB symptoms. 30 Antimuscarinic Treatment Options o Darifenacin extended release tablets 7.5mg, 15mg o Fesoterodine fumarate extended-release tablets 4mg, 8mg o Oxybutynin chloride 5mg regular (immediate release) or extended release tablets 5 mg, 10 mg ; gel 10%; transdermal continuous delivery, twice weekly dosing, 36 mg (3.9 mg / day system) o Solifenacin succinate tablet, 5 mg, 10 mg o Tolterodine L-tartrate regular or extended release capsules 2 mg, 4 mg o Trospium chloride coated tablet 20 mg Selective beta 3-adrenoceptor agonist 30 o Mirabegron extended-release tablets 25 mg and 50 mg Second-Line Pharmacotherapy Botulinum toxin type A is also now approved in Canada for intradetrusor injections for the treatment of OAB in adult patients who have an inadequate response to or are intolerant of antimuscarinic medication. 40 Antimuscarinic Treatment Antimuscarinics are the mainstay of treatment for OAB. They have been shown to reduce the frequency of micturition and episodes of urgency urinary incontinence, with high levels of evidence. 8,41,42 First-line treatment is with the antimuscarinics These agents help relieve OAB symptoms, especially when combined with non-pharmacological approaches (i.e., pelvic floor muscle training and normalizing fluid intake) Patients should be educated about the onset of effect, which may take several weeks A major meta-analysis of trials of antimuscarinic agents for OAB found antimuscarinics efficacious compared to placebo. Differences in the relative efficacy of the agents was not apparent, except that some results showed statistical significance in favour of the higher dosage of propiverine, fesoterodine, and solifenacin over placebo and lower dose antimuscarinics

12 Side Effects Antimuscarinics differ in their frequency of administration, receptor selectivity and specificity, binding affinity, and other characteristics. The primary sites of activity are the M2 and M3 receptors of the bladder, which mediate contraction. Selectivity for muscarinic receptors is the main reason for variation in side effects across the antimuscarinic agents. Action on muscarinic receptors in the body beyond the detrusor muscle leads to side effects: 8,31 39 The side effect profile of each antimuscarinic differs with possible adverse effects that can, depending on the agent, include dry mouth, blurred vision, pruritus, tachycardia, somnolence, impaired cognition, headache, and constipation. (For complete prescribing information, see product monographs.) Cautions and Contraindications Antimuscarinic contraindications to check for include: 8,31 39 These agents should be used with caution in patients with renal insufficiency. Antimuscarinics are not contraindicated but should be used with caution in patients with bladder outlet obstruction. Urinary retention was reported in postmarketing experience with patients taking antimuscarinic medications or mirabegron, and in patients with bladder outlet obstruction. Monitoring is advised when administering antimuscarinics in patients with clinically significant bladder obstruction, due to risk of urinary retention. Antimuscarinics are contraindicated in patients with uncontrolled narrow glaucoma, urinary retention, gastric retention, or unstable cardiovascular status. Interactions Antimuscarinic interactions to check for include: 8,31 39 Drugs that may increase antimuscarinic effects: amantadine, antihistamines, disopyramide, nefopam, monoamine oxidase inhibitors, and tricyclic antidepressants. CYP3A4 inhibitors: Solifenacin and fesoterodine levels may increase in the presence of potent CYP3A4 inhibitors. Dose adjustment is recommended (refer to the individual product monograph per agent) in patients taking moderate or strong CYP3A4 inhibitors such as fluconazole, ketoconazole, itraconazole, miconazole and clarithromycin. CYP3A4 inducers: Induction of CYP3A4 may lead to reduced plasma levels of the active metabolite of solifenacin and fesoterodine. Concomitant use of CYP3A4 inducers such as rifampicin or carbamazepine is not recommended. Antiarrythmics: Darifenacin and tolterodine may increase risk of arrythmias when given with antiarrythmics. 12

13 Mirabegron Mirabegron is a novel,oral, once-daily, selective beta-3 adrenoceptor agonist that has shown similar efficacy to antimuscarinics. 8,30 Mirabegron acts on the storage phase of bladder function to cause smooth muscle relaxation, resulting in increased bladder capacity and lengthened interval between voiding. 8,27,30,44 Side Effects Mirabegron is generally well tolerated; the most commonly reported adverse reactions (>3% of patients taking mirabegron 50mg/day) were hypertension, urinary tract infection, headache, and nasopharyngitis. The incidence of dry mouth and other side effects was similar in rate to placebo. 30 Cautions and Contraindications Mirabegron is contraindicated in: 30 Patients with hypersensitivity to the drug, its packaging, or ingredients Patients with severe uncontrolled hypertension defined as systolic blood pressure 180 mmhg Hypertension and/or diastolic blood pressure 110 mmhg (mirabegron has not been studied in this patient The percentage of participants population) experiencing increase in blood Patients should be educated about the onset of pressure beyond baseline, or effect, which may take several weeks Patients who are pregnant (mirabegron has not hypertension, in phase 3 trials of been studied in this patient population) mirabegron was 7.6% for placebo; Mirabegron should be used with caution in patients with 11.3% for mirabegron 25mg; and bladder outlet obstruction. Urinary retention was reported 7.5% for mirabegron 50mg. in postmarketing experience with patients taking mirabegron or antimuscarinic medications, and patients with bladder outlet obstruction. Caution is advised when administering mirabegron in patients with clinically significant bladder obstruction or in patients taking antimuscarinic drugs, due to risk of urinary retention. 30 Interactions Mirabegron is a moderate inhibitor of CYP2D6. 30 The dose of mirabegron should not exceed 25 mg when co-administered with narrow therapeutic index CYP2D6 substrates, such as flecainide, propafenone, metoprolol, and desipramine. Mirabegron is a weak inhibitor of permeability-glycoprotein (P-gp). 30 For patients who are initiating a combination of mirabegron and digoxin, the lowest dose for digoxin should be prescribed initially. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect. The potential for inhibition of P-gp by mirabegron should be considered when mirabegron is combined with sensitive P-gp substrates e.g. dabigatran. 13

14 Following a single dose administration of 25 mg warfarin, mirabegron had no effect on the warfarin pharmacodynamic endpoints such as International Normalized Ratio (INR) and prothrombin time. The effect of mirabegron on multiple doses of warfarin has not been fully investigated. 30 For complete prescribing information, see product monograph. Botulinum Injections Botulinum injections are now indicated in Canada for the treatment of OAB when there has been inadequate response to antimuscarinic* therapy. 40 *Now that mirabegron is available in Canada, it presents another first-line option for OAB treatment that can be tried in advance of second line options. About Botulinum Injections 40 Clostridium botulinum type A, a neurotoxin, is injected into the detrusor muscle via a flexible or rigid cystoscope. The needle is inserted into the detrusor, and 20 injections are delivered (see Figure 4). Clinical improvement may occur within 2 weeks. Patients may be considered for reinjection when the clinical effect of the previous injection has diminished, but no sooner than 3 months from the prior bladder injection. Figure 4. Botulinum Injections Adverse Reactions Most common adverse reactions with Botulinum injections and the rate at which they occurred in the first 12 weeks after intradetrusor Injection in double-blind, placebo-controlled clinical trials: 40 urinary tract infections (26%) dysuria (11%) 14

15 bacteriuria (8%) urinary retention (6%) increased residual urine volume* (3%) pollakiuria (2%) Procedure-related events: dysuria (6%) and hematuria (2%) * Elevated PVR not requiring catheterization If your patient has had botulinum injections for OAB, they might mention to you that they received catheterization. Some patients experience urinary retention after treatment and may require catheterization. Catheterization was initiated in 6.5% following treatment versus 0.4% in the placebo group. Patients who are not catheterizing prior to treatment may subsequently require catheterization for urinary retention. In patients who are not catheterizing, post-void residual urine volume should be assessed within 2 weeks post-treatment and periodically as medically appropriate up to 12 weeks. Patients should be instructed to contact their physician if they experience difficulties in voiding. 40 Warnings Serious Warnings and Precautions: 40 Adverse events after treatment with botulinum toxin include rare spontaneous reports of death, sometimes associated with anaphylaxis, dysphagia, respiratory compromise, pneumonia, and/or other significant debility. There have also been rare reports of adverse events involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes. Some of these patients had risk factors including pre-existing cardiovascular disease. New onset or recurrent seizures have also been reported, typically in patients who are predisposed to experiencing these events. The exact relationship of these events to the botulinum toxin injection has not been established. Should only be given by physicians with the appropriate qualifications and experience in the treatment and the use of required equipment. Other Interventions Other interventions to address overactive bladder symptoms include: 45,46 Electrical detrusor muscle stimulation o implanted electrical neuromodulation devices that act to modulate detrusor contractions o types include sacral neuromodulation or percutaneous posterior tibial nerve stimulation o treatment modality for patients with refractory OAB o mechanisms of action not fully understood Acupuncture (needle or laser) Surgery (bladder augmentation or substitution) 15

16 A Comparison of Oral Antimuscarinics versus Other Interventions in Elderly Women: A 2013 study of daily incontinence frequency in elderly women (n= 229) compared 1 month of maintenance treatment: 46 Group A: Antimuscarinic treatment (trospium (60 mg/day) + solifenacin (40 mg/day)) Group B: electrical stimulation of the detrusor muscle Group C: laser puncture Group D: placebo The researchers found that clinical and urodynamic results achieved with the high dose antimuscarinic treatment (Group A) were maintained for at least 7 months. Electrical stimulation of the urinary bladder was found to be less effective (see Figure 5). In groups C and D, deterioration in results was observed at 6-8 months. 46 Figure 5: Frequency of Incontinence Episodes versus Duration of Treatment Antimuscarinic treatme patients (group A) achi urodynamic and clinica were maintained for at months. Kosilov et al. Int Neurourol J. Dec 2013; 17(4):

17 Case Study 2: The Complex Patient Elizabeth is 83 years old and has several medical conditions, including type 2 diabetes, hypertension, dyslipidemia, diabetic retinopathy, osteoarthritis, and a history of two episodes of delirium associated with acute illness. Elizabeth also has OAB symptoms that include urgency, frequency, and urgency incontinence. Her medications include metformin, sitagliptin, ramipril, atorvastatin, low dose ASA, and ibuprofen. You know that the OAB symptoms are troublesome for Elizabeth and affect her quality of life, but you are concerned about recommending addition of an OAB treatment in the context of her current comorbidity and polypharmacy, especially since she has had two episodes of delirium. Case Challenge Test your current knowledge: You know that the antimuscarinics that do not cross the blood-brain barrier are less likely to cause cognitive effects. Additionally, brain penetration is low for antimuscarinics that are P-gp substrates. These include: a) trospium, oxybutynin, and darifenacin b) oxybutynin, solifenacin, and tolterodine c) darifenacin, solifenacin, and tolterodine d) 5-HMT (fesoterodine), darifenacin, and trospium Cognitive Side Effects Despite the higher prevalence of OAB among older adults, concerns about the possibility of cognitive impairment as a side effect of antimuscarinic treatment likely contribute to the under-treatment of OAB in this patient group. Cognitive impairment is a concern when using antimuscarinic agents because the M1 and M2 muscarinic receptors are expressed densely in the prefrontal cortex and hippocampus, which have roles for attention, executive function, and memory. 11,12,22,47,48 Older individuals have added risks that include: increased permeability of the bloodbrain barrier, changes in hepatic and renal function, and the presence of comorbidities and concomitant drugs that may have additive antimuscarinic effects or compete for metabolic resources. 11,12,22,47,48 However, antimuscarinics vary in their effects. Differences in properties are important to consider, especially: 12,47 interactions with the M1 receptors in the central nervous system binding profiles lipophilicity ability to cross the blood-brain barrier 17

18 Brain penetration has been found to be low for antimuscarinics that are hydrophilic quaternary amines and P-gp substrates (5-HMT (fesoterodine), darifenacin, trospium), and higher for those that are lipophilic tertiary amines that are not P-gp substrates (oxybutynin, solifenacin, and tolterodine) Effects on Memory in the Elderly: Darifenacin vs Oxybutynin A 2006 study of antimuscarinic effects on memory in elderly subjects found no significant difference between darifenacin and placebo on delayed recall (mean difference, -0.06, p=0.908). However, oxybutynin ER resulted in memory impairment, with significantly lower scores than placebo and darifenacin (mean differences, -1.30, p=0.011 and -1.24, p=0.022, respectively) for delayed recall on the Name-Face Association Test at week 3. Additional tests of delayed recall indicated significant memory impairment with oxybutynin ER (but not with darifenacn) versus placebo at certain time points. 52 Ask the Expert In the complex older patient who has OAB in the context of multiple comorbidities and polypharmacy, what are the potential risks and benefits of choosing to add a treatment for OAB? Evidence in the Complex Older Patient DuBeau 2014 A 2014 study by DuBeau et al is the first antimuscarinic study in a community based, significantly older, medically complex elderly population with urgency urinary incontinence. In this study, flexible dose fesoterodine significantly improved urgency urinary incontinence episodes versus placebo, and was generally well tolerated. 53 Additionally, the fesoterodine group had significant reductions in micturitions (p <0.001) and daytime and nocturnal urgency episodes (p <0.001 and p= 0.02, respectively) versus placebo (see Figure 6). 53 Figure 6: Change in frequency and urgency after 4 and 12 weeks for patients treated with fesoterodine vs placebo 53 A B C Change from baseline to weeks 4 and 12 in bladder diary variables for A) frequency, measured in micturitions per day, B) urgency episodes per day, and C) nocturnal urgency episodes per day. PBO = placebo. FESO = fesoterodine. Data represent full analysis set for patients reporting symptoms at baseline. Asterisk indicates p <0.05 vs placebo. 18

19 SOFIA Trial Also, in the SOFIA Trial*, in654 elderly OAB patients with multiple comorbidities and polypharmacy, treatment with the antimuscarinic fesoterodine demonstrated efficacy in reducing urgency episodes and urgency urinary incontinence episodes after 12 weeks of treatment, compared with placebo. Findings from the SOFIA Trial* 54 Fesoterodine was found to be generally well tolerated in elderly OAB patients with multiple comorbidities and polypharmacy. The most frequently reported adverse events were dry mouth (6.0% placebo and 23.5% fesoterodine) and constipation (4.3% placebo and 11.1% fesoterodine), which were mild to moderate in intensity in most patients. No overall differences in safety and efficacy were observed between patients <65 years and those >65 years; however, the incidence of antimuscarinic adverse events was higher in patients >75 years as compared to younger patients. There were no changes in Mini-Mental State Examination score and very few adverse cognitive events were reported in either the fesoterodine or placebo groups. Case Study 3: Optimizing Dose in the Older Patient Edna is a 79-year-old woman with OAB symptoms that include urgency, nocturia, and urgency urinary incontinence. She also has occasional stress incontinence. She has practiced behavioural interventions, but observed little change symptoms tracked in her voiding diary after 6 weeks of bladder retraining, normalized fluids, and a trial of reduced caffeine intake. Edna then began treatment of a low-dose immediate-release antimuscarinic (oxybutynin 2.5 mg BID). Edna experienced few if any side effects, but has had an inadequate response with less than 50% improvement in symptoms. Case Challenge Based on the above evidence for the elderly population, which of the following statements about dose and formulation applies, when flexible dosing with lower and higher dose options is available: a) Lower doses of antimuscarinics are usually required to achieve optimal efficacy in the elderly; also, immediate-release formulations are preferable. b) Higher doses of antimuscarinics are usually required to achieve optimal efficacy in the elderly; also, immediate-release formulations are preferable. c) Lower doses of antimuscarinics are usually required to achieve optimal efficacy in the elderly; also, extended-release formulations are preferable. d) Higher doses of antimuscarinics are usually required to achieve optimal efficacy in the elderly; also, extended-release formulations are preferable. 19

20 Dosing Considerations in the Elderly Some key considerations when selecting an antimuscarinic and dose for elderly patients include: 11,53,54,54,55 When flexible dosing is available, the higher dose option might be required to achieve optimal efficacy in the elderly. A guiding principle is to start low and go slow. Initiate at the lowest available dose form (see Table 2) and then increase dose gradual to achieve efficacy as tolerated. If side effects occur, flexible dosing options allow for dose reductions (see Table 3). Immediate-release formulations should be avoided for elderly patients, to minimize side effects. Tell the patient that the side effects will appear before the beneficial effect on OAB symptoms. It takes about 4 to 6 weeks to see the optimal response. The magnitude of reduction in urinary urgency after four weeks is a good guide as to whom may need a dose increase Table 2: Available Dosing Forms Name Available Dosing Maximum Daily Dose Darifenacin ER 7.5 mg 15 mg 15 mg Fesoterodine ER 4 mg 8 mg 8 mg Oxybutynin 2.5 mg 5 mg 1 mg/ml (syrup) 20 mg (5 mg QID) Oxybutynin ER 5 mg 10 mg 30 mg (5 mg X6) Oxybutynin transdermal patch 1 patch (36 mg) 1 patch every 3 to 4 days Oxybutynin transdermal gel 1 sachet (10 % oxybutynin) 1 sachet Solifenacin 5 mg 10 mg 10 mg Tolterodine 1 mg 2 mg 4 mg (2 mg BID) Tolterodine ER 2 mg 4 mg 4 mg Trospium 20 mg 40 mg (20 mg BID) 20

21 Table 3: Dose Adjustments for Antimuscarinics Drug Half-life (hours) Renal Dose Adjustment Liver Dose Adjustment Darifenacin (ER) None CP class B: 7.5 mg/od CP class C: avoid Fesoterodine (ER) 7 CrCl<30: 4 mg/od CP class C: avoid Oxybutynin IR/ER 2 3/13.2 Caution advised Caution advised Solifenacin CrCl<30: 5 mg/od Tolterodine (IR) 2.2 CrCl<30: 1 mg BID IR CP class B: 5 mg/od CP class C: avoid CP class A or B: caution advised CP class C: avoid Trospium 20/35 CrCl<30: 20 mg/od (IR) CP class B: caution advised CP = Child-Pugh Adapted from Famakinwa et al. Current Bladder Dysfunct Rep. 2012;7: Adherence The pharmacist plays a key role in supporting adherence to therapy. Pharmacists are in a unique position to identify and address signs of non-adherence. Tips for ensuring adherence: Ask patients about tolerability concerns and whether they find they can stick to their treatment without side effects Support patients with any side effects they might be experiencing (aids for dry mouth or constipation, for example) Educate patients about the duration of treatment before benefits are seen (usually several weeks), and the importance of adherence for outcomes. Initial side effects may be overcome, and the treatment effect may take a few weeks. Ensure that patients understand their dosing and administration Check for the role of any drug interactions 21

22 Key Points Overactive bladder (OAB) is a prevalent and bothersome condition that is under-diagnosed and under-treated. OAB increases in prevalence with age but is not necessary consequence of aging. Pharmacists play an important role in identifying and supporting management of OAB in this patient population. Symptoms of OAB include urinary urgency, frequency, and nocturia. Urinary incontinence may or may not be present. OAB has a significant impact on quality of life. The recommended first approach to management is with behavioural interventions. First-line pharmacotherapy is antimuscarinic treatment. A novel treatment for overactive bladder is the selective beta-3 adrenoceptor agonist mirabegron. If antimuscarinic treatment fails, botulinum toxin injections are now a second line option for treatment in Canada. OAB occurs in men in the same prevalence as in women. In men, lower urinary tract symptoms associated with benign prostatic hyperplasia commonly overlap with OAB symptoms. Antimuscarinic treatment prescribed together with alpha blocker has been shown to reduce OAB symptoms. Elderly complex patients on polypharmacy who have OAB have been found to benefit from the addition of OAB treatment with antimuscarinics. The group of antimuscarinic treatments that are most likely to have cognitive side effects are those that are not P-gp substrates because these penetrate the blood-brain barrier. To achieve optimal symptom control, elderly patients might require the higher dose of antimuscarinic when flexible dose options are available. Flexible antimuscarinic dose options allow for treatment to be adjusted, starting at a low dose and increasing, as tolerated, to achieve efficacy. Discussion Forum 1. What approaches do you use when counselling elderly patients who are on antimuscarinic therapy for OAB? 2. Which product attributes do you consider in recommending a therapy for OAB treatment in elderly patients? 22

23 Post-Test 1. Overactive bladder is characterized by: a. Urinary urgency, usually associated with frequency and nocturia b. Urinary urgency usually associated with frequency and incontinence c. Urinary urgency, usually associated with frequency and pain d. Urinary frequency, usually associated with urge and stress incontinence 2. Which of the following is not a red flag that should prompt referral to a urologist? a. hematuria b. painful bladder c. incontinence d. palpable bladder 3. The Canadian Urological Association recommends that the first approach to management of OAB should be: a. Behavioural modifications b. Botulinum toxin A injections c. Beta-3 AR therapy d. Antimuscarinics 4. True or false? Antimuscarinics are contraindicated for use in patients with bladder outlet obstruction. o True o False 5. Botulinum toxin type A is also now approved in Canada for intradetrusor injections, for what use? a. As first-line pharmacological treatment of overactive bladder b. As second-line pharmacological treatment of overactive bladder for patients who have failed on first-line treatment c. Only for overactive bladder due to a neurological condition d. Only for overactive bladder with recurrent UTI 6. True or false? Voiding and storage symptoms commonly overlap in men with enlarged prostate The storage symptoms characteristic of OAB are reported to be more bothersome than voiding symptoms. o True o False 7. True or false? The antimuscarinic agents that most penetrate the blood-brain barrier are the permeability-glycoprotein (P-gp) substrates. o True o False 23

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