Antimuscarinic drugs for overactive bladder Ilan Z. Kafka MD 2009

Overactive Bladder Defining symptoms of overactive bladder syndrome (OAB) are: Urinary urgency with or without incontinence Frequency Nocturia 1. Abrams P, Cardozo L, Fall M et al., The standardization of terminology of lower urinary tract function: report from the Standardization Sub-committee of the International Continence Society”, Neurourol. Urodyn. (2002);21: pp. 167–178.

Overactive Bladder Frequency Urination at night Urgency 8 or more visits to the toilet per 24 hours Urination at night • 2 or more visits to toilet during sleeping hours Urgency Sudden, strong desire to urinate Urge Incontinence Sudden & involuntary loss of urine OAB

Overactive Bladder Adapted from Tubaro et al. 2004.

Overactive Bladder Local pathology Metabolic factors Medications infection bladder stones bladder tumors interstitial cystitis outlet obstruction Metabolic factors diabetes polydipsia Medications diuretics antidepressants antihypertensives hypnotics & sedatives narcotics & analgesics Other factors pregnancy psychological issues

Ideal Pharmacologic Treatment for OAB Safety Metabolic drug-drug interactions CNS effects Cardiovascular safety Efficacy Alleviate or significantly improve symptoms Improve QOL Tolerability Fewer AEs

Distribution of Muscarinic Receptors in Target Organs of the Parasympathetic Nervous System Heart Stomach and esophagus Dyspepsia Iris/ciliary body Lacrimal gland Blurred vision Dry eyes Tachycardia Dizziness Somnolence Impaired memory and cognition CNS Salivary glands Dry mouth Colon Constipation Bladder (detrusor muscle) This is a “build” slide showing the distribution of peripheral cholinergic (ie, muscarinic) receptors throughout the body Muscarinic receptors are located in the CNS, iris and ciliary body, lachrymal gland, salivary glands, heart, gallbladder, stomach, colon, and bladder Agents that are selective for the bladder are preferable over agents that may potentially target other regions of the body Blockade of muscarinic receptors outside the bladder may result in undesired side effects such as dry mouth (the most common side effect), constipation, and CNS side effects (such as dizziness, somnolence, and cognitive impairment), and effects on the stomach and eyes Abrams P, Wein AJ. The Overactive Bladder— A Widespread and Treatable Condition. 1998.

Distribution of Muscarinic Receptors in Target Organs of the Parasympathetic Nervous System

Distribution of cholinergic and adrenergic receptors in the urinary bladder

Antimuscarinic Treatment Options DRUG DOSE FREQUENCY Tolterodine LA (Detrusitol) 4 mg Once-daily Oxybutynin XL (Lyrinel) 5–15 mg Oxybutynin (Novitropan) 5–30 mg BID or TID Oxybutynin transdermal patch 3.9 mg/d 1 patch BIW Trospium (Spasmex) 15 mg TID Solifenacin (Vesicare) 5–10 mg Darifenacin (Enablex) 7.5–15 mg Fesoterodine (Toviaz) 4-8mg OD-BID

Are All Antimuscarinics the Same? A meta-analysis found: All antimuscarinics were proven effective for thetreatment of OAB Individual antimuscarinic profiles are different There is some evidence of differences among adverse- event (AE) profiles There are differences in tolerability profiles, which may be clinically significant A systematic review and meta-analysis of randomized controlled trials with antimuscarinic drugs for overactive bladder. Novara G, Galfano A, Secco S, D'Elia C, Cavalleri S, Ficarra V, Artibani W. Eur Urol. 2008 Oct;54(4):740-63.

Comparative efficacy antimuscarinic medications Study Drugs Compared Efficacy Side Effects Pooled data (Cochrane, 2005) Oxybutinin and tolterodine Similar in most outcome variables Slightly less dry mouth and withdrawals with tolterodine Oxybutinin ER and tolterodine ER Slightly less dry mouth with tolterodine ER OPERA (Diokno et al, 2003) Slightly less dry mouth with tolterodine ER, overall tolerability similar Trospium and oxybutinin (Halaska et al, 2003) Oxybutinin and trospium Slightly less dry mouth with trospium STAR (Chapple et al, 2005) Solifenacin and tolterodine ER Solifenacin had slightly better efficacy than tolterodine ER Similar rates of side effects Tolterodine and fesoterodine (Chapple et al, 2008) Tolterodine and fesoterodine Fesoterodine had slightly better efficacy than tolterodine ER A systematic review and meta-analysis of randomized controlled trials with antimuscarinic drugs for overactive bladder. Novara G, Galfano A, Secco S, D'Elia C, Cavalleri S, Ficarra V, Artibani W. Eur Urol. 2008 Oct;54(4):740-63.

Not All Antimuscarinic Agents Are the Same Structural differences Molecular size, polarity, permeability Pharmacokinetics and pharmacodynamics Metabolism and excretion/Drug-drug interaction Efficacy : Tolerability : Safety Receptor specificity, organ selectivity, patient variability (individual, age, race, gender) Khullar V, et al. Urology. 2006;68(2 suppl):38-48. Shaya FT, et al. Am J Manag Care. 2005;11(4 suppl):S121-S129. Staskin DR. Drug Aging. 2005;22:1013-1028. Wein AJ. Urol. 2003;62(5 suppl 2):20-27. Pak RW, et al. Curr Urol Rep. 2003;4:436-440.

Comparison of antimuscarinic Drugs Hepatic Impairment Renal Impairment Half-Life (h) SELECTIVITY DRUG Caution 13–19 Selective, predominantly M3 Darifenacin Mild/moderate: start with 4 mg, increase dose cautiously to 8mg Severe: 4mg 7 Non-Selective Fesoterodine 2–3 Selective, predominantly M1/M3 Oxybutynin Max dose 30mg 14-22 Propiverine Mild/moderate: no adjustment Severe: max 5mg 45–68 Solifenacin Mild/moderate: no data Severe: max 2_1mg IR or 2mg ER Tolterodine 2–3, 5-HMT 3-4 Tolterodine Mild/moderate: caution Severe: max 20mg 10–20 Trospium

Antimuscarinic drug Receptor affinity How do medications used to treat urinary incontinence affect the cerebral function of the elderly? Urologe 2007 · 46:387–392

Anticholinergic drugs used for OABS and drugs that can potentiate their adverse effects Drugs that can potentiate AE’s Anti-arrythmics Anti- depressants Anti-Diarrheal Antihstamines Antipsychotics Muscle Relaxants Anticholinergic Agents Anti- emetics Drugs to treat Parkinson’s Antispasmodics Mydriatics/Cyclopegics

Cognitive Function in Patient Receiving Antimuscarinic Therapy Antimuscarinics used in the treatment of overactive bladder differ in their potential to affect cognitive function. In particular, treatment with agents that block M1/M3 receptors in the brain are known to cause cognitive impairment. Darifenacin and tolterodine stand out as having been shown to not cause impairment of memory or other cognitive functions in randomized clinical trials. Preserving cognitive function for patients with overactive bladder: evidence for a differential effect with darifenacin. Kay GG, Ebinger U. Int J Clin Pract. 2008 Nov;62(11):1792-800..

ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER FES 4 or 8mg od vs.placebo (PL) n = 1135 FES 4 or 8mg od vs.placebo (PL) Active control arm of tolterodine extended release (TOL ER) 4mg od Two randomized, double blind, phase III, 12-week studies Primary endpoints (a) the reduction from baseline (BL) in the mean number of voids per 24-hour period (b) the reduction in the mean number of episodes of urge incontinence per 24-hour period both assessed over a 3-day period at study end, (c) treatment response derived from a 4-category pt-assessed treatment benefit scale.

ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER * p < 0.01, ** p < 0.001 vs PL Mean Change in Baseline in No. of Voids/24 hrs Kate McKeage , Gillian M. Keating Fesoterodine;Drugs 2009; 69 (6): 731-738

ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER * p < 0.01, ** p < 0.001 vs PL Mean Change in Baseline in No. episodes in Urge Incontinence/ 24h Kate McKeage , Gillian M. Keating Fesoterodine;Drugs 2009; 69 (6): 731-738

ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER * p < 0.01, ** p < 0.001 vs PL Patient Responding to Treatment (%) Kate McKeage , Gillian M. Keating Fesoterodine;Drugs 2009; 69 (6): 731-738

ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER y = incidence <1%. Kate McKeage , Gillian M. Keating Fesoterodine;Drugs 2009; 69 (6): 731-738

ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER 2008 Nov;102(9):1128-32. -Post hoc analysis -n=1135 -HrQol- Incontinent vs. All -Max Dose Fesoterodine (8mg) vs Max Dose Tolterodine (4mg)

ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER Comparison of fesoterodine and tolterodine in patients with overactive bladder.Chapple CR, Van Kerrebroeck PE, Jünemann KP, Wang JT, Brodsky M. BJU Int. 2008 Nov;102(9):1128-32.

ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER Comparison of fesoterodine and tolterodine in patients with overactive bladder.Chapple CR, Van Kerrebroeck PE, Jünemann KP, Wang JT, Brodsky M. BJU Int. 2008 Nov;102(9):1128-32.

ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER Comparison of fesoterodine and tolterodine in patients with overactive bladder.Chapple CR, Van Kerrebroeck PE, Jünemann KP, Wang JT, Brodsky M. BJU Int. 2008 Nov;102(9):1128-32.

ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER BJU Int. 2010; Vol 105( 1):p58-56 n=636 12 week follow-up - double-blind, double dummy, placebo-controlled, RCT Endpoints - Changes from baseline to week 12 in UUI episodes (primary endpoint), -Total and nocturnal voids, urgency episodes, severe urgency episodes, and frequency-urgency sum per 24 h; mean voided volume per void (MVV); OAB questionnaire (OAB-q), Patient Perception of Bladder Condition (PPBC), and Urgency Perception Scale (UPS). - Safety and tolerability

ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER *P < 0.05 vs placebo; †P < 0.05 fesoterodine vs tolterodine ER.

ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER *P < 0.05 vs placebo; †P < 0.05 fesoterodine vs tolterodine ER. *P < 0.001 fesoterodine vs placebo; †P = 0.014 fesoterodine vs tolterodine ER (post hoc comparison). The tolterodine ER vs placebo comparison was not significant (P = 0.167). Patient Perception of Bladder Condition Urgency Perception Scale †P < 0.001 fesoterodine vs tolterodine ER (post hoc comparison); ‡P < 0.001 tolterodine vs placebo (post hoc comparison).

ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER Comparison of fesoterodine and tolterodine in patients with overactive bladder BJU International Volume 102, Issue 9, Date: November 2008, Pages: 1128-1132 Christopher R. Chapple, Philip E. Van Kerrebroeck, Klaus-Peter Jünemann, Joseph T. Wang, Marina Brodsky

ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER Urology ARTICLE IN PRESS. 2009 Nov 13 N= 358 men fesoterodine 4 mg- n =120 fesoterodine 8 mg, n = 114 placebo, n =124 subanalysis of pooled data

ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER * P .05 vs placebo; † P .05 vs fesoterodine 4 mg.

ANTIMUSCARINIC DRUGS FOR OVERACTIVE BLADDER

Conclusions OAB is a highly prevalent condition As our population ages, rates will increase OAB has a large impact on our patient’s quality of life Patients perceive benefit with therapy and improvements in quality of life have been demonstrated Pharmacotherapy is better in combination with other non pharmacological therapies!!

Conclusions Multiple OAB agents are available Many are well proven over years of use and research New choices do not necessarily mean better choices Clinical effectiveness is key Range of side effects and incidences M1/M3 selectivity may lead to additional unwanted AEs

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