The International Continence Society

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1 REPORTS Safety and Tolerability of Tolterodine for the Treatment of Overactive Bladder in Adults Richard G. Roberts, MD, JD; Alan D. Garely, MD; and Tamara Bavendam, MD Abstract This article evaluates the safety and tolerability of tolterodine for the treatment of overactive bladder (OAB), which is defined as urinary urgency with or without urgency incontinence, usually with frequency and nocturia, but without infection or pathology. OAB affects tens of millions of people worldwide. Data are summarized from clinical trials and from postmarketing surveillance studies. (Am J Manag Care. 2005;11:S158-S162) The International Continence Society (ICS) has defined overactive bladder (OAB) as urinary urgency with or without urge incontinence, usually with frequency and nocturia, in the absence of proven infection or obvious pathology. 1 The ICS has recognized OAB as a significant symptom syndrome affecting millions of people worldwide. Tolterodine is a competitive, nonselective pure muscarinic receptor antagonist 2 that was developed specifically for the treatment of OAB. Tolterodine is indicated for symptoms of urinary frequency, urgency, and urge incontinence associated with OAB. The agent has been shown to reduce micturition frequency and the number of episodes of urge incontinence and to increase the volume voided per micturition. 3 Tolterodine is available in immediaterelease (IR) and extended-release (ER) formulations, which have been shown Ascend to Media be ated with asthma and osteoporosis. billion, which is similar to the costs associ- 10 bioequivalent in their pharmacologic profile. 4 The ER formulation has improved efficacy and tolerability compared with the IR formulation. 5 OAB: Scope of the Problem Recent studies have demonstrated that OAB affects tens of millions of people worldwide. In the United States, the National Overactive Bladder Evaluation (NOBLE) program showed that 16.5% of the adult population had symptoms of OAB, including 16% of men and 16.9% of women. 6 The percentage translates to almost 35 million people. OAB is not unique to the United States. A study of 6 European countries showed an OAB prevalence of 16.6% among adults aged 40 years and older, 7 virtually identical to the prevalence found in the NOBLE program in the United States. The prevalence of OAB increases with age and was estimated to affect 22 million people in the 6 European countries. Because the prevalence of OAB increases with age, the overall burden of the condition will almost certainly grow with the continued aging of the population in the United States and other Western countries. OAB affects all aspects of quality of life (QOL), including physical, social, psychological, occupational, domestic, and sexual functioning. Patients with OAB have to use the toilet more frequently than unaffected individuals because of urgency, and incontinence has been associated with an increased risk of falls and fractures. 8,9 OAB has a significant economic impact. In the United States for the year 2000, the total cost of OAB was estimated to be $12.6 Approximately 90% of the costs come in the form of direct expenses that include diagnosis, treatment, and consequences, such as skin infection and irritation. 11 However, OAB involves substantial indirect costs that include lost wages, as well as intangible costs associated with decreased QOL. DDAJMC (G) S158 THE AMERICAN JOURNAL OF MANAGED CARE JULY 2005

2 Safety and Tolerability of Tolterodine for the Treatment of Overactive Bladder in Adults Evidence of Tolterodine Efficacy in OAB. Tolterodine improves objective urodynamic variables in patients with OAB. Two double-blind, placebo-controlled trials evaluated doses of tolterodine ranging from 0.5 mg to 4 mg twice daily. 12,13 The trials showed a dose-response relationship for volume at first contraction, maximum cystometric capacity, and volume at normal desire to void. One of the studies showed a doseresponse relationship for micturition diary parameters, including frequency, leakage, and the number of incontinence pads used. 14 The dose-response effect on urodynamic variables was confirmed in a pooled analysis of 4 randomized, double-blind, placebo-controlled studies. 3 Double-blind, placebo-controlled trials have demonstrated improvement in micturition diary parameters for tolterodine IR 2 mg twice daily or 1 mg twice daily and tolterodine ER 4 mg once daily In the 2 largest trials, improvement from baseline was significantly greater with tolterodine IR 2 mg twice daily and tolterodine ER 4 mg once daily than with placebo for all micturition variables. 5,16 The efficacy of tolterodine was maintained during open-label follow-up for as long as 12 months for both tolterodine IR 2 mg twice daily 22,23 and tolterodine ER 4 mg once daily. 24 Studies that included subjective assessments of improvement have provided additional confirmation of tolterodine efficacy. 17,22-24 Tolterodine Safety and Tolerability. The following tolterodine safety and tolerability data came from clinical trials provided by the pharmaceutical company for FDA approval as well as peer-reviewed published studies and a prescription event monitoring (PEM) study. Much of the data are included in the manufacturer s full prescribing information. 25,26 In the remainder of this article, the tolerability and safety profiles of tolterodine IR, tolterodine ER, oxybutynin IR, and oxybutynin transdermal delivery system (TDS) are compared. Other pharmacologic treatments for OAB are now available, including trospium, solifenacin, and darifenacin. However, these agents are not discussed as they are relatively new, and head-to-head trials have not been conducted. Antimuscarinic Effects. The most commonly reported adverse event associated with tolterodine has been dry mouth. In phase 3 clinical trials, dry mouth occurred in 35% of 986 patients receiving tolterodine IR 2 mg twice daily for 12 weeks compared with 10% of 683 patients who received placebo. Additionally, 24% of 505 patients treated with tolterodine ER 4 mg once daily reported dry mouth compared with 8% of 507 patients who received placebo. 25,26 Severe dry mouth occurred in only 1% to 5% of patients treated with tolterodine IR or tolterodine ER in several large trials. 5,10,16,18,21 Moreover, severe dry mouth was reported in 2% to 3% of patients during open-label follow-up for as long as 12 months Dry mouth appears to be less common with tolterodine than with oxybutynin. Several large, randomized, double-blind studies and a pooled analysis of 4 trials demonstrated significantly less dry mouth with tolterodine IR 2 mg twice daily compared with oxybutynin IR 5 mg 2 or 3 times daily. 19,20,27,28 The incidence of moderate to severe dry mouth was 3 to 5 times greater with oxybutynin IR 5 mg 2 or 3 times daily compared with tolterodine IR 2 mg twice daily. 19,27,28 The incidence of severe dry mouth was increased 5-fold with oxybutynin IR 5 mg 2 or 3 times daily compared with tolterodine IR 2 mg twice daily. 28 One recent study comparing tolterodine ER 4 mg once daily with oxybutynin transdermal patch (TDS) 3.9 mg daily did find that the incidence of dry mouth was significantly greater than placebo (1.7%) in the tolterodine ER cohort (7.3%), but not in the oxybutynin TDS cohort (4.1%). 29 However, oxybutynin TDS was also associated with skin irritation, which resulted in a higher discontinuation rate in the oxybutynin TDS cohort (10.7%) than in the tolterodine ER cohort (1.6%). In a comparison of different formulations of the 2 drugs, tolterodine IR 2 mg twice daily was associated with a similar incidence of moderate to severe dry mouth compared with oxybutynin ER 10 mg once daily. 30 When ER formulations of the 2 drugs were compared, tolterodine ER 4 mg caused significantly less dry mouth than oxybutynin ER 10 mg, and the dry mouth was less severe. 30,31 VOL. 11, NO. 4, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S159

3 REPORTS According to the manufacturer, other antimuscarinic effects include dry eyes and abnormal vision. These effects were reported by 10% of patients treated with tolterodine in clinical trials. 25,26 A PEM study in the United Kingdom (N = ) found that visual defects attributable to adverse drug reaction occurred in 0.6% of patients treated with tolterodine. 32 Tolterodine is contraindicated in patients with uncontrolled narrowangle glaucoma. 25,26 Gastrointestinal (GI) Events. Dyspepsia, constipation, abdominal pain, and flatulence were reported by 1% to 10% of patients who received tolterodine in clinical trials. 25,26 The IR and ER formulations are associated with a similar incidence of GI adverse events. 5 A multicenter, randomized, double-blind study demonstrated an incidence of abdominal pain that was similar between patients treated with tolterodine IR 2 mg twice daily or placebo. The incidence of constipation with tolterodine IR was double that of the placebo group. 21 During open-label administration of tolterodine IR 2 mg twice daily for as long as 12 months, abdominal pain was reported by 6% of patients in 2 different studies, and constipation occurred in 7% of patients. 22,23 Longterm follow-up of patients treated with tolterodine ER 4 mg once daily demonstrated a 3% incidence of constipation and a 2% incidence of dyspepsia. 24 The incidence of GI events tends to be lower in patients treated with tolterodine compared with those treated with oxybutynin. For example, a randomized, doubleblind, placebo-controlled trial showed that dyspepsia occurred in 5% of patients given placebo, 9% of those treated with tolterodine IR 2 mg twice daily, and 23% of patients treated with oxybutynin IR 5 mg 3 times daily. 20 A pooled analysis of 4 double-blind, placebo-controlled, randomized trials demonstrated a 6% incidence of dyspepsia with tolterodine IR 2 mg twice daily and 11% with oxybutynin IR 5 mg 3 times daily. 27 Labeling of tolterodine includes decreased intestinal motility and hemorrhage. Both types of events have been reported infrequently. 25,26 The PEM study from the United Kingdom showed that dyspepsia and constipation were reported in <2% of patients during the first 6 months after tolterodine became available. 32 Tolterodine is contraindicated in patients with gastric outlet obstruction and should be used with caution in patients with GI obstructive disorders. 25,26 Nervous System Events. According to the manufacturer, nervous system adverse events have occurred in 1% to 10% of patients treated with tolterodine in clinical trials. The events include headache, dizziness/vertigo, somnolence, and fatigue. 25,26 Placebo-controlled studies of tolterodine IR 2 mg twice daily and tolterodine ER 4 mg once daily showed the incidence of headache did not exceed 6% and was similar to that in placebo patients. 5,10,16,21 During open-label administration for up to 12 months, headache was reported by 6% to 7% of patients treated with tolterodine 2 mg twice daily 23,24 and by 2.4% of patients treated with tolterodine ER 4 mg once daily. 24 In the UK PEM study, the incidence of headache, dizziness, fatigue, and somnolence was <2% each during the first 6 months after the launch of tolterodine. 32 Direct comparisons between tolterodine and oxybutynin have generally shown similar rates of nervous system events. The only notable differences relate to somnolence and dizziness, both of which favor tolterodine. 19,27,28,33 Confusion and hallucinations have been reported in <1% of patients receiving tolterodine in clinical trials. In the UK PEM study, which documented 9 probably or possibly related events among patients, hallucinations, predominantly visual and occurring mostly in elderly women, were an unexpected finding. 32 Urinary Events. According to the manufacturer, dysuria occurs in <10% of patients treated with tolterodine. 25,26 The UK PEM study found a 2% reported incidence of micturition disorder and a 0.5% reported incidence of urinary retention. 32 Other Events. Edema associated with tolterodine is almost always mild and periph- S160 THE AMERICAN JOURNAL OF MANAGED CARE JULY 2005

4 Safety and Tolerability of Tolterodine for the Treatment of Overactive Bladder in Adults eral. 25,26 A multicenter, double-blind trial demonstrated a 1% incidence of peripheral edema in patients randomized to tolterodine IR 2 mg twice daily, tolterodine ER 4 mg once daily, or placebo. 5 Tachycardia is a class effect of antimuscarinic drugs. The UK PEM study reported 17 cases of tachycardia or palpitations and 21 cases of chest pain with use of tolterodine. 32 Other postmarketing cardiovascular events discussed in the manufacturer s label include ventricular arrhythmia, atrial fibrillation, cardiac failure, palpitations, bradycardia, collapse, transient ischemic attacks, and hypertension. Each of those events is reported infrequently, and insufficient evidence exists to conclude that a causal relationship exists with tolterodine. 25,26 Tolterodine is contraindicated in patients with urinary retention and impaired gastric emptying. It should be used with caution in patients with clinically significant bladder outflow obstruction. Safety in Special Populations Older Patients. Age does not appear to influence the safety profile of tolterodine. Randomized, double-blind studies showed no clinically important changes in clinical chemistry, hematologic parameters, or electrocardiogram recordings in older patients treated with tolterodine. 15,34 One placebo-controlled trial assessed tolterodine IR 1 mg and 2 mg twice daily in patients 65 years of age and older, 14 and another placebo-controlled trial assessed tolterodine ER 4 mg once daily for 12 weeks in patients aged 65 years of age and older compared with younger patients. 15 Dry mouth occurred in a similar incidence of older patients compared with younger patients and was the only adverse event that occurred significantly more often with tolterodine than placebo in older patients. Most instances of dry mouth were mild to moderate in intensity. All adverse events occurred at a similar frequency in younger and older patients, except for headache, which was more common in younger patients. 15 The incidence of dry mouth is lower with tolterodine than with oxybutynin. A randomized trial compared tolterodine IR 2 mg twice daily for 10 weeks and oxybutynin IR 2 mg 3 times daily, increasing to 5 mg for the remaining 8 weeks. The mean age of the study population was 65 years. A higher proportion of patients receiving oxybutynin had dry mouth, severe dry mouth, and dry mouth resulting in withdrawal from the study. 34 Hepatic and Renal Impairment. Tolterodine IR achieved a higher serum concentration and a prolonged elimination half-life when volunteers with liver cirrhosis were compared with healthy volunteers. 35 Urine is the major excretion route of tolterodine. As a consequence, the maximum recommended dosage is 1 mg twice daily for the IR formulation and 2 mg once daily for the ER formulation for patients with hepatic or renal impairment. Pregnancy and Lactation. Tolterodine is a US Food and Drug Administration pregnancy category C drug and should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No data are available on excretion of tolterodine in breast milk, so use during lactation should be avoided. 25,26 In the UK PEM study, 6 women took tolterodine during the first trimester. The reported outcomes of the pregnancies were 5 live births with no congenital abnormalities and 1 spontaneous abortion. 32 Conclusion Tolterodine is associated with few adverse events, and most adverse events associated with tolterodine are of mild or moderate severity. Data accumulated since the launch of the drug in September 1997 indicate that tolterodine is well tolerated in the treatment of OAB. Dry mouth is associated with antimuscarinics and is the most commonly reported adverse drug reaction associated with tolterodine. This condition is usually mild to moderate in intensity. Clinical studies have shown that dry mouth occurs less frequently with tolterodine than with oxybutynin. The safety profile of tolterodine in older adults is similar to that in younger adults. VOL. 11, NO. 4, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S161

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Tolterodine: superior tolerability than and comparable efficacy to oxybutynin in individuals 50 years old or older with overactive bladder: a randomized controlled trial. J Urol. 2001;165: Abrams P. Evidence for the efficacy and safety of tolterodine in the treatment of overactive bladder. Int J Clin Pharmacol Ther. 1997;35: S162 THE AMERICAN JOURNAL OF MANAGED CARE JULY 2005

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