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Pediatric drug development is challenging when a product is studied for a pediatric disease that has a different underlying etiology and pathophysiology compared to the adult disease. Neurogenic bladder dysfunction (NBD) is such a therapeutic area with multiple unsuccessful development programs. The objective of this study was to critically evaluate clinical trial design elements that may have contributed to unsuccessful drug development programs for pediatric NBD. Trial design elements of drugs tested for pediatric NBD were identified from trials submitted to the U.S. Food and Drug Administration. Data were extracted from publically available FDA reviews and labeling and included trial design, primary endpoints, enrollment eligibilities, and pharmacokinetic data. A total of four products were identified. Although all four programs potentially provided clinically useful information, only one drug (oxybutynin) demonstrated efficacy in children with NBD. The lack of demonstrable efficacy for the remainder of the products illustrates that future trials should give careful attention to testing a range of doses, using objectively measured, clinically meaningful endpoints, and selecting clinical trial designs that are both interpretable and feasible. Compiling the drug development experience with pediatric NBD will facilitate an improved approach for future drug development for this, and perhaps other, therapeutic areas., (© 2014, The American College of Clinical Pharmacology.)

The study included 95 female patients of 65 to 74 years (average age 67,1 years), who previously (more than 6 months before this study) took a course of monotherapy with hydrochloride trospium in higher dosages with unstable or weak effect. In this study, all patients were divided into three groups and were treated with two antimuscarinic drugs. The majority of older women suffering from OAB and treatment-resistant taking one antimuscarinic drug in high doses showed a significant positive progress in a state by adding a second antimuscarinic agent. The received side effects do not exceed thereof in comparison with treatment with a single drug.

To examine the efficacy, safety and tolerability of tolterodine in children with overactive bladder in comparison with standard treatment i.e. oxybutynin as demonstrated in randomized clinical trials and other studies. A systematic search was done to screen the studies evaluating the effect of tolterodine in children with non-neurogenic overactive bladder. Results of studies were pooled and compared. Efficacy was determined from micturition diaries and dysfunctional voiding symptoms score. Safety and tolerability were assessed from the reported treatment emergent adverse events. A total of six randomized clinical trials and 11 other studies of tolterodine in children with urinary incontinence were included in the present systematic review. The dose of tolterodine used in different settings ranged from '0.5 to 8 mg/day' instead of '0.5 to 8 mg/kg per day' and the duration of studies ranged from 2 weeks to 12 months. Both extended and immediate release preparations of tolterodine were shown to have comparable efficacy and tolterodine proved to have comparable efficacy with better tolerability than oxybutynin in these studies. It can be concluded that tolterodine is efficacious in treatment of urinary incontinence in children. Moreover, its efficacy is comparable to oxybutynin, the most commonly prescribed anticholinergic in this condition, while having better tolerability. Hence, it can be considered as first line therapy for the treatmentof urinary incontinence in children.

Objective: To carry out a cost-utility analysis comparing initial treatment with solifenacin 5 mg/day vs oxybutynin immediate-release (IR) 15 mg/day for the treatment of patients with overactive bladder (OAB) from the perspective of the U.K. National Health Service (NHS)., Methods: A Markov model with six health states was developed to follow a cohort of OAB patients treated with either solifenacin or oxybutynin during a 1-year period. Costs and utilities were accumulated as patients transited through the health states in the model and a drop-out state. Some of the solifenacin patients were titrated from 5 mg to 10 mg/day at 8 weeks. A proportion of drop-out patients were assumed to continue treatment with tolterodine ER. Utility values were obtained from a Swedish study and pad use was based on a multinational clinical trial. Adherence rates for individual treatments were derived from a U.K. database study. For pad use and utility values, the drop-out state was split between those patients who were no longer receiving treatment and those on second-line therapy. Patients on second-line therapy who drop-out were referred for a specialist visit. Results were expressed in terms of incremental cost-utility ratios., Results: Total annual costs for solifenacin and oxybutynin were £504.30 and £364.19, respectively. First-line drug use represents 49% and 4% of costs and pad use represent 23% and 40% of costs for solifenacin and oxybutynin, respectively. Differences between cumulative utilities were small but were greater for solifenacin (0.7020 vs. 0.6907). The baseline incremental cost-effectiveness ratio was £12,309/QALY., Conclusion: Under the baseline assumptions, solifenacin would appear to be cost-effective with an incremental cost-utility of less than £20,000/QALY. However, small differences in utility between the alternatives and the large number of drop-outs means that the results are sensitive to small adjustments in the values of utilities assigned to the drop-out state.

Objective: To assess if oxybutynin and tolterodine have an effect on simple reaction time in healthy volunteers., Methods: Simple reaction time was evaluated before and 90 minutes after the oral administration of oxybutynin and tolterodine in a cross-over design. Twenty seven healthy volunteers, aged 26 to 48 years, were included in the study. The electromyographic activity of the flexor digitorum superficialis muscle that was used for the response was recorded, and premotor time was measured., Results: The mean age of the study group was 33.1 ± 7.4 years. Mean premotor times before oxybutynin and before tolterodine administration were statistically non-significant. Mean premotor times after the administration of oxybutynin and tolterodine were significantly longer than the initial premotor times (p = 0.003)., Conclusions: The results of the study showed that oxybutynin and tolterodine prolonged the simple reaction time. The prolonged simple reaction time may suggest a perceptive impairment. The potential for perceptive impairment as a side effect of oxybutynin and tolterodine might suggest a negative impact on the rehabilitation interventions and the activities of daily living because of central nervous system effects.

Background: Pharmacotherapy constitutes an important adjunct to behavioral therapy for the treatment of overactive bladder (OAB). Tolterodine and oxybutynin are commonly prescribed drugs for OAB treatment that exert their beneficial effect by suppressing bladder muscle contractions. However, high discontinuation rates have been observed for these drugs in clinical trials, as well as in real-world settings, in part due to adverse effects. Extended-release (ER) formulations were introduced with an improved tolerability profile over immediate-release (IR) versions of the 2 drugs. No study has compared persistence and adherence to therapy for both the ER and IR versions of tolterodine and oxybutynin., Objective: To compare persistence, adherence, and switch rates for the IR and ER formulations of oxybutynin and tolterodine for patients enrolled in a regional managed care plan., Methods: Study patients were adults (aged e 18 years), with at least 1 pharmacy claim for either tolterodine extended-release (tol-ER), oxybutynin extended-release (oxy-ER), tolterodine immediate-release (tol-IR), or oxybutynin immediate-release (oxy-IR) during the period from July 1, 1999, to December 31, 2003, and were continuously eligible for benefits from 6 months before through 12 months after the initial OAB pharmacy claim (index) date. A retrospective cohort study design was used following patients from the index date to the occurrence of non-persistence with the index medication (i.e., a gap of > 45 days between successive prescription fills or a switch to any other OAB medication), or the end of a 1-year follow-up period, through December 31, 2004. Switching was defined as any change from the index medication, including a change in dose form (e.g., tol-IR to tol-ER), to one of the other 3 study drugs, or to a different OAB treatment (e.g., trospium chloride, oxybutynin patch, flavoxate, hyoscyamine sulfate, or propantheline bromide) during the follow-up period. Adherence was measured as the proportion of patients with a medication possession ratio (MPR) of at least 80%. MPR was calculated as (1) the sum of days supply for all pharmacy claims except the last pharmacy claim, divided by (2) the total number of days from the first fill date to the fill date of the last pharmacy claim. The association of drug therapy with study outcomes was assessed with bivariate and adjusted (multivariate) analyses. Multivariate analyses controlled for demographic and clinical characteristics, plan type, patient out-of-pocket cost for the index medication, and year of therapy initiation., Results: 1,117 patients had at least 1 pharmacy claim for an OAB study drug (n = 454 for tol-ER [40.6%], n = 249 for oxy-ER [22.3%], n = 306 for tol-IR [27.4%], n = 108 for oxy-IR [9.7%]), of whom 81.6% were women. The mean (standard deviation [SD]) age of the study population was 55.7 (14.5) years. Only 53.7% had at least 1 OAB diagnosis recorded during the 18-month eligibility period. 44.5% of patients did not have a refill after the initial (index) pharmacy claim (39.4% for oxy-ER, 42.7% for tol-ER, 46.1% for tol-IR, and 59.3% for oxy-IR; P = 0.004). Only 13.2% persisted with treatment for at least 1 year (tol-ER = 15.0%, oxy-ER = 15.3%, tol-IR = 11.4%, oxy-IR = 6.5%; P = 0.050). The median days to discontinuation (non-persistency) were 31.0 overall, 33.0 for tol-ER, 34.0 for oxy-ER, 32.0 for tol-IR, and 0 for oxy-IR; P = 0.010. The overall switch rate as a percentage of all study patients was 13.3%, ranging from 9.9% for tol-ER, 13.7% for tol-IR, 16.5% for oxy-ER, and 19.4% for oxy-IR; P = 0.020. Of patients who refilled their initial prescription at least once, 24.0% made a medication switch. Adherence rates as measured by percentage of patients with MPR >or= 80% were 30.3% overall and higher for the ER formulations: 35.2% for tol-ER, 36.1% for oxy-ER, 23.5% for tol-IR, and 14.8% for oxy-IR; P < 0.001., Conclusions: Adherence was significantly better for ER than IR agents. The high rate of non-persistence (44.5%) following the first (index) prescription highlights the need for medication counseling by health care professionals.

Objective: To evaluate the effects of individual and condition characteristics on satisfaction with extended release tolterodine or oxybutynin in overactive bladder (OAB)., Methods: Data were from the 2005 National Health and Wellness Survey, an annual, nationally representative, self-administered, internet-based survey of 40,000+ US adults (age 18+). Inclusion criteria for analysis were diagnosed OAB and using extended release tolterodine or oxybutynin but no other prescription medications for OAB. Satisfaction with extended release tolterodine or oxybutynin was rated on a five-point scale from 1 = not at all satisfied to 5 = extremely satisfied. Linear regression was used to evaluate independent effects demographics, patient perception of OAB, duration of use, requesting of medication, type of prescribing physician, medication compliance, and mental and physical health-related quality of life (Medical Outcomes Study, Eight-item Short-Form Health Survey; SF-8) on treatment satisfaction., Results: There were 345 patients who met the inclusion criteria. Apparent predictors of medication satisfaction, in order of magnitude of effect, were: feelings that OAB is just an inconvenience (standardized beta = -0.28; p < 0.001); less impact of OAB on daily life (standardized beta = 0.24; p < 0.001); longer duration of use (standardized beta = 0.10; p = 0.052); overwhelming urges to urinate (standardized beta = 0.10; p = 0.061); younger age (standardized beta = -0.10; p = 0.054); and more frequent medication use (standardized beta = 0.09; p = 0.096)., Limitations: Data were cross-sectional and self-reported by patients via the internet., Conclusions: Patient treatment satisfaction is affected by perceptions of OAB symptoms and impact, as well as consistent, long-term use of prescription treatments. Clinicians should reinforce to patients the importance of long-term compliance for successful treatment.

Objective: Interstitial cystitis is a condition with a poorly understood etiology and, consequently, various treatment options have been described in the literature, with a less than optimal outcome. The aim of this study was to examine the role of a combination of intravesical hydrocortisone and heparin, together with oral bladder sedatives and systemic triamcinolone, for the treatment of interstitial cystitis., Material and Methods: A total of 26 patients who were diagnosed as having interstitial cystitis were treated with weekly intravesical hydrocortisone (200 mg) and heparin (25,000 IU) in physiological saline for 6 weeks. In addition, they were given oral bladder sedatives such as oxybutynin or tolterodine. Ulcerative, refractory and recurrent cases were treated with intramuscular triamcinolone (40 mg) weekly for 6 weeks., Results: All patients experienced an improvement in symptoms within 48 h of their first intravesical instillation. While 19 patients (73%) experienced almost complete pain relief, five of the remaining seven patients improved with intramuscular triamcinolone. Frequency reduced from a mean of 23.2 to 10.9 voids per day and was acceptable in 21 patients (80%). Six patients (23%) had a relapse of symptoms in the form of pain and were treated satisfactorily by means of intramuscular triamcinolone. The mean duration of follow-up was 18.3 months., Conclusion: A combination of intravesical hydrocortisone and heparin, along with oral bladder sedatives and systemic steroids, has been used with encouraging results in a small group of patients with interstitial cystitis.

Early studies of extended-release oxybutynin in patients with overactive bladder used adjusted-dose regimens ranging from 5 to 30 mg/day to achieve an optimal balance of efficacy and tolerability. The safety and tolerability of extended-release oxybutynin at a fixed dose of 10 mg once daily (commonly prescribed in clinical practice) is reported using pooled data from 2 multicenter, randomized, double-blind, parallel-group trials with a similar study design. One study compared extended-release oxybutynin with immediate-release tolterodine 2 mg bid. The other study compared extended-release oxybutynin with extended-release tolterodine 4 mg qd. In total, 576 patients received extended-release oxybutynin, 399 received extended-release tolterodine, and 193 received immediate-release tolterodine. The incidence of adverse events (AEs) was similar in the three treatment groups (extended-release oxybutynin, 70%; extended-release tolterodine, 64%; and immediate-release tolterodine, 79%). The most common adverse event was dry mouth (extended-release oxybutynin, 29%; extended-release tolterodine, 22%; and immediate-release tolterodine, 33%). Other AEs occurring in more than 5% of patients in any treatment group included constipation, diarrhea, headache, urinary tract infection, pain, dyspepsia, and peripheral edema, with no apparent difference across treatment groups. Most AEs (>90%) were mild or moderate in intensity in all treatment groups. The proportion of patients who discontinued study medication due to AEs was 6.1, 4.8, and 7.8% in the extended-release oxybutynin, extended-release tolterodine, and immediate-release tolterodine groups, respectively. In total, 1.2, 1.0, and 1.6% of patients in the extended-release oxybutynin, extended-release tolterodine, and immediate-release tolterodine groups, respectively, discontinued study medication due to dry mouth.

This study assessed the effect of the proton pump inhibitor omeprazole on the bioavailability of the extended-release formulations of oxybutynin and tolterodine. Forty-four healthy volunteers received each of 4 treatments in a 4-period crossover design. The treatments consisted of osmotically controlled extended-release oxybutynin chloride tablets at 10 mg/d or extended-release tolterodine tartrate capsules at 4 mg/d, with and without preceding treatment with 20 mg omeprazole daily for 4 days. Blood samples collected predose and at scheduled time points for 36 hours postdose were analyzed for oxybutynin and its active metabolite, N-desethyloxybutynin, or tolterodine and its active 5-hydroxymethyl metabolite, as appropriate. The AUCinfinity ratios for oxybutynin and its metabolite with and without prior omeprazole fell within the 80% to 125% range (accepted as the criterion for bioequivalence), as did those for tolterodine and its active moiety. The peak concentration ratios for oxybutynin and metabolite also conformed to this range; those for tolterodine did not. Increasing gastric pH with omeprazole does not substantially alter the pharmacokinetic properties of extended-release oxybutynin but may alter those of extended-release tolterodine.

Objective: To examine levels of persistence and compliance as well as the economic impact of extended-release tolterodine (tolterodine ER) versus immediate- and extended-release oxybutynin (oxybutynin IR or oxybutynin ER) among commercially-insured patients with overactive bladder (OAB)., Methods: Patients with OAB who initiated tolterodine ER, oxybutynin IR, or oxybutynin ER between January 2001 and December 2002 were identified from the PharMetrics Patient-Centric database; the first medication used in this timeframe was used for treatment group assignment (ie, patients were only in 1 group). Exploratory assessment of persistency and compliance was conducted among all treated patients: subjects were matched 1:1 based on the estimated propensity score for tolterodine ER in remaining analyses. Measures included patient characteristics as well as levels of medication, outpatient and inpatient resource utilization, and costs. Primary comparisons were made descriptively; costs were evaluated using generalized linear models with a gamma distribution and log-link function., Results: Compliance did not differ between tolterodine ER (77.4%) and oxybutynin ER (74.3%), but was lower for oxybutynin IR (60.9%). Mean (+/- standard deviation) duration of therapy was higher for tolterodine ER (139 +/- 132 days) versus oxybutynin ER (115 +/- 122) and oxybutynin IR (60 +/- 85). Totals of 7257 and 5936 matched pairs were available for tolterodine ER versus oxybutynin ER and oxybutynin IR comparisons, respectively. The mean age was 54 years in all groups; the majority was women. Utilization of outpatient and inpatient medical services was consistently lower among tolterodine ER patients in both comparisons. Total costs were slightly lower for tolterodine ER versus oxybutynin ER (dollar 8303 +/- dollar 18 802 vs dollar 8862 +/- dollar 18 684) and oxybutynin IR (dollar 9975 +/- dollar 24860 vs dollar 10521 +/- dollar 22 602); differences were significant after multivariate adjustment., Conclusions: Use of tolterodine ER results in comparable compliance to oxybutynin ER and longer duration of use relative to either form of oxybutynin. In addition, tolterodine ER may be cost-effective relative to oxybutynin IR or oxybutynin ER among commercially-insured persons with OAB.

Objective: The objective of this study was to compare 1-year total healthcare costs for patients with overactive bladder (OAB) initiating treatment with extended-release formulations of tolterodine and oxybutynin: tolterodine tartrate extended-release capsules (tolterodine ER) versus extended-release oxybutynin chloride (oxybutynin ER)., Methods: A model was developed from the payer perspective using data from the PharMetrics Patient-Centric database. Monthly discontinuation rates were derived from a cohort of newly treated patients with OAB (tolterodine ER, n = 15 394 or oxybutynin ER, n = 7934). All were assumed to be receiving therapy for at least 1 month. Medical management costs were based on reimbursement for all services for a matched cohort of patients taking tolterodine ER and oxybutynin ER. Medical management costs for those discontinuing therapy were based on patients receiving OAB care without pharmacotherapy (n = 29 992). Drug costs were from AnalySource (December 2004)., Results: After the 11-month follow-up period, 21% of patients taking tolterodine ER and 15% of patients taking oxybutynin ER remained on original therapy. One-year average total costs per patient for those started on tolterodine ER were dollar 8876 and dollar 9080 for oxybutynin ER, a difference of dollar 204 per year. Sensitivity analyses indicated results were robust to changes in drug cost and probability of discontinuation. When discontinuation rates were held equal, cost differences continued to favor tolterodine ER (21%, dollar 272/yr; 15%, dollar 233/yr)., Conclusion: Those taking tolterodine ER had lower monthly drug and medical management costs. This resulted in a total average annual cost savings of dollar 204 per patient for those started on tolterodine ER. At the end of 1 year, patients with OAB were more likely to remain on original drug treatment taking tolterodine ER versus oxybutynin ER.

Objective: This study was undertaken to compare the central nervous system (CNS) tolerability profiles of the extended-release formulations of oxybutynin chloride and tolterodine tartrate in the treatment of women with overactive bladder (OAB), as observed in the OPERA (Overactive bladder: Performance of Extended Release Agents) trial., Study Design: The OPERA trial was a randomized, double-blind, active-control comparison of the efficacy and safety of extended-release oxybutynin (10 mg/d) and extended-release tolterodine (4 mg/d) given to 790 women with OAB for 12 weeks. The incidence of reported CNS events was compared between the treatment groups by using the Fisher exact test., Results: The incidence of CNS adverse events was 9% and 8% for the oxybutynin and tolterodine treatment groups, respectively. The difference between groups was not statistically significant. All reported CNS adverse events were rated as mild or moderate in severity. There were no serious treatment-related adverse events in either group, and discontinuation because of a CNS adverse event was infrequent., Conclusion: The extended-release formulations of oxybutynin and tolterodine were observed to be associated with a similar low incidence of CNS adverse events, which were mostly mild or moderate in severity.

Women with urge or mixed incontinence were randomized to a daily dose of 10 mg extended-release oxybutynin chloride (qd) or tolterodine tartrate 4 mg (2 mg bid) for 12 weeks. Subjects completed 7-day voiding diaries at baseline and at 12 weeks. A total of 315 women were treated. At the end of the study, extended-release oxybutynin chloride was more effective than twice-daily tolterodine tartrate as measured by urge and total incontinence episodes (p=0.038, p=0.030, respectively). Overall, the reduction in micturition frequency between groups was not significantly different. In women aged 64 years and younger (comprising 63% of the population) extended-release oxybutynin was more effective than tolterodine for urge (p=0.005) and total incontinence (p=0.005), and for micturition frequency (0.024). Adverse events were infrequent, mostly mild, and similar between treatment groups. We concluded that daily extended-release oxybutynin chloride (10 mg) was more effective than tolterodine tartrate (2 mg bid) in treating urge and total incontinence. The incidences of dry mouth, CNS events, and other adverse events were similar for both drugs.

Background: Overactive bladder (OAB) is a condition characterized by urgency, increased frequency of micturition, or urge incontinence. It affects a considerable segment of the population, particularly with increasing age. Pharmacotherapy is one of the most common approaches to the treatment of OAB., Objective: This article describes the development and results of a model comparing health-economic outcomes for the new extended-release (XL) formulation of oxybutynin and immediate-release (IR) tolterodine in a population of community-dwelling Canadian adults with OAB., Methods: A Markov model was developed to compare health-economic outcomes over the course of 1 year. Effectiveness and treatment-persistence data were derived from the OBJECT (Overactive Bladder: Judging Effective Control and Treatment) trial, a 3-month comparison of oxybutynin XL 10 mg and tolterodine IR 4 mg, and were used, together with data from the literature (identified through a MEDLINE search of articles published between 1990 and 2003), to project outcomes beyond the trial period. Severity-specific cost profiles for incontinence were developed. In the principal analyses, cost items were limited to drug therapy, physician visits, use of pads or other protection, and laundry costs. Costs are reported in 2002 Canadian dollars., Results: Costs after 1 year were estimated to be an average of $32 less per patient for oxybutynin XL compared with tolterodine IR, and 3.1 additional patients in every 100 who received oxybutynin XL were expected to attain complete continence compared with those who received tolterodine. During the course of 1 year, patients receiving oxybutynin XL were expected to have a mean 16.5 additional incontinence-free days compared with those receiving tolterodine IR. The results were sensitive to relative drug prices. In the other sensitivity analyses, however, oxybutyrin XL maintained its advantage over a wide range of inputs., Conclusion: The results of these analyses suggest that when priced equivalently, oxybutynin XL would reduce costs and provide better results than tolterodine IR over 1 year of treatment.

Background: In general, extended-release (ER) formulations are designed to prolong the duration of efficacy and reduce the adverse effects of a drug. These formulations often contain the entire daily dose in a single tablet. Therefore, failure of the ER mechanism not only diminishes the desired benefits, but may temporarily expose the patient to drug concentrations higher than those released from a conventional tablet. In this study we determined whether pH has an effect on drug release from the ER formulations of oxybutynin (OROS technology) and tolterodine (membrane coated beads) in vitro and in vivo., Study Design: In vitro studies were based on standardised dissolution experiments for each drug in media of different pH (artificial gastric fluid at pH 1.2, artificial intestinal fluid at pH 7.5, and water). In the two separate, identically designed in vivo studies, single doses of each drug were administered alone and with an antacid to male and female healthy volunteers aged 18-45 years. The randomised, crossover, open-label in vivo studies employed a validated assay to determine plasma concentrations of tolterodine and its metabolite 5-hydroxymethyl tolterodine (5-HM), or oxybutynin and its metabolite N-desethyloxybutynin., Results: The in vitro study showed similar slow and steady drug release from ER-oxybutynin in each pH medium, with 64-71% released after 12 hours. Drug release from ER-tolterodine was steady and slow in artificial gastric fluid, with 72.5% of drug released after 12 hours. However, drug release was much faster in artificial intestinal fluid and water, where 69.8% and 69.1%, respectively, of the drug was released within 4 hours. These in vitro results were consistent with the findings of the in vivo studies. In vivo, the pharmacokinetic profile (peak plasma concentration [C(max)] and area under the concentration-time curve) of ER-oxybutynin was similar after administration with or without antacid, whereas C(max) values of both tolterodine and 5-HM increased significantly when ER-tolterodine was administered with antacid (p < or = 0.017 vs ER-tolterodine alone)., Conclusions: Changes in pH affected the release of tolterodine from ER-tolterodine, while they had no effect on the release of oxybutynin from the proprietary ER technology used in ER-oxybutynin. The technology employed in ER formulations thus determines sensitivity of drug release to external factors.

Introduction: Oxybutynin and tolterodine are two drugs widely used for the management of overactive bladder and urge urinary incontinence. The once-daily, extended-release formulations benefit from being well tolerated and efficacious. However, their costs, compared with generic immediate-release (IR) oxybutynin, are significantly greater. This study compared the cost effectiveness of oxybutynin extended-release (Oxy-XL), tolterodine extended-release (Tol-ER), tolterodine immediate-release (Tol-IR) and oxybutynin immediate-release (Oxy-IR)., Study Design: A cost-effectiveness model., Methods: A systematic review that identified appropriate randomised clinical trials provided evidence on efficacy. Empirical models of drug effects (number of incontinent-free weeks) and persistence (proportion of patients still on therapy) were constructed in order to determine clinical effectiveness which was combined with cost data (direct medical costs to the UK NHS, year 2001 values) to calculate the drugs' cost-effectiveness from the perspective of the NHS. Univariate sensitivity analyses were conducted to test the robustness of the results., Patients: Hypothetical cohort of patients with urge incontinence associated with overactive bladder., Main Outcome Measures and Results: The incremental cost per incontinent-free week for Oxy-IR (versus no treatment) ranged from pound sterling 2.58 to pound sterling 16.59. Oxy-XL and Tol-ER were more effective than Oxy-IR but at additional costs per incontinent-free week. Tol-IR did not appear to be a cost-effective option as it was less effective and more costly than the extended-release formulations. Uncertainty surrounding the health and cost consequences of early discontinuation affected these results, although the model results were robust to parameter uncertainty., Conclusion: Oxy-IR, Oxy-XL and Tol-ER appear to be cost-effective options for the management of urge incontinence from the NHS perspective. A decision among the treatments depends on the acceptable cost per additional incontinent-free week.

Objective: To compare extended-release (ER) tolterodine and immediate-release (IR) oxybutynin with placebo in Japanese and Korean patients with an overactive bladder (OAB)., Patients and Methods: Men and women aged >or= 20 years with symptoms of urinary urgency, urinary frequency (>or= 8 micturitions/24 h), urge incontinence (>or= 5 episodes/week) and symptoms of OAB for >or= 6 months were randomized to double-blind treatment with tolterodine ER 4 mg once daily, oxybutynin IR 3 mg three times daily or placebo for 12 weeks. Efficacy assessments included changes from baseline in numbers of incontinence episodes per week, voids/24 h and mean volume voided/void. Patient perceptions of bladder condition, urgency and treatment benefit were also assessed., Results: In all, 608 patients were randomized to treatment with tolterodine (240), oxybutynin (246) or placebo (122). More patients prematurely withdrew on oxybutynin (23%) than with tolterodine (10.4%) or placebo (16.4%). After 12 weeks of treatment, the median number of incontinence episodes/week was reduced significantly more in the tolterodine (79%; P= 0.0027) and oxybutynin groups (76.5%; P= 0.0168) than on placebo (46.4%). There were also significantly greater improvements in the number of voids/24 h and volume voided/void with tolterodine and oxybutynin than with placebo. More patients in the tolterodine and oxybutynin than in the placebo groups reported improvements in perceived bladder condition, ability to hold urine and treatment benefit. Patients treated with oxybutynin reported more adverse events than those treated with tolterodine or placebo. Dry mouth was significantly more common with oxybutynin than with tolterodine (53.7% vs. 33.5%; P < 0.001), and occurred in 9.8% of placebo patients., Conclusion: Tolterodine ER has similar efficacy but is better tolerated than oxybutynin IR in Japanese and Korean patients with OAB.

Objectives: To compare the efficacy and safety of an oxybutynin transdermal delivery system (OXY-TDS) and oral, long-acting tolterodine (TOL-LA) with placebo in previously treated patients with urge or mixed urinary incontinence., Methods: After withdrawal of their current antimuscarinic therapy, 361 adult patients were randomized to 12 weeks of double-blind, double-dummy treatment with twice weekly OXY-TDS 3.9 mg/day, daily TOL-LA 4 mg, or placebo. Evaluations included change from baseline in patient urinary diary symptoms, incontinence-specific quality of life, and safety., Results: OXY-TDS 3.9 mg/day and TOL-LA 4 mg/day significantly reduced the number of daily incontinence episodes (median change -3 OXY-TDS and -3 TOL-LA versus -2 placebo; P <0.05), increased the average void volume (median change 24 and 29 mL versus 5.5 mL, P <0.01), and improved quality of life (incontinence impact questionnaire [IIQ] total score, P <0.05; Urogenital Distress Inventory Irritative Symptom subscale, P <0.05) compared with placebo. The most common adverse event for OXY-TDS was localized application site pruritus (14% versus 4% placebo) accompanied by a low incidence of systemic side effects (eg, dry mouth 4.1%). Anticholinergic adverse events occurred with greatest frequency during TOL-LA treatment (dry mouth 7.3% versus 1.7% placebo, P <0.05)., Conclusions: OXY-TDS and TOL-LA are effective and comparable treatments for patients with urge and mixed incontinence. OXY-TDS improves systemic safety with regard to anticholinergic side effects. Local skin irritation occurs in some OXY-TDS patients.

Objective: To compare the efficacy and tolerability of extended-release formulations of oxybutynin chloride and tolterodine tartrate in women with overactive bladder., Patients and Methods: The OPERA (Overactive bladder: Performance of Extended Release Agents) trial was a randomized, double-blind, active-control study performed at 71 US study centers from November 21, 2000, to October 18,2001. Extended-release formulations of oxybutynin at 10 mg/d or tolterodine at 4 mg/d were given for 12 weeks to women with 21 to 60 urge urinary incontinence (UUI) episodes per week and an average of 10 or more voids per 24 hours. Episodes of UUI (primary end point), total (urge and nonurge) incontinence, and micturition were recorded in 24-hour urinary diaries at baseline and at weeks 2, 4, 8, and 12 and compared. Adverse events were also evaluated., Results: Improvements in weekly UUI episodes were similar for the 790 women who received extended-release formulations of oxybutynin (n = 391) or tolterodine (n = 399). Oxybutynin was significantly more effective than tolterodine in reducing micturition frequency (P = .003), and 23.0% of women taking oxybutynin reported no episodes of urinary incontinence compared with 16.8% of women taking tolterodine (P = .03). Dry mouth, usually mild, was more common with oxybutynin (P = .02). Adverse events were generally mild and occurred at low rates, with both groups having similar discontinuation of treatment due to adverse events., Conclusions: Reductions in weekly UUI and total incontinence episodes were similar with extended-release formulations of oxybutynin and tolterodine. In the oxybutynin group, micturition frequency was significantly lower, and the percentage of women reporting no urinary incontinence episodes was significantly higher compared with the tolterodine group. Dry mouth was more common with oxybutynin, but tolerability was otherwise comparable, including adverse events involving the central nervous system.

Purpose: We compare the tolerability and efficacy of extended release oxybutynin chloride, and immediate release and long acting tolterodine tartrate in children with nonneurogenic diurnal urinary incontinence and symptoms of overactive bladder., Materials and Methods: Children with a history of diurnal urinary incontinence were arbitrarily assigned to extended release oxybutynin, immediate release tolterodine or long acting tolterodine. The dose was titrated until effective (onset of complete diurnal urinary continence), maximal recommended dosage was achieved or bothersome anticholinergic side effects developed. An independent observer recorded the dose used, anticholinergic side effects and efficacy of therapy (incidence of urinary frequency, urgency, posturing and urinary incontinence)., Results: The study included 86 girls and 46 boys. There were no statistically significant differences among the 3 treatment groups regarding the presence of peripheral or central nervous system anticholinergic side effects. Extended release oxybutynin and long acting tolterodine were significantly more effective at reducing daytime urinary incontinence than immediate release tolterodine (p <0.01 and 0 <0.05, respectively). Extended release oxybutynin was significantly more effective then long acting tolterodine for complete resolution of diurnal incontinence (p <0.05)., Conclusions: Extended release oxybutynin and long acting tolterodine are more effective than immediate release tolterodine in decreasing diurnal urinary incontinence. Extended release oxybutynin chloride is more effective than either immediate or long acting tolterodine for control of daytime urinary incontinence and urinary frequency.

In the United States alone, approximately 17 million men and women have symptoms of overactive bladder (OAB). For many years, oxybutynin was the drug of choice for treating OAB. Although it provided effective treatment, multiple daily doses were required, and adverse events, such as dry mouth and constipation, were decided drawbacks. Controlled drug delivery systems seen in commercially available OAB formulations alter the pharmacokinetics of antimuscarinic medications in ways that maintain efficacy and allow once-daily dosing and reduction of adverse events. In the future, OAB medications will not only incorporate new chemical entities, such as the S-enantiomer of oxybutynin, but will also use novel drug delivery technologies, including transdermal patches and bladder implants.

Two newer antimuscarinic anticholinergic drugs--tolterodine and extended-release oxybutynin--are approximately as effective in treating overactive bladder as immediate-release oxybutynin, but are more tolerable. I review clinical trial data on the newer agents.

Objective To compare the tolerability and clinical efficacy of tolterodine and oxybutynin in the treatment of Hong Kong Chinese women with an overactive bladder. Patients and methods A randomized controlled trial was conducted at two urogynaecology centres in Hong Kong. In all, 106 women with urodynamically confirmed detrusor instability were recruited. Baseline severity assessments included a visual analogue scale (VAS), urinary diary and urinary pad-test. The women were randomized to receive either oral tolterodine 2 mg or oxybutynin 5 mg twice daily for 10 weeks. Treatment responses were assessed at 4 and 10 weeks using the VAS and urinary diary. Treatment tolerability was assessed at baseline, 4 and 10 weeks using the Xerostomia Questionnaire. A urinary pad-test was repeated at 10 weeks. Results The perceived change from baseline VAS was better in the tolterodine than the oxybutynin group after 10 weeks of treatment (per-protocol analysis, P = 0.043). The two drugs were effective in reducing the symptoms of frequency (P < 0.001). Tolterodine was significantly better than oxybutynin in reducing urinary leakage (urinary pad-test; median change - 5.00 g vs 0 g, P = 0.019). Both drugs caused a significant worsening of dry mouth (overall dryness, P < 0.005; discomfort, P < 0.005; sleep, P = 0.021; speaking, P = 0.045; swallowing, P = 0.004; and liquid consumption, P = 0.017). Conclusions Both oxybutynin and tolterodine were effective in ameliorating the severity of the symptoms of detrusor instability. Tolterodine was better than oxybutynin in both subjective and objective outcome measures, but both drugs caused similar worsening of dry mouth that may limit the tolerability of these medications.

Background: This double-blind, multicenter study compared the efficacy and tolerability of tolterodine (Pharmacia, Los Angeles, USA) with that of oxybutynin (Alza, Palo Alto, USA) in Asian patients with overactive bladder., Methods: Two-hundred-and-twenty-eight adults with overactive bladder symptoms were randomized to receive tolterodine 2 mg twice daily (bid) (n = 112) or oxybutynin 5 mg bid (n = 116). After 8 weeks' treatment, changes in micturition diary variables, patients' perception of treatment benefit, and tolerability endpoints were determined., Results: The mean (+/- SD) number of micturitions/24 h decreased by 2.6 +/- 2.9 (-21%) with tolterodine and 1.8 +/- 4.2 (-15%) with oxybutynin (both P = 0.0001 vs baseline). The mean number of incontinence episodes/24 h decreased by 2.2 +/- 2.3 (-85%) in the tolterodine group and by 1.4 +/- 1.8 (-58%) in the oxybutynin group (both P = 0.0001 vs baseline). Patient perception of treatment benefit was over 70% in each treatment group. Adverse events were significantly lower in the tolterodine group compared with oxybutynin-treated patients (55% vs 82%; P = 0.001). Dry mouth was reported by significantly fewer patients on tolterodine, compared with oxybutynin (35% vs 63%; P = 0.001) and withdrawals due to adverse events were lower in the tolterodine group than with those treated with oxybutynin (10% vs 16%). There were no safety concerns., Conclusions: Tolterodine 2 mg bid is equally or more effective than oxybutynin 5 mg bid in the treatment of Asian patients with overactive bladder, and shows significantly better tolerability. This may enhance compliance during long-term treatment.

Objective: To compare the efficacy and tolerability of extended-release oxybutynin chloride and tolterodine tartrate at 12 weeks in participants with overactive bladder., Subjects and Methods: The OBJECT (Overactive Bladder: Judging Effective Control and Treatment) study was a prospective, randomized, double-blind, parallel-group study conducted between March and October 2000 at 37 US study sites. Participants who had between 7 and 50 episodes of urge incontinence per week and 10 or more voids in 24 hours received extended-release oxybutynin, 10 mg/d, or tolterodine, 2 mg twice daily. The outcome measures were the number of episodes of urge incontinence, total incontinence, and micturition frequency at 12 weeks adjusted for baseline., Results: A total of 315 women and 63 men were randomized and treated, and 332 participants (276 women, 56 men) completed the study. At the end of the study, extended-release oxybutynin was significantly more effective than tolterodine in each of the main outcome measures: weekly urge incontinence (P=.03), total incontinence (P=.02), and micturition frequency episodes (P=.02) adjusted for baseline. Both drugs improved symptoms of overactive bladder significantly from baseline to the end of the study as assessed by the 3 main outcome measures (P<.001). Dry mouth, the most common adverse event, was reported by 28.1% and 33.2% of participants taking extended-release oxybutynin and tolterodine, respectively (P=.32). Rates of central nervous system and other adverse events were low and similar in both groups., Conclusions: Extended-release oxybutynin was more effective than tolterodine as measured by end-of-study urge incontinence, total incontinence, and micturition frequency episodes. Both groups had similar rates of dry mouth and other adverse events.

The objective of this study is to evaluate the cost effectiveness of two new treatments for overactive bladder: once-daily controlled-release oxybutynin, and twice-daily tolterodine, with a comparison with oxybutynin immediate release. Also estimated are the potential cost savings to a health plan budget resulting from increased utilization of the most cost-effective treatment. The design is a decision-tree model based on clinical trial data and expert panel estimates with a six-month time horizon conducted from a payer perspective. The primary outcome measure used in the analysis was treatment success, with success defined as zero incontinence episodes per week. A secondary outcome measure was the expected number of continent days. As first-line therapy, controlled-release oxybutynin is the most cost-effective treatment as measured by expected cost per success and expected cost per continent days. Controlled-release, once-daily oxybutynin yielded the highest expected success rate and the highest number of expected continent days. The expected cost of treatment with controlled-release oxybutynin was lower than tolterodine and equivalent to immediate-release oxybutynin. Increased utilization of controlled-release oxybutynin results in an estimated saving of $0.007 to $0.026 per member per month for a hypothetical HMO. The model was robust, incorporating all assumptions based on univariate and multivariate sensitivity analysis. Initiating treatment with controlled-release oxybutynin is the most cost-effective approach to treatment for overactive bladder.