Year : 2002 | Volume
: 19 | Issue : 1 | Page : 73--78
Efficacy and safety of tolterodine in subjects with symptoms of overactive bladder: An open label, noncomparative, prospective, multicentric study
Department of Urology and Renal Transplantation, SGPGIMS, Lucknow, India
Department of Urology and Renal Transplantation, SGPGIMS, Rai Bareilly Road, Lucknow - 226 014
Objective: To evaluate the clinical efficacy and safety of Tolterodine 2 mg twice daily in Indian subjects with symptoms of overactive bladder including frequency, urgency with or without urge incontinence.
Methods: This multicentric open-label, noncomparative, prospective study was conducted at 7 centers across India. Eligible patients were assigned to treatment with Tab. Tolterodine 2 mg twice daily for 8 weeks. Subjects were seen at visit ](day 3 to 10), visit 2 (day 1) and after 8 weeks of treatment. Micturition charts were completed prior to visit 2 and visit 3. Efficacy variables included change, from baseline to 8 weeks of treatment in the mean number of micturitions, incontinence episodes/24 hours, mean volume voided per micturition and subjects«SQ» perception of treatment benefit. Efficacy was evaluated from patients«SQ» micturition diaries. Patients were also assessed for adverse events during the treatment.
Results: A total of 127 subjects with symptoms of overactive bladder were enrolled. 8 weeks«SQ» treatment with Tolterodine resulted in improvement in assessment of all symptoms of overactive bladder Significant decreases from baseline in both the frequency of micturition (mean ± SD of -2.5 ± 5.0 per 24 hours, p=0.0001) and the number of incontinence episodes per 24 hours (-1.5±3.8, p=0.0051) and a significant increase in mean volume voided per micturition (+26±55 ml, p=0.0001) were obtained. Treatment was well tolerated and most subjects (71.4%) did not experience any adverse events during the study. The most common adverse event was dry mouth (10.3%). 5 subjects were withdrawn due to adverse events and all the subjects recovered uneventfully.
Conclusions: Treatment with Tolterodine 2 mg twice daily was effective and safe in Indian subjects with the symptoms of overactive bladder as assessed by both objective and subjective criteria.
|How to cite this article:|
Kumar A. Efficacy and safety of tolterodine in subjects with symptoms of overactive bladder: An open label, noncomparative, prospective, multicentric study.Indian J Urol 2002;19:73-78
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Kumar A. Efficacy and safety of tolterodine in subjects with symptoms of overactive bladder: An open label, noncomparative, prospective, multicentric study. Indian J Urol [serial online] 2002 [cited 2021 Apr 20 ];19:73-78
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Overactive bladder is characterized by symptoms of frequency, urgency and urge incontinence and is thought to affect at least 10% of the population.  The actual figure may be higher because the condition remains underreported as a result of the embarrassment felt by the sufferers. Overactive bladder results from involuntary detrusor contractions during the filling phase. It is generally agreed that the contractions of the human detrusor is mediated by the cholinergic muscarinic receptors and therefore muscarinic receptor antagonists have been used for many years in the management of the overactive bladder. 
Oxybutynin has been shown to be effective in the treatment of overactive bladder but its usefulness is limited by classic antimuscarinic side effects.  At least 50% of the patients treated with Oxybutynin experience dry mouth, which is often severe enough to result in discontinuation of treatment. , Thus there is a need for new, effective antimuscarinic agent with less pronounced antimuscarinic side effects, particularly dry mouth.
Tolterodine is a new potent muscarinic receptor antagonist that was specifically developed for the treatment of frequency, urgency and urge incontinence associated with overactive bladder.  Tolterodine binds with high affinity and specificity to muscarinic receptors; it has negligible affinity for other potential targets. Pharmacological in vivo studies have shown that Tolterodine has greater selectivity for the urinary bladder than for the salivary glands. , In vitro studies have shown that Tolterodine has a high affinity and specificity for muscarinic receptors being equipotent to Oxybutynin at the muscarinic receptors at the bladder, but having 8 times less affinity than Oxybutynin for the muscarinic receptors in the salivary gland. ,,
Tolterodine is rapidly absorbed from the gastrointestinal tract after oral administration, with peak concentrations achieved within I to 2 hours. In most subjects it is metabolized by hepatic cytochrome P450 isoenzymes (CYP2D6), resulting in formation of a major pharmacologically active metabolite. The antimuscarinic properties of the metabolite are similar to those of Tolterodine including its in vivo selectivity for the urinary bladder. , Tolterodine has a half-life of 2 to 3 hours, with approximately 77% excreted in urine and 17% in feces. 
Several studies have established that Tolterodine 2 mg twice a day is the optimal dose and is equally effective as oxybutynin. However Tolterodine was superior to Oxybutynin with respect to incidence of and severity of dry mouth. In those studies that were followed by open longterm treatment, 70% of the subjects continued treatment for 12 months.
This trial was designed to investigate the efficacy and safety profile of Tolterodine 2 mg twice a day in Indian subjects with symptoms of overactive bladder.
Material and Methods
This was an open label, noncomparative, prospective, multicentric national trial conducted at 7 centers in India between December 1999 and October 2000. The study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines and local ethics committee of each participating center approved the study protocol.
Male or female subjects aged at least 18 years and having symptoms of overactive bladder for at least 6 months; urinary frequency ( > 8 micturitions per 24 hours), urinary urgency with or without urge incontinence, and mean urinary volume per micturition Exclusion criteria:
Subjects were excluded from the study if they had significant stress incontinence, hepatic or renal disease (> twice the reference range of serum bilirubin, AST and ALT), symptomatic urinary tract infection, recurrent UTIs, interstitial cystitis, haematuria, clinically significant bladder outlet obstruction, any contraindication to anticholinergic therapy, received any treatment for overactive bladder within 14 days preceding visit 2, indwelling catheter or history of intermittent self-catheterization, pregnant or nursing women and women of childbearing potential who had not employed adequate contraception during 3 months immediately prior to trial or within one month of trial discontinuation.
Subjects were initially enrolled in to a 10 day washout/ run-in period (7 day washout followed by 3 day run-in) and, if eligible, were then assigned to treatment with Tab. Tolterodine 2 mg twice daily for 8 weeks. The 7-day washout period could be omitted if subjects had not received therapy for overactive bladder in the 7 days prior to study entry. Subjects were seen at visit 1 (Day 3 or 10), visit 2 (Day 1), and after 8 weeks of treatment (visit 3).
At visit 1 demographic data, relevant disease history, previous treatment for overactive bladder, concurrent disease, symptoms and concomitant medications were recorded. Informed signed consent was obtained. A blood sample was taken from all the subjects for measurement of routine laboratory safety variables. In female subjects, a urine sample was obtained for pregnancy testing. Micturition charts were dispensed. At visit 2, completed micturition charts were collected and subject eligibility was determined. Eligible subjects were supplied with Tolterodine 2 mg tablets and instructed to complete a micturition chart during the 3 days prior to visit when micturition chart was collected and assessments included concomitant medications, clinical biochemistry and hematology tests, subject's perception of treatment benefit, and adverse event reporting. Efficacy was evaluated at visit 3 or withdrawal by means of micturition chart data completed by the subject and the subject's perception of treatment benefit as assessed by questioning.
Primary efficacy variable was urinary frequency assessed as the mean number of micturitions per 24 hours over the 3-day period on the micturition charts. The primary efficacy endpoint was the change from baseline to week 8. Secondary efficacy endpoints were change in the mean number of incontinence episodes; urinary volume voided and subjects perception of treatment benefits assessed on the binominal scale (yes/no) at visit 3 or withdrawal. The benefit if any was evaluated as "little benefit" or much "benefit".
The common and drug class-related adverse events were followed for at least 2 weeks after completion of the study. All serious adverse events were followed until they resolved or were assessed by the investigator as "chronic" or "stable".
The study was planned to include 125 subjects, which would be sufficient to achieve adequate power (>80%) to detect a mean decrease from baseline of 2 micturitions per 24 hours after 8 weeks of treatment.
All statistical tests were two-sided with a level of significance of 0.05. Primary and secondary efficacy endpoints were analyzed using the Student's one sample t-statistics. The subject's perception of treatment was analyzed as the proportion of subjects in the different answer categories. Changes over time in clinical and laboratory safety variables were analyzed using the Student's one sample t-test.
A total of 127 subjects were enrolled in the study, 126 had screening and baseline assessments and 100(79%) subjects completed the study. Of the 127 subjects enrolled in the study who were included in intent to treat (ITT) population, 1 subject withdrew consent before taking any study medication and was excluded from the safety population (n=126). In addition, there were 26 subjects who were withdrawn and 28 subjects with at least one major protocol violation. Therefore, the per-protocol (PP) population consisted of 72 subjects. The mean age of enrolled subjects were 46.4 years (range 19 to 88 years), and male:female ratio was 68(54%): 59(46%). The mean body mass index was 24.0 kg/m 2 [Table 1]. At screening all subjects reported symptoms of frequency and urgency, as required by the entry criterion.
A total of 66(52%) subjects had history of incontinence, either urge or mixed in nature, 98% of subjects had documented micturition frequency of 7.8 per 24 hours, and 44% had episodes of incontinence and 96% of subjects had baseline mean void volume of 220 ml.
34% of the subjects had previously received therapy for overactive bladder. Most of these subjects (29 of 43) had used oxybutynin, and only 5 subjects had reported both good efficacy and no or acceptable side effects. I subject had previously taken Tolterodine.
Of the 100 subjects with follow-up data, mean (± standard deviation) exposure to Tab. Tolterodine 2 mg twice daily was 60.8 days (range 53 to 97 days). Overall 82% subjects were compliant to Tolterodine.
A total of 40(31.5%) subjects received concomitant medications during the study. The most common concomitant medications were Amlodepine (6.3% of subjects), Atenolol (5.5%). Nifedipine (3.9%), Doxazosin and Paracetamol (each reported for 3.1% of subjects).
1. Change in number of micturitions per 24 hour
The primary efficacy endpoint was the change from baseline in mean number of micturitions per 24 hours as assessed by micturition chart recording over 3-day periods. The mean number of micturitions per 24 hours decreased by 2.5 ± 5.0 micturitions per 24 hours (p=0.0001) [Table 2].
2. Number of incontinence episodes per 24 hours
Among the 54 subjects who reported incontinence episodes at baseline, decrease in the number of incontinence episodes was 1.5±3.8 (mean ± SD) incontinence episodes per 24 hours from baseline to week 8 (p=0.0051) [Table 2].
Mean volume voided per micturition:
Increase in the urinary volume voided from baseline to week 8 was 26 ±55 (mean±SD) ml (p=0.0001) [Table 2].
Subjects' perception of the treatment benefit:
At the end of treatment, 70% of subjects reported at least some treatment benefit with Tolterodine, and nearly 50% of subjects reported much benefit.
A total of 36(28.6%) subjects reported atleast one adverse event (AE). Greater than 70% of subjects did not report any AE [Table 3]. The most commonly affected body systems were the autonomic nervous system and the central and peripheral nervous system, with 11.1% and 7.1% of subjects reporting AEs in these systems, respectively.
A total of 24(50%) of the 48 treatment-emergent AEs were considered study-drug related, of which almost half 13(10.3%) were dry mouth and urinary retention in 3(2.4%).
Fever was experienced by 5(4%) subjects. All the subjects recovered on discontinuation of the study drug without any residual effect. Only 1 of the 5 cases of fever was considered related to the study drug. No subject experienced any serious AE during the study.
Discontinuation due to adverse events:
5 subjects were withdrawn from the study because of adverse events, reason for withdrawal includes 3 subjects because of urinary retention, 1 subject was withdrawn due to anxiety and paraesthesia and another due to hypokinesia and dry mouth. All of the AEs except anxiety and paraesthesia were judged related to study medication, and all of the subjects recovered.
Clinical laboratory evaluation:
Although a number of subjects had clinical laboratory values that were outside the reference range, no trends with regard to treatment could be discerned. Many subjects had abnormal values at both evaluations, and a number of subjects had shifts from normal to outside the reference range and vice versa. Shifts during the treatment that were considered by the investigator to be clinicallysignificant included 3 male subjects with asymptomatic increase in hepatic enzymes, 3 female subjects with red and/or white blood cells in the urine (likely secondary to urinary tract infection), and 1 female subject with low leucocyte count.
The symptoms of overactive bladder vary in intensity with time but rarely disappear completely. Early in the course, frequency of micturition and urgency predominate and leakage of urine may become a problem as the condition progresses. Muscarinic receptor antagonists, which decrease detrusor muscle activity and may result in increase in bladder capacity, are generally regarded as the mainstay of treatment for overactive bladder. A decrease in frequency of micturition and episodes of incontinence does not occur immediately, as modification of the voiding habits is a gradual process. Thus, even if not clinically apparent to the patient, the successful treatment of an overactive bladder can be confirmed by an increase in the volume voided per micturition, indicating that the bladder capacity has increased. This may lead to an improvement in the patient's frequency of micturition and ability to avoid incontinence. Muscarinic receptor antagonists however have high incidence of side effects, principally dry mouth. ,, which is a major disadvantage leading to poor patient compliance and discontinuation of treatment in a substantial proportion of subjects. The more commonly prescribed Oxybutynin is associated with dry mouth in at least half of the patients and may result in discontinuation of treatment in up to 25% of patients.  In an attempt to improve the tolerability of therapeutic alternatives, Tolterodine, an agent with less pronounced effect on the salivary gland has been developed. , Tolterodine has been shown to be effective and well-tolerated in studies conducted primarily in Caucasian subjects, with a significantly lower incidence of dry mouth than that observed with Oxybutynin.
This open-label, multicentric, non-comparative study was conducted to gain additional experience of the efficacy and safety of Tolterodine for the treatment of symptoms of overactive bladder in India. Unlike the expected disease profile, the majority of subjects in this population were male (54%) and relatively young (mean age 46.4 years). Many subjects (34%) had previously been treated for overactive bladder (in most cases with Oxybutynin), but few reported both good efficacy and none acceptable side effects.
Treatment with Tab. Tolterodine 2 mg twice daily for up to 8 weeks was effective in this subject population, as assessed by both objective (micturition chart variables) and subjective (subjects' assessment of treatment benefits) criteria. Treatment resulted in highly significant decreases in micturition frequency (p=0.0001) and number of incontinence episodes (p=0.0051) and a significant increase in the urinary volume voided per micturition (p=0.0001). Moreover, the majority of subjects (70%) reported at least some treatment benefit; and 46% of subjects reported much treatment benefit.
In addition to being efficacious, Tolterodine was well tolerated. The overall incidence of AEs was 28.6%, with dry mouth (10.3%) the only frequent event. Other AEs typically associated with antimuscarinic agents were infrequent in this study population. ,, Moreover, there were only 3 cases of urinary retention, and all recovered upon discontinuation of treatment. There were numerous shifts in hematology and clinical biochemistry values both into and out of the normal reference range that may be representative of the study population. This and the different demographics than in other populations studied may account for the 3 clinically significant elevations in hepatic enzyme levels and the 5 incidences of fever. These adverse experiences have not been associated with Tolterodine treatment in the extensive clinical experience of this drug to date.
In conclusion, the results of this study are consistent with the excellent efficacy and good tolerability profile of Tolterodine observed in Caucasian subjects. Treatment with Tab. Tolterodine 2 mg twice daily for up to 8 weeks was effective in Indian subjects, as assessed by both objective (micturition chart variables) and subjective criteria, and was well tolerated.
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