Extended-release formulations of oxybutynin and tolterodine exhibit similar central nervous system tolerability profiles: A subanalysis of data from the OPERA trial

doi:10.1016/j.ajog.2005.03.036

American Journal of Obstetrics and Gynecology

Volume 192, Issue 6, June 2005, Pages 1849-1854

https://doi.org/10.1016/j.ajog.2005.03.036 Get rights and content

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.

Section snippets

Design and methods

The original study was a double-blind, randomized comparison of the efficacy and safety of extended-release oxybutynin (10 mg/d) with extended-release tolterodine (4 mg/d) in 790 women with OAB. The study design and methods have been described elsewhere.¹⁷

Participants were asked during scheduled visits after 2, 4, 8, and 12 weeks of treatment if they had experienced adverse events. The protocol stipulated that adverse events occurring before a participant started taking the study drug or more

Incidence of CNS adverse events

More than 90% of the 790 participants in this trial did not report any CNS adverse event during the 12-week treatment period or 3-day period immediately after the final dose of study drug. The 5 CNS adverse events that occurred in more than 1% of either treatment group were dizziness, somnolence, insomnia, depression, and hypertonia (Table I). The overall incidence of CNS adverse events was 9% for the extended-release oxybutynin treatment group and 8% for the extended-release tolterodine

Comment

In this direct comparison of extended-release oxybutynin and extended-release tolterodine, neither agent elicited clinically problematic CNS adverse events. The incidence of CNS adverse events was reported at rates between 1.2% and 4.3% for extended-release oxybutynin and between 1.1% and 5.2% for extended-release tolterodine over the entire treatment period; none of the observed differences between the drugs was statistically significant. When CNS adverse events did occur, they were usually

Conclusions

In the current analysis of CNS adverse event data from the OPERA trial, extended-release oxybutynin and extended-release tolterodine had low and similar incidences of CNS adverse events. Neither drug elicited clinically problematic CNS adverse events. The percentage of participants who discontinued the trial because of CNS adverse events was low for both drugs. None of the observed differences between the drugs was statistically significant. Significant differences in the CNS tolerability

References (25)

M.-A. Harvey et al.
Tolterodine versus oxybutynin in the treatment of urge urinary incontinence: a meta-analysis
Am J Obstet Gynecol
(2001)
J. Malone-Lee et al.
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)
M.M. Goldenberg
An extended-release formulation of oxybutynin chloride for the treatment of overactive urinary bladder
Clin Ther
(1999)
E. Versi et al.
Dry mouth with conventional and controlled-release oxybutynin in urinary incontinence. The Ditropan XL Study Group
Obstet Gynecol
(2000)
M.B. Chancellor et al.
A comparison of the effects on saliva output of oxybutynin chloride and tolterodine tartrate
Clin Ther
(2001)
R.A. Appell et al.
Prospective randomized controlled trial of extended-release oxybutynin chloride and tolterodine tartrate in the treatment of overactive bladder: results of the OBJECT Study
Mayo Clin Proc
(2001)
Y. Reinberg et al.
Therapeutic efficacy of extended release oxybutynin chloride, and immediate release and long acting tolterodine tartrate in children with diurnal urinary incontinence
J Urol
(2003)
A.C. Diokno et al.
Prospective, randomized, double-blind study of the efficacy and tolerability of the extended-release formulations of oxybutynin and tolterodine for overactive bladder: results of the OPERA trial
Mayo Clin Proc
(2003)
J.H. Brown et al.
Muscarinic receptor agonists and antagonists
L. Nilvebrant
The mechanism of action of tolterodine
Rev Contemp Pharmacother
(2000)

P. Van Kerrebroeck et al.

Clinical efficacy and safety of tolterodine compared to oxybutynin in patients with overactive bladder

Neurourol Urodyn

(1997)

P. Abrams et al.

Tolterodine, a new antimuscarinic agent: as effective but better tolerated than oxybutynin in patients with an overactive bladder

Br J Urol

(1998)

Cited by (33)

Vibegron (RVT-901/MK-4618/KRP-114V) Administered Once Daily as Monotherapy or Concomitantly with Tolterodine in Patients with an Overactive Bladder: A Multicenter, Phase IIb, Randomized, Double-blind, Controlled Trial [Figure presented]
2019, European Urology
Citation Excerpt :
Antimuscarinics (eg, oxybutynin, tolterodine, solifenacin, imidafenacin, and fesoterodine), which block postjunctional muscarinic receptors in the detrusor muscle to inhibit muscle contractures, have been the only available OAB pharmacotherapy for decades. Antimuscarinics lack bladder selectivity, resulting in unwanted side effects such as dry mouth, constipation, and central nervous system (CNS) side effects [6–8]. This influences patient satisfaction with treatment, leading to discontinuation, switching, or both [6,9,10].
Antimuscarinics have shown modest efficacy with unwanted side effects in patients with overactive bladder (OAB). Efficacy of vibegron, a new β3-adrenergic receptor agonist, for OAB is unknown.
To evaluate the efficacy of once-daily oral vibegron in OAB patients (primary), and its safety, tolerability, and efficacy when administered alone or concomitantly with tolterodine (secondary).
International, phase IIb, randomized, double-blind, placebo- and active comparator–controlled, two-part superiority trial (2011–2013) in OAB-wet or OAB-dry patients aged 18–75 yr (NCT01314872).
Part 1: once-daily oral vibegron monotherapy (3 [V3], 15 [V15], 50 [V50], or 100 [V100] mg), tolterodine extended release 4 mg (TER4), or placebo for 8 wk, or combination V50/TER4 for 4 wk and then V50 for 4 wk; part 2: V100/TER4, V100, TER4, or placebo for 4 wk.
Average daily micturitions at week 8 of part 1 (primary); urge incontinence episodes, total incontinence episodes, and urgency episodes (secondary).
Overall, 1395 patients were randomized. From baseline to week 8, V50 and V100 significantly decreased average daily micturitions (least square mean difference [95% confidence interval], −0.64 [−1.11, −0.18]; p = 0.007 and −0.91 [−1.37, −0.44]; p < 0.001, respectively) and the number of urge incontinence episodes (−0.72 [−1.11, −0.33] and −0.71 [−1.10, −0.32], respectively; both p < 0.001) versus placebo. All vibegron doses were well tolerated. The incidence of dry mouth was higher with TER4 than with vibegron monotherapy. Results are limited by the relatively short treatment duration.
Once-daily V50 and V100 improved OAB symptoms; vibegron was well tolerated as monotherapy and concomitantly with tolterodine. Further development is warranted.
Antimuscarinics, commonly used to treat overactive bladder, produce modest efficacy and unwanted side effects. In this study, a different type of drug (vibegron) was efficacious and safe, alone or with an antimuscarinic (tolterodine).
Risk of serious falls associated with oxybutynin and tolterodine: A population based study
2011, Journal of Urology
We compared the short-term risk of falls among recipients of oxybutynin or tolterodine to treat urinary incontinence.
We conducted a population based, retrospective cohort study with propensity score matching among patients 66 years old or older who commenced treatment with oxybutynin or tolterodine in Ontario, Canada. The primary outcome was a hospital visit for a fall within 90 days of drug initiation. Secondary outcomes included hospital visits for fractures, delirium or all cause mortality.
We found no difference in the risk of falls among users of oxybutynin vs tolterodine (adjusted hazard ratio 1.04, 95% CI 0.95 to 1.14). Secondary analyses revealed no differential risk of fractures (aHR 0.96, 95% CI 0.82 to 1.13) or delirium (aHR 0.90, 95% CI 0.66 to 1.23) associated with oxybutynin. However, statistically significant increases in the risk of all cause hospitalization (aHR 1.12, 95% CI 1.07 to 1.17) and death (aHR 1.20, 95% CI 1.07 to 1.35) were seen with oxybutynin.
Oxybutynin was not associated with a short-term increased risk of hospital visit for falls, fractures or delirium compared to tolterodine. Further research is needed to confirm whether oxybutynin is associated with an increased risk of hospitalization or death.
Sacral Nerve Stimulation for Refractory Overactive Bladder in the Elderly Population
2009, Journal of Urology
Citation Excerpt :
Adding an antimuscarinic is reasonable and generally safe when behavioral therapy fails.10 However, concern persists regarding real or perceived cognitive side effects when anticholinergics are used in elderly patients.3 Moreover, a large proportion of elderly individuals are intolerant of this class of drugs due to systemic side effects in the context of preexisting maladies, such as constipation, glaucoma etc, as well as drug-drug interactions.11
We determined the long-term outcome of sacral nerve stimulation for refractory overactive bladder in the elderly population.
We performed a prospective longitudinal study to better characterize the outcome of sacral nerve stimulation in female patients 70 years old or older with refractory overactive bladder. Demographic and perioperative data were recorded. Patients were followed postoperatively for evidence of successful stage conversion, device durability and efficacy, and postoperative complications. Patients were retrospectively compared to a cohort of female patients younger than 70 years with refractory overactive bladder. Statistical analysis was performed.
Between July 2001 and February 2008, 19 elderly female patients with refractory overactive bladder underwent stage 1 lead placement. Of the patients 17 (90%) who reported greater than 50% improvement in symptoms based on a 1-week followup voiding log underwent implantable pulse generator placement. No intraoperative or immediate postoperative complications were noted. At a mean followup of 48.5 months 11 patients (65%) had a functional implantable pulse generator with greater than 50% objective improvement over baseline. Compared to matched patients younger than 70 years elderly patients had a similar conversion rate and adverse events but were significantly more likely to undergo device removal (p = 0.018).
Based on our experience elderly patients have a high conversion rate, few adverse events, and a high level of device efficacy and durability with sacral nerve stimulation. Although more mature multicenter data are needed, it appears that sacral nerve stimulation in geriatric patients is safe and efficacious, and should be judiciously offered to those with refractory voiding symptoms.
Short-Term Efficacy of Botulinum Toxin A for Refractory Overactive Bladder in the Elderly Population
2008, Journal of Urology
We determined the efficacy of intravesical botulinum toxin A injection for refractory overactive bladder in elderly patients.
Patients 75 years or older with refractory urinary urgency were prospectively evaluated and offered treatment of symptoms with botulinum toxin A. A voiding log was obtained and urodynamics were performed before treatment. Patients underwent injection of 200 U botulinum toxin A (Botox®) into the detrusor muscle at 20 sites under cystoscopic guidance. Patients were followed postoperatively for evidence and duration of success, and treatment related complications.
From January 2006 to June 2007, 18 females and 3 males with a mean age of 81.2 years (range 75 to 92) in whom detrusor overactivity was confirmed on urodynamics and who were refractory to or intolerant of antimuscarinics were treated with intravesical botulinum toxin A. Preoperatively the mean ± SD number of daily voids was 11.4 ± 1.67 and the mean number of pads per day was 4.0 ± 0.89. One month after treatment 16 of the 21 patients (76%) reported greater than 50% improvement in symptoms after 1 injection. Specifically there was a significant improvement in the mean number of voids per day (5.19 ± 0.83, p <0.001) and in the number of pads used daily (1.3 ± 0.60, p <0.001). Two of the remaining 5 patients demonstrated greater than 50% improvement following repeat injection, while 3 did not show improvement after 2 injections. Mean time to deterioration was 7.12 months. There were no treatment related complications.
Intravesical botulinum toxin A for detrusor overactivity in the elderly population appears to be efficacious and durable. Given its low incidence of adverse events, it should be considered a viable treatment option in this population.
13 Drugs that affect autonomic functions or the extrapyramidal system
2008, Side Effects of Drugs Annual
Citation Excerpt :
Antimuscarinic drugs that are used in management of bladder hyperactivity and incontinence are designed to have a very limited effect on the nervous system. However, there is no absolute guarantee of this, as has been shown by a subanalysis of data from the OPERA (Overactive Bladder: Performance of Extended Release Agents) study, in which modified-release tolterodine 4 mg/day and modified-release oxybutynin 10 mg/day over 12 weeks were compared in 790 women with overactive bladders (33C). The incidence of nervous system adverse effects was similar in the two groups (8 and 9%).
This chapter describes drugs that affect autonomic functions or the extrapyramidal system. The chapter includes a special review of a very intriguing adverse effect of the use of dopamine receptor agonists, the apparent link with pathological gambling. Dobutamine is very commonly used in stress echocardiography. One well-recognized complication is nonsustained ventricular tachycardia. The prognostic implications have been considered in 1,266 consecutive patients, of whom 65 (5.1%) had this dysrhythmia. After 3 years of follow-up, there was no significant difference in all-cause mortality between patients who had ventricular tachycardia and those who did not (22 versus 17%). Further analysis showed that patients who had (i) nonsustained ventricular tachycardia, (ii) no evidence of inducible ischemia, and (iii) a moderately reduced ejection fraction (0.35–0.45) had significantly reduced chances of survival. In this chapter, an overview of drugs that stimulate both alpha- and beta-adrenoceptors is given. Noradrenaline (norepinephrine), ephedra, ephedrine, and pseudoephedrine are discussed. Drugs that predominantly stimulate alpha₁-adrenoceptors are described. Studies on phenylephrine and phenylpropanolamine are also discussed in the chapter.
The Application of Evidence-Based Principles of Care in Older Persons (Issue 6): Urinary Incontinence
2007, Journal of the American Medical Directors Association

View all citing articles on Scopus

This study was supported by ALZA Corporation, Mountain View, Calif, and Ortho-McNeil Pharmaceutical, Raritan, NJ.

Presented at the 71st Annual Meeting of the Central Association of Obstetricians and Gynecologists, October 13-16, 2004, Washington, DC.

View full text

Transactions of the 71st Annual Meeting of the Central Association of Obstetricians and GynecologistsExtended-release formulations of oxybutynin and tolterodine exhibit similar central nervous system tolerability profiles: A subanalysis of data from the OPERA trial

Objective

Study design

Results

Conclusion

Section snippets

Design and methods

Incidence of CNS adverse events

Comment

Conclusions

Am J Obstet Gynecol

J Urol

Clin Ther

Obstet Gynecol

Clin Ther

Mayo Clin Proc

J Urol

Mayo Clin Proc

Muscarinic receptor agonists and antagonists

The mechanism of action of tolterodine

Rev Contemp Pharmacother

Clinical efficacy and safety of tolterodine compared to oxybutynin in patients with overactive bladder

Neurourol Urodyn

Tolterodine, a new antimuscarinic agent: as effective but better tolerated than oxybutynin in patients with an overactive bladder

Br J Urol

Transactions of the 71^st Annual Meeting of the Central Association of Obstetricians and Gynecologists
Extended-release formulations of oxybutynin and tolterodine exhibit similar central nervous system tolerability profiles: A subanalysis of data from the OPERA trial