Abstract
Immediate-release oxybutynin was the gold standard for pharmacologic treatment of overactive bladder for nearly 30 years. Intolerable systemic side effects, in particular dry mouth, limited its clinical utility, resulting in poor patient compliance with dosing regimens. Multiple studies have demonstrated the vastly superior tolerability of tolterodine, extended-release tolterodine, and extended-release oxybutynin over that of immediate-release oxybutynin at equivalent doses, and in the case of extended-release oxybutynin even to twice the dose of the original immediate-release form. With different drug delivery systems and, perhaps, with better bladder selectivity, these new oral agents have favorable side effect profiles, which translate into higher patient compliance and fewer treatment withdrawals or dosage reductions.
Key words: Antimuscarinic agents, Drug delivery systems, Overactive bladder, Urinary incontinence
Overactive bladder (OAB) is characterized by the urinary symptoms of frequency, urgency, and urge incontinence as a result of involuntary detrusor contractions during bladder filling. Such contractions are predominantly under the control of the parasympathetic nervous system. Acetylcholine released from the parasympathetic nerve endings activates the M3 muscarinic receptors on the detrusor smooth muscles and modulates bladder contractility. Antimuscarinic agents inhibit the binding of acetylcholine to the muscarinic receptors and suppress involuntary detrusor contraction.1 Immediate-release oxybutynin was the gold standard in pharmacologic treatment of OAB for almost three decades. Its antimuscarinic (M3) activity is nonselective for the urinary bladder, resulting in significant systemic side effects, particularly dry mouth, that limit its clinical utility.2,3 Even though alternative routes of administration of oxybutynin, such as intravesical instillation,4–6 intravesical implant,7 and rectal suppository,8 are available, oral agents remain the mainstay in treatment of OAB. Newer pharmacologic agents (eg, tolterodine) and modified drug delivery mechanisms for oxybutinin (ie, extended-release oxybutinin) have revolutionized the treatment of OAB.4,5
The Challenge
New drugs are always compared not only to placebo but also to immediate-release oxybutynin, because of its long history and established efficacy.6 Originally identified in the 1960s as a potential treatment for gastrointestinal hypermobility, oxybutynin was found to be effective in inhibiting involuntary bladder contractions. It is a receptor subtype-specific antagonist that binds with higher affinity to the M3 muscarinic receptors than to the other receptor subtypes (M1, M2, M4, and M5). Oxybutynin also has direct spasmolytic (musculotropic) and local anesthetic effects on the detrusor.
Even though the clinical efficacy of immediate-release oxybutynin is well documented, dose-related antimuscarinic side effects are frequent. Dry mouth is the most common and bothersome complaint, followed by constipation, blurred vision, dry eyes, urinary retention, and drowsiness. These systemic side effects occur because oxybutynin is not target specific to the lower urinary tract. It also inhibits M3 receptors in the salivary glands, which mediate salivary secretion, and M3 receptors in the intestines, which regulate bowel peristalsis. Clinically, immediate-release oxybutynin appears more potent in causing dry mouth than in inhibiting detrusor instability. The adverse effects, particularly dry mouth, are often severe enough to cause poor patient compliance, suboptimal dosing, and even drug discontinuation. Only 18%–22% of patients treated with immediate-release oxybutynin remained on the medication after 6 months due to intolerable side effects.9,10 Since OAB is a chronic debilitating condition requiring long-term treatment, it is important that pharmacologic therapy be not only effective but also well tolerated. The challenge has been to develop antimuscarinic agents that are as effective as immediate-release oxybutynin but without the side effect loads.
Tolterodine
Bladder Selectivity
Tolterodine (Detrol®) was the first drug developed specifically for the treatment of OAB. It is a competitive muscarinic antagonist that exhibits similar affinities for muscarinic receptor subtypes M1 to M5. Unlike immediate-release oxybutynin, which is a receptor subtype-specific agent (for M3), tolterodine may be a more target-specific drug that possesses stronger selectivity for the urinary bladder than for the salivary glands. In an anesthetized cat model of only six cats, tolterodine appeared more potent in inhibiting detrusor instability than salivation. This is in contrast to immediate-release oxybutynin, which exhibited the opposite tissue-selective profile.11,12 In a pilot study with healthy volunteers, tolterodine was well tolerated and exhibited greater objective and subjective antimuscarinic effects on detrusor function than on salivation.13 However, in another study on the effects on salivary volume, at 2 hours following tolterodine (2 mg) or immediate-release oxybutynin in healthy volunteers, there was less suppression of salivary volume with immediate-release oxybutynin; however, there was a complete return to normal by 10 hours in the volunteers taking tolterodine, and those taking immediate-release oxybutynin took longer to regain their respective salivary volume. In addition, another group taking extended-release oxybutynin (10 mg) had a constant salivary volume that was only slightly below that of those who were given placebo.14 The precise mechanism responsible for any bladder-selective property of tolterodine remains to be elucidated, and whether it is related to the differential affinities of the muscarinic receptors in salivary glands and those in detrusor muscles for tolterodine and for immediate-release oxybutynin or its metabolites remains to be confirmed in the human.4
Dosage
The recommended dosage of tolterodine is 2 mg twice a day based on phase 2 dose-ranging studies. No dose adjustment is necessary on the basis of metabolic phenotype (cytochrome P450 “extensive” vs “poor” metabolizers). 15 Obviously, as the dosage of tolterodine increases, clinical response improves but tolerability declines. At a dosage of 2 mg twice a day, the incidence of adverse effects, including dry mouth, is similar to that found with placebo, but clinical efficacy is comparable to that of immediate-release oxybutynin. A lower dose (1 mg twice a day) results in less favorable improvements in maximum cystometric capacity and volume at first contraction in urodynamic tests. A higher dose (4 mg twice a day) quadruples post-void residual volume (from 48 mL to 163 mL) and may increase the risk of urinary retention.15,16 The rate of dry mouth also approaches 56% at the higher dose.12 Ultimately, the recommended dosage of tolterodine was set at 2 mg twice a day with the aim of achieving efficacy similar to that of immediate-release oxybutynin but without the same side effect burden.6
Pharmacokinetics
The half-life of tolterodine is approximately 4 hours. Progression to peak therapeutic action is rapid. In phase 1 clinical trials with healthy volunteers, tolterodine exerted a marked inhibitory effect on bladder function within 2 hours after a single oral dose.13,17 However, clinically noticeable decreases in voiding frequency and incontinence episodes do not occur immediately when behavioral aspects of patients are taken into account. Modification of voiding habits is a gradual process, and it takes a period of time for the patient to trust the enhanced control that he or she begins to experience from the medication. Patients achieve approximately 70% of the maximum effects within 2 weeks of treatment initiation.18,19 Optimal relief of OAB symptoms is achieved after 8 weeks of treatment.6,18,20 Clinical response is sustained for at least a year in patients who are compliant and continue to take the medication.8
Tolerability of Tolterodine over Immediate-Release Oxybutynin
The tolerability of tolterodine over immediate-release oxybutynin has been demonstrated by numerous phase 3 clinical trials. Most of these were prospective, randomized, multi-center, placebo-controlled, parallel-group, double-blind studies that directly compared tolterodine to immediate-release oxybutynin and placebo in patients who had urodynamically confirmed and/or clinically significant bladder overactivity.18,21,22 Many of these trials were 12 weeks in duration and virtually identical in study design, a feature that permitted data pooling and meta-analysis to include over 1000 patients, increasing statistical power.23,24
Phase 3 randomized trials have consistently demonstrated comparable objective and subjective efficacy between tolterodine and immediate-release oxybutynin. Tolterodine reduced the micturition frequency by 17%–21%, reduced urge incontinence episodes by 47%, and increased mean volume per micturition (which is a surrogate measurement of bladder capacity) by 21%–27%.18,21 Improvements in voiding diary variables were comparable between patients who were randomized to receive 2 mg twice a day of tolterodine and those receiving 5 mg three times a day of immediate-release oxybutynin (see Table 1), with the exception that immediate-release oxybutynin appeared to more effective in relieving urge urinary incontinence than tolterodine in one study (−71% versus −47%, respectively).18 These objective improvements in voiding diary parameters were clinically relevant to the patient, as they translated into subjective improvements in the patient’s perception of bladder symptoms. When asked to rate their symptoms on an analog scale, 52% of tolterodine patients reported an improvement in symptom scores after 12 weeks of treatment, compared with 50% and 39% of patients taking oxybutynin and placebo, respectively.23
Table 1.
Tolterodine (Detrol) vs Immediate-Release Oxybutynin
| Outcome | Study | Tolterodine | Oxybutynin | Placebo | Comments |
|---|---|---|---|---|---|
| Frequency of micturition | Abrams et al18 | −21% | −19.5% | −10.5% | Tolterodine and immediate-release oxybutynin demon-strated comparable efficacy. |
| Drutz et al21 | −17% | −17% | −9% | ||
| Number of urge | Abrams et al | −47% | −71% | −19% | |
| incontinence episodes | Drutz et al | −46% | −52% | −27% | |
| Volume per micturition | Abrams et al | +27% | +31% | +7% | |
| Drutz et al | +21% | +34% | +8% | ||
| Percent of patients with | Abrams et al | 89% | 97% | 81% | Tolterodine exhibited tolerability superior to that of immediate-release oxybutynin. |
| side effects | Drutz et al | 78% | 90% | 75% | |
| Appell et al23 | 75% | 93% | 78% | ||
| Percent of patients | Abrams et al | 50% | 86% | 21% | |
| with dry mouth | Drutz et al | 30% | 69% | 15% | |
| Appell et al | 40% | 78% | 40% | ||
| Percent of patients | Abrams et al | 14% | 51% | (not reported) | |
| with moderate to | Drutz et al | 9% | 44% | (not reported) | |
| severe dry mouth | Appell et al | 17% | 60% | 6% | |
| Percent of patients | Abrams et al | 8% | 17% | 12% | |
| who withdrew due | Drutz et al | 6% | 21% | 7% | |
| to side effects | Appell et al | 8% | 20% | 5% | |
| Percent of patients | Abrams et al | 8% | 32% | 2% | |
| who reduced dosage | Drutz et al | 7% | 23% | 4% | |
| due to side effects | Appell et al | 9% | 32% | 4% |
Despite comparable efficacy at their recommended doses, tolterodine was better tolerated than immediate-release oxybutynin. Dry mouth was still the most common adverse effect.18,21,23 However, with tolterodine, there was a lower incidence of dry mouth and, as assessed by patients on an analog scale, there was a lower intensity of dry mouth when it occurred. Half as many patients experienced dry mouth in the tolterodine arm (30%–50%) as in the oxybutynin group (69%–87%). Most patients with dry mouth in the tolterodine arm reported it to be mild, whereas most patients in the immediate-release oxybutynin group reported it as moderate or severe (see Table 1). In studies that permitted dose reduction to prevent drug discontinuation, the frequency and intensity of dry mouth remained higher among patients who reduced their oxybutynin dosage from 5 mg three times per day to 2.5 mg three times per day (due to adverse effects), compared with those who remained on the regular dose of tolterodine (2 mg twice a day).18
Fewer patients in the tolterodine arm withdrew from the study (6%–8% vs 17%–21% in the oxybutynin arm) or reduced their dosage (7%–8% vs 23%–32% in oxybutynin) as a result of adverse effects.18,21,23 The equivalent clinical efficacy and superior tolerability of tolterodine compared to immediate-release oxybutynin translate into higher patient compliance and fewer treatment withdrawals or dosage reductions. Tolterodine overcomes the current limitations of immediate-release oxybutynin and offers a therapeutic advantage in terms of improved tolerability. There are suggestions that tolterodine improves overall quality of life (QOL) as measured by the Medical Outcomes Study-36 (MOS-36) 36-item short-form (SF-36) instrument of OAB patients to a greater extent than oxybutynin or placebo, even though at this time, no disease-specific QOL tool has been developed for patients with OAB.25
In clinical practice, immediate-release oxybutynin is commonly started at a lower initial dose of 2.5 mg three times daily and then titrated up to 5 mg three times daily to achieve a balance between efficacy and tolerability.26–28 A study was therefore performed to compare tolterodine with immediate-release oxybutynin using an upward titration protocol (started at 2.5 mg, then increased to 5 mg three times a day after 2 weeks) in patients over 50 years of age to determine whether tolterodine was better tolerated than immediate-release oxybutynin in that clinical scenario. Not surprisingly, despite the upward titration strategy, tolterodine still exhibited comparable efficacy and superior tolerability to those of immediate-release oxybutynin.20
Long-Term Tolerability
The long-term tolerability of tolterodine was demonstrated by open-label studies, even though randomized trials that directly compare long-term adverse effects of tolterodine to those of immediate-release oxybutynin are lacking. Only 9% and 15% of tolterodine patients withdrew from open-label studies due to side effects at 9 months and 12 months, respectively. Another 13% and 23% opted for dose reduction at the end of 9 months and 12 months, respectively.29,30 This is in contrast to immediate-release oxybutynin; only 18% of OAB patients remained on this therapy after 6 months due to intolerable side effects.2,10 Retrospective analysis of a filled-prescription pharmacy database also confirmed that more OAB patients remained on tolterodine therapy than on immediate-release oxybutynin after 6 months of treatment.9 A poor response to oxybutynin in the past does not preclude patients from being able to tolerate long-term treatment with tolterodine. In fact, tolterodine was well tolerated in 89% of patients who had previously found oxybutynin to be unacceptable. There is no evidence that antimuscarinic side effects worsened over time with long-term use.29
Safety
When clinical trials of tolterodine first began, there was concern over the cardiac safety of the medication, since it is closely related to terodiline, a drug that was removed from the market in the 1980s because of concerns over arrhythmias and acute cardiac events. In almost every tolterodine study, patients were very closely monitored and evaluated with respect to ECG changes and potential adverse cardiac events. Other than a slight dose-dependent increase in heart rate (3–12 beats per minute),15,31,32 and a corresponding shortening in uncorrected QT interval, which one would expect from the antimuscarinic activity of tolterodine, no clinically relevant changes in corrected QT intervals or ECG morphology were apparent.32 No serious adverse cardiac event attributed directly to tolterodine use has been documented in any of more than a few dozen well-conducted clinical trials.
Overall, central nervous system (CNS) side effects are rare.19,33 Unlike immediate-release oxybutynin and its major metabolite (N-desethyloxybutynin), which cross the blood-brain barrier and theoretically may cause CNS adverse effects such as somnolence and cognitive impairment,34 tolterodine has lower lipophilicity and therefore, probably less penetration into the CNS,35,36 but it must be remembered that tertiary amines all pass through the blood-brain barrier, and both oxybutynin and tolterodine are tertiary amines. Although tolterodine caused fewer disturbances on quantitative-topographic electroencephalogram than oxybutynin in healthy volunteers,37 and the reported incidence of somnolence in patients treated with immediate-release oxybutynin was 11.9%, whereas in patients on tolterodine it was 3.0%,38 it must be remembered that clinical problems have not been demonstrated in patients on extended-release oxybutynin, which may, again, mean that CNS problems, if any, on oxybutynin may relate to metabolites of oxybutynin and not the parent compound.
Tolterodine has no deleterious effects on blood pressure or on hematologic or biochemical laboratory values during long-term treatment.29 It is safe and well tolerated in the elderly over 65 years of age.20,39 No cardiac arrhythmogenic events were noted in a study that exclusively recruited patients over 65 years of age.39 Although based on limited numbers of subjects, with short follow-ups, another study found that tolterodine (0.1 mg/kg/day in two divided doses) appeared to be safe in pediatric meningomyelocele patients with detrusor hyperreflexia.40
Extended-Release Oxybutynin
OROS Drug Delivery System
An extended-release formulation of oxybutynin (Ditropan XL®) was released in 1999.38 This once-a-day formulation uses a patented oral osmotic (OROS®) drug delivery system to slowly release a controlled amount of oxybutynin into the gastrointestinal tract over a 24-hour period. Physically, extended-release oxybutynin resembles a conventional tablet, but it consists of two core compartments—a drug layer containing the active ingredient (oxybutynin) and a push layer containing osmotically active compounds—wholly surrounded by a semipermeable membrane with a laser-drilled orifice on the drug side. Water in the gastrointestinal tract enters the tablet and mixes with the oxybutynin to form a suspension. Water also enters the push layer through the semipermeable membrane via osmosis. The push layer expands and pushes the suspended drug out of the orifice into the gastrointestinal tract for absorption.
More Stable Serum Concentration
Aside from the convenience of once-daily administration, extended-release oxybutynin eliminates the three times daily peak-to-trough serum concentration fluctuation associated with immediate-release oxybutynin. Such marked variation in oxybutynin level is thought to contribute to the intolerable dose-dependent side effects of the drug. Studies with adult volunteers have shown a smoother peak-to-trough fluctuation of plasma concentration with each dosing of extended-release oxybutynin. Plasma level rises slowly over 4–6 hours and remains fairly constant over the 24-hour dosing interval.41,42 Steady-state concentration is reached by day 3 of administration. In addition, the peak serum concentration of oxybutynin in the extended-release formulation is 2.5 times lower than that of the conventional formulation.41 Lower peak value and more stable serum concentration are the pharmacokinetic hallmarks of extended-release oxybutynin.
Less First-Pass Metabolism
Oxybutynin is metabolized by the cytochrome P450 enzyme system in the liver and the small intestinal wall (“first-pass” metabolism). The primary metabolite, N-desethyloxybutynin, is largely responsible for systemic side effects, particularly dry mouth.41–43 There is evidence that although oxybutynin and N-desethyloxybutynin have similar effects on the detrusor, N-desethyloxybutynin is more potent in the salivary glands and causes more severe dry mouth than the parent compound.
Immediate-release oxybutynin, like most other oral medications, is absorbed primarily in the small intestine and drains into the portal system. It undergoes extensive first-pass metabolism in the upper gastrointestinal tract, producing high serum levels of N-desethyloxybutynin, which causes intolerable side effects. In contrast, extended-release oxybutynin is protected inside a nondisintegrating OROS capsule. It is released at a steady rate for 24 hours, spending only 3–5 hours in the upper gastrointestinal tract. Most of it is released in the colon, where first-pass metabolism is much less extensive than in the small bowel.44,45 As a result, first-pass metabolism is proportionally reduced, the serum ratio of N-desethyloxybutynin to oxybutynin is reduced, and less severe dry mouth may be experienced.42 This hypothesis is supported by a pilot study that showed that mean bioavailability was higher for oxybutynin (153%) and lower for N-desethyloxybutynin (69%) in extended-release oxybutynin than with immediate-release oxybutynin.41
Improved Tolerability over Immediate-Release Oxybutynin
More stable serum concentration together with less first-pass metabolism may explain the improved tolerability of extended-release oxybutynin over immediate-release oxybutynin.
Extended-release oxybutynin caused less suppression of saliva output and less severe dry mouth than immediate-release oxybutynin in healthy adult volunteers.41,42 Whereas patients taking extended-release oxybutynin and immediate-release oxybutynin had similar reductions in urge incontinence (83% and 76%–87%, respectively) and total incontinence episodes (80%–81% and 75%–86%, respectively), indicating equivalent clinical efficacy,43,46 the incidence and severity of dry mouth were lower in the extended-release oxybutynin group (see Table 2). Dry mouth of any severity was reported by 68% and 87% of patients in the extended-release oxybutynin and immediate-release oxybutynin groups, respectively (P = .04).43 Moderate or severe dry mouth occurred in 25% and 46%, respectively (P = .03). Dry mouth was still the most common side effect of the extended-release formulation (68%), followed by somnolence (38%), constipation (30%), and blurred vision (28%). With the exception of dry mouth, extended-release oxybutynin and immediate-release oxybutynin were comparable in terms of the rates of systemic side effects.
Table 2.
Extended-Release Oxybutynin vs Immediate-Release Oxybutynin
| Outcome | Study | Extended-Release | Immediate-Release | Comments |
|---|---|---|---|---|
| Oxybutynin | Oxybutynin | |||
| Number of urge | Anderson et al43* | −84% | −88% | Extended-release and immediate-release oxybutynin demonstrated equivalent efficacy. |
| incontinence episodes | Versi et al46 | −83% | −76% | |
| Percent of patients | Anderson et al | 41% | 40% | |
| achieving total continence | ||||
| Percent of patients | Anderson et al | 87% | 94% | |
| with side effects | ||||
| Percent of patients | Anderson et al | 68% | 87% | Extended-release oxybutynin is better tolerated than immediate-release oxybutynin. |
| with dry mouth | Versi et al | 48% | 59% | |
| Percent of patients | Anderson et al | 25% | 46% | |
| with moderate | Versi et al | 4% (at 5 mg/day) | 7% (at 5 mg/day) | |
| to severe | 9% (at 10 mg/day) | 26% (at 10 mg/day) | ||
| dry mouth | 19 (at 15 mg/day) | 39 (at 15 mg/day) | ||
| 40 (at 20 mg/day) | 45 (at 20 mg/day) | |||
| Percent of patients | Anderson et al | 15% | 13% | |
| who withdrew due | Versi et al | 3% | 6% | |
| to side effects |
Dosage up to 30 mg/day was allowed in the extended-release randomized arm.
In one open-label study, 7.8% of OAB patients discontinued extended-release oxybutynin at the end of 12 weeks because of adverse effects.47 Notably, neither the comparative43,46 nor the open-label studies47 have a placebo arm, so the extent of placebo effects cannot be ascertained. Whether the more favorable side effect profile of extended-release oxybutynin translates into higher patient compliance and fewer treatment withdrawals or dosage reductions remains to be studied in placebo-controlled trials. For patients whose bladder symptoms have been stabilized on immediate-release oxybutynin, switching to extended-release oxybutynin reduces the side effects without compromising clinical efficacy.48
Maximum clinical benefit is achieved by the fourth week and is sustained through 12 weeks of maintenance therapy. The optimal dosage appears to be between 5 and 15 mg daily. In one trial, 70.8% of participants chose a maintenance dose of 5–15 mg, whereas 17% used a dose of 25–30 mg daily. Although the latter doses are higher than the maximum recommended dose, only 5.4% of these patients discontinued treatment due to antimuscarinic side effects.47 Up to 30 mg per day of extended-release oxybutynin has been used safely in controlled studies.43 Extended-release oxybutynin may provide important therapeutic options for motivated patients who require a higher dose to achieve optimal relief of OAB symptoms without experiencing excessive side effects (eg, neurogenic bladder).
Safety and Efficacy in the Elderly
Extended-release oxybutynin appears to be safe in the elderly. In a long-term, open-label, community-use study, there was a very low incidence of CNS side effects, including changes in mental acuity and memory.49 Over 50% of patients in that community-based study were over 65 years of age. The drug demonstrated comparable efficacy across all age groups. In a different open-label study evaluating urge incontinence, nearly equal numbers of patients older and younger than 65 years old achieved complete urinary continence.46 In addition, the rates of dry mouth were similar. These results are important, since urge urinary incontinence is not only prevalent among the elderly (affecting 12%–38% over the age of 60)50 but is also the second leading cause of patient admissions to nursing homes.51
Long-Term Tolerability and Compliance
Historically, only 18%–22% of patients remained on long-term (over 6 months) treatment with immediate-release oxybutynin,9,10 in contrast to the case with extended-release oxybutynin; 60% of patients remained on the latter drug at 12 months, at doses of 15 mg or less.49 Overall QOL is improved with long-term treatment of extended-release oxybutynin, as sleep disturbance is reduced and incontinence impact questionnaire scores are lowered. Of patients taking extended-release oxybutynin, 80% reported that the medication worked well or very well and 88% were pleased or extremely pleased with the results. Only 16% of patients discontinued therapy due to adverse effects over the 12-month study period; the majority of these did so by 3 months.
Extended-Release Oxybutynin Versus Tolterodine
One prospective, randomized, double-blind, parallel-controlled study directly compared extended-release oxybutynin (10 mg daily) to tolterodine (2 mg twice a day) (see Table 3).52 Extended-release oxybutynin appeared to be more effective than tolterodine in reducing voiding frequency (26.9% vs 21.9%), urge incontinence episodes (76.2% vs 67.6%), and total incontinence episodes (75.2% vs 65.6%). The incidence of dry mouth (28.1% with extended-release oxybutynin vs 33.2% with tolterodine), the severity of dry mouth (moderate to severe: 10.2% vs 10.9%), and rates of treatment discontinuation due to side effects (7.6% vs 7.8%) showed no statistically significant difference.
Table 3.
Extended-Release Oxybutynin vs Immediate-Release Tolterodine
| Outcome | Extended-Release | Immediate-Release | P Value | Comments |
|---|---|---|---|---|
| Oxybutynin | Tolterodine | |||
| Number of urge | −76% | −68% | .03 | Extended-release oxybutynin is more effective than immediate-release tolterodine in reducing urinary frequency, urge incontinence, and total incontinence. |
| incontinence episodes/wk | ||||
| Number of total | −75% | −66% | .02 | |
| incontinence episodes/wk | ||||
| Number of micturitions/wk | −27% | −22% | .02 | |
| Percent of patients | 28% | 33% | .32 | Side effect profiles and rates of withdrawal are similar with extended-release oxybutynin and immediate-release tolterodine. |
| with dry mouth | ||||
| Percent of patients with | 10% | 11% | .87 | |
| moderate to severe dry mouth | ||||
| Percent of patients who | 8% | 8% | (not reported) | |
| withdrew due to side effects |
Data from Appell et al.52
Extended-Release Tolterodine
An extended-release, once-daily formulation of tolterodine (Detrol LA®) is now available.53 It uses a different extended-release technology from the OROS, system. It has been found that gastric pH may affect the bioavailability of the drug and that if extended-release tolterodine is taken with antacids, the drug is released too soon and the effective time of the medication may be shortened and the tolerability reduced.6 In contrast, the drug metabolism and bioavailability of extended-release oxybutynin are not affected by dietary intake of antacids. Pharmacokinetic studies in healthy volunteers suggested that the extended-release formulation of tolterodine has a smoother peak-to-trough concentration profile than immediate-release tolterodine.54
In the largest placebo-controlled study ever conducted in patients with OAB (more than 1500 patients), extended-release tolterodine (4 mg daily) demonstrated efficacy and tolerability superior to those of immediate-release tolterodine (2 mg twice a day). Both extended-release and immediate-release tolterodine significantly reduced number of incontinence episodes, voiding frequency, and pad use compared to placebo.55 Notably, the extended-release formulation was reported to be 18% more effective than regular tolterodine in reducing the median number of incontinence episodes (see Table 4) (P < .05). The physiological explanation for improved efficacy is not clear; the difference may be related to statistical variations induced in the performance of the analysis.
Table 4.
Extended-Release Tolterodine vs Immediate-Release Tolterodine
| Outcome | Extended-Release | Immediate-Telease | Placebo | Comments |
|---|---|---|---|---|
| Tolterodine | Tolterodine | |||
| Number of | −53%* | −46%* | −30% | *Extended-release tolterodine is 18% more effective than immediate-release tolterodine in reducing the median number of incontinence episodes per week (P < .05). |
| incontinence | ||||
| episodes/wk | ||||
| Number of total | −32% | −30% | −19% | |
| micturitions/24 hrs | ||||
| Volume voided | +24% | +21% | +10% | |
| per micturition | ||||
| Number of pads | −36% | −36% | −13% | |
| used/24 hrs | ||||
| Percent of patients | 23%† | 30%† | 8% | †Patients taking extended-release tolterodine have less dry mouth than those taking regular tolterodine (P < .02). |
| with dry mouth | ||||
| Percent of patients | 5% | 5% | 6% | |
| who withdrew due | ||||
| to side effects |
Data from Van Kerrebroeck et al.55
The most common adverse effect was dry mouth. Aside from this, all other systemic side effects were seen with similar frequency in the treatment groups and the placebo group. In the extended-release arm, 23% of patients experienced dry mouth, of whom 1.8% reported severity that interfered significantly with patient’s usual functioning.55 Patients taking extended-release tolterodine had a 23% lower incidence of dry mouth than those taking regular tolterodine (P < .02), even though the rates of drug withdrawal (5%) were similar between the two groups at the end of 12 weeks. Extended-release tolterodine was reported to be more effective in reducing urge incontinence and better tolerated than the immediate-release formulation.
Head-to-head comparative studies between extended-release tolterodine and extended-release oxybutynin are underway but have yet to be published. Both extended-release tolterodine and extended-release oxybutynin offer therapeutic advantages over immediate-release forms of these drugs, but it remains uncertain if either drug is better than the other in terms of efficacy, tolerability, and compliance.
Main Points.
Oral agents remain the mainstay in treatment of overactive bladder (OAB).
Immediate-release oxybutynin is effective for OAB but has significant side effects, especially dry mouth, which may reduce patient compliance with dosage regimens.
Tolterodine has effectiveness equal to that of immediate-release oxybutynin with fewer and less severe side effects.
Extended-release formulations of oxybutynin and tolterodine have greater tolerability than the immediate-release forms of these drugs.
Long-term control of incontinence and OAB requires continuing medication use, and patients are more likely to comply with the drugs they are prescribed with better side effect profiles.
References
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