Recent Clinical Studies of New Pharmacologic Agents and Their Efficacy in the Treatment of Incontinence

Abstract

Two agents for the control of overactive bladder—tolterodine (TOL) and extended-release oxybutynin (Oxy-XL)—have been evaluated in a number of studies for their efficacy in urge incontinence. Studies have demonstrated that TOL achieved a 20% reduction in the frequency of voiding and a 45% reduction in urge incontinent episodes. Efficacy was comparable between TOL and immediate-release oxybutinin (Oxy-IR), the standard anticholinergic comparator. There is a delay of some weeks in achieving relief with TOL, but thereafter there is a continued decrease in the total number of both micturitions and incontinent episodes in 24 hours. Trials demonstrated that there were no safety concerns at all with TOL. In particular, there was a lower incidence of dry mouth with TOL than with Oxy-IR. Dose-ranging studies established that TOL produced the lowest incidence of side effects while maintaining efficacy. In a long-term, community-use study of Oxy-XL, there was a very low incidence of central nervous system side effects, including mental acuity and memory. Among elderly nursing home patients, Oxy-XL achieved a 90% reduction in weekly urge incontinence episodes and an 86% decrease in pad use. Oxy-XL was shown to cause a significantly lower reduction in salivary output than Oxy-IR and TOL. In a recent head-to-head comparison study, there were significant differences found between Oxy-XL and TOL. Other studies have shown that the administration of Oxy-XL results in a significantly lower production of the metabolites responsible for anticholinergic side effect, particularly dry mouth, than with the standard release form, owing largely to the elimination of a first-pass effect. A long-acting form of TOL resulted in a 53% reduction in incontinent episodes. Both these anticholinergic agents have been shown to have excellent efficacy and tolerability. But the future of OAB therapy lies in targeting other mechanisms responsible for incontinence.

Tolterodine (Detrol), from Pharmacia & Upjohn, which has been available for about 3 years, and extended-release oxybutynin (Ditropan-XL), from Alza Pharmaceuticals, which has been available for about a year and a half, are relatively recent agents for the control of overactive bladder (OAB).

Particular interest in these agents is not for stress incontinence per se but for urge incontinence, represented by the classic “key in the door” syndrome. The principal drugs of choice for incontinence in this country and internationally have been anticholinergic medications, although other drugs are used in association with them.

New drugs are always compared not only against placebos but to immediate-release oxybutynin (Oxy-IR) because of its long history and established efficacy, although it has many side effects. In fact, most pharmaceutical companies have been trying to develop anticholinergic agents that are as effective as the original Oxy-IR but without the side-effect load, so that the patients who remain compliant with the drug regimen will stay on the medication for its utility.

Tolterodine

Pharmacia & Upjohn devoted extensive resources to the largest-ever clinical development program for tolterodine (TOL), its OAB medication. At the time of this author’s initial review for them,¹ there were 29 studies conducted in 15 different countries. To the present time there have been many more, and a significant number of patients have been followed.

Study goals. One goal for the TOL clinical studies was to have a 20% reduction in the frequency of voiding, which was achieved. The studies sought a 50% reduction with respect to urge-incontinent episodes, but achieved a 45% reduction. As a result, the drug is recommended for those patients who have lesser degrees of OAB. It is presented as the drug of choice for those particular patients with urinary urgency and frequency, but less so for those with incontinence. Initial studies showed a comparable efficacy between TOL and Oxy-IR, but TOL never quite achieved the overall efficacy of Oxy-IR.¹ One very important issue, however, needs to be considered when making comparisons. So many patients stop using Oxy-IR that it is difficult to have a valid comparison, especially when there is another other drug available that has fewer side effects and will be used for significant periods of time in those patients.

Incontinence-related problems. The first problem to address with OAB is the number of voids in 24 hours; the second is the number of incontinent episodes in 24 hours; and the third is the volume voided at each micturition. An important aspect of TOL therapy is that for significant changes to take place (meaning that the patient notices change), the patient needs to take this medication for 5 to 8 weeks. Several other drugs provide relief earlier in the course of treatment.

Although there is a delay in relief when taking TOL, there is also continued improvement occurring over a significant period of time. That is, although there may be some delay in the onset of improvement with TOL, the total number of micturitions in 24 hours and the total number of incontinent episodes in 24 hours continues to decrease for a period of 6 months, while there is also an increase in the volume voided during that period of time. In addition, this improvement was sustained from that point onward for at least a year for the patients who were followed in that particular study.² The decrease in incontinent episodes and the increase in volume voided over an extended period of time are the most significant and important benefits of this drug, especially because the positive effects are most definitely sustained if the patients stay on the medication.

Safety and tolerability. When clinical trials of TOL first began, there was a great deal of concern because it is related to terodiline, a drug studied in the late 1980s in the United States by Forest Laboratories. Terodiline was marketed in Europe and at that time was found to be associated with arrhythmias and acute cardiac events. Because the studies had just begun here in the United States, the drug was pulled voluntarily by Forest Laboratories. Based on these adverse events with terodiline, patients in the TOL studies were very closely monitored and evaluated with respect to EKGs and other cardiovascular parameters. In actuality TOL is very different from terodiline, without any of the calcium channel activity. The trials demonstrated that there were no safety concerns with TOL, and it has had an excellent safety profile.¹

The major adverse event that frequently causes patients to drop out of studies with Oxy-IR has always been dry mouth. With TOL, 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 did occur. This was manifested in the studies^1,3,4 by fewer dose reductions and fewer patient withdrawals because of this side effect.

Of note here is that two doses of TOL were offered: 1 mg twice a day for the geriatric population, and 2 mg twice a day. The studies included dosages that ranged between 4 mg and 6 mg per day; one study used 8 mg per day.¹ An important concern here is that when TOL dosages increase, efficacy improves but tolerability decreases. Ultimately the dosage was set at 4 mg total per day or 2 mg bid. The aim was to achieve efficacy equal to agents already available, specifically Oxy-IR, but without the same side effect issue. It was found, though, that more patients were withdrawing on placebo than on the 1 mg bid dose, whereas 2 mg bid led to a slightly greater but not significant rate of withdrawal than for placebo. An animal study suggested that TOL produces less dry mouth than does Oxy-IR because of an unexplained selectivity of TOL for M2 and/or M3 receptors found in the bladder over those in the salivary glands.⁵

There has been some speculation that oxybutynin enters the brain and hence has more central nervous system (CNS) effects than TOL. This is based on the higher lipophilicity characteristic of oxybutynin over TOL. Dmochowski and Appell⁶ demonstrated that the incidence of CNS side effects in a large patient population given Oxy-XL is quite small. Moreover, any tertiary amine can pass through the blood-brain barrier.

Oxybutynin-XL Studies Central nervous system side effects

Alza Pharmaceuticals presented a long-term study⁷ of community use of oxybutynin-XL (Oxy-XL) at the International Continence Society meeting and has done some comparative studies with Oxy-XL versus Oxy-IR and TOL with respect to salivary gland output.⁸

The 1-year, open-label study was done with patients who were not prescreened. There were over 1000 patients from different kinds of communities in the United States. The patients dosed themselves: they started out with one 5 mg tablet of Oxy-XL per day and were allowed to increase it each week as needed. Thus they were titrated based upon their own assessment of side effects and efficacy. The key element here is that, at 3 months, the patients who were going to have problems had experienced them and had either dropped out of the study, stopped using the medication, or continued with it. The study looked at all the different types of reported adverse events that could be related to the CNS and found a very low incidence, including mental acuity and memory. Additionally, over 50% of the patients in this community-based study were over the age of 65.

In addition, a double-blind, placebo-controlled study of Oxy-XL was completed on geriatric patients in long-term nursing home care.⁹ They had a 90% reduction in weekly urge incontinence episodes and an 86% decrease in pad use. These results are clinically important because urinary incontinence is the second leading cause of patient admissions to nursing homes.¹⁰

Evaluation of salivary output. A study was done to evaluate patients’ ability to produce saliva after taking Oxy-XL (10 mg) or Oxy-IR (5 mg).¹¹ There was a significant reduction in salivary output in the patients taking Oxy-IR, but not for those taking 10 mg of Oxy-XL. An additional study was conducted that included TOL as well as Oxy-XL and Oxy-IR.⁸ No significant differences were found between Oxy-XL and TOL. It is interesting to note that when the results are viewed over time, it appears that people produce more saliva throughout the day, as was the case with the patients given the placebo. However, in both the Oxy-IR and TOL groups, there was a marked decrease in salivary production around 2 hours post-ingestion of the medication that gradually returned to normal. With Oxy-XL, a constant level of salivary output exists, so that the baseline is the same as the value at the end of the day.

Oxybutynin metabolites. The literature suggests that metabolites of oxybutynin are important in causing some of the intolerable side effects, especially dry mouth.¹² In addition, delivery routes that bypass the upper gastrointestinal tract appear to result in much less metabolite formation and fewer anticholinergic side effects.¹³ Oxy-IR itself is metabolized by the P-450 cytochrome system in the liver and the gut wall, especially in the upper gastrointestinal tract. This metabolic step limits drug bioavailability, producing high levels of N-desethyloxybutynin (desoxy). The key behind the success with Oxy-XL is that most of it is absorbed in the large bowel, where there is no P-450 to metabolize it. Thus for Oxy-XL, the ratio of oxybutynin to desoxy is greater than that for Oxy-IR.

Ketoconazole blocks the P-450 system. Oxy-IR and Oxy-XL have been administered to patients with and without ketoconazole, and the quantity of metabolite produced by these agents in each group was compared.¹³ There was a statistically significant greater increase in the metabolite for Oxy-IR than for Oxy-XL when these were administered to patients without ketoconazole. Based on the results of this and the saliva-production study, it appears that metabolites play a major role in causing side effects, specifically dry mouth.

There has been a recent study involving 380 patients in a 3-month, direct comparison of Oxy-XL and TOL for efficacy and tolerability.¹⁴ The results demonstrated similar excellent tolerability of both medications. Results indicate that 10 mg Oxy-XL yielded significantly fewer episodes of incontinence, total incontinence, and voiding frequency problems than 4 mg TOL (2 mg bid).

Long-Acting Tolterodine

Pharmacia has recently finished a study with a long-acting form of TOL called Detrol-LA.¹⁵ This is a 4 mg once-a-day dose, administered through a different extended-release technology. This particular technology requires that patients do not ingest antacids. If this medication is taken with antacids, the capsule releases too soon and the effective time of the medication will be shortened. There was a 53% reduction in incontinent episodes with this drug during the trials—slightly better than data on the 2 mg bid—when the results were given as the arithmetic mean continence score. In contrast, when presented as the median, rather than the mean number of incontinent episodes, there was a 71% reduction in incontinence.¹⁶

Conclusion

Based on a variety of studies, both Oxy-XL and TOL, two recently developed anticholinergics, have been shown to have excellent efficacy and tolerability and further establish the reliability of anticholinergics in treatment of OAB. However, treatment of the overactive bladder must now go beyond anticholinergic medications and target other important mechanisms thought to be responsible for incontinence.

Main Points.

• Anticholinergic agents are the drug of choice for incontinence in the United States and are the chief agents for comparison trials, in addition to placebo.

• Tolterodine is indicated principally for patients with urinary urgency and frequency but less so for incontinence.

• Important issues in evaluating overactive bladder therapy are the number of voids and incontinent episodes in 24 hours, and the volume voided at each micturition.

• Relief with tolterodine may delayed for up to 8 weeks but continues for 6 months thereafter.

• Both tolterodine and Oxy-XL have excellent safety and efficacy profiles.

• The major adverse event—dry mouth—occurs less with tolterodine than with Oxy-IR.

• Oxy-XL causes little reduction of saliva production compared with Oxy-IR, because most of it is not metabolized in the liver or upper GI tract, resulting in a lower formation of metabolites responsible for dry mouth.

• Mechanisms other than those addressed by anticholinergics must be targeted by future therapies for OAB.