New Oral Medications for Overactive Bladder

New Oral Medications for Overactive Bladder

Improving Quality of Life Not a Small Matter

Dr Baum is Clinical Associate Professor of Urology, Tulane Medical School, New Orleans, La.

It is estimated that 33 million adults in the United States suffer from overactive bladder (OAB), a disorder with a price tag in the billions (World J Urol. 2003;20:327-336) that often goes untreated, in part because many patients mistakenly believe that no treatment is available or are too embarrassed to discuss it.

Because many patients are unaware that incontinence is a treatable condition, or think it is a natural part of aging, or are embarrassed to discuss it, they often develop coping behaviors to manage the symptoms. These behaviors include restricting fluids, carrying extra clothing, “mapping” bathroom locations, or not leaving their homes.

Patients’ Misconceptions as Barriers to Treatment

• “Normal part of the aging process.”
• “Not severe enough to treat.”
• “Too embarrassing to discuss.”
• “No treatment available.”

However, anticholinergic medications have been around for years, including such familiar names as oxybutinin (Ditropan) and tolterodine (Detrol) and new oral therapies are being developed that may offer new options for this condition, which though not life-threatening, can nevertheless be just as debilitating as other medical conditions. As one of my patients put it succinctly, “Overactive bladder doesn’t take your life, it just steals it from you.”

Recognizing OAB Symtoms

The diagnosis of OAB can be reached by a thorough history and questions directed at establishing the voiding frequency and incontinence episodes. The following signs and symptoms are sufficient to establish the diagnosis of OAB:

• Frequency: ≥8 visits to the toilet in 24 h
• Nocturia: ≥2 visits to the toilet in the night
• Urgency: sudden, strong urge to urinate
• Urge incontinence: sudden, involuntary loss of urin

Be sure to ask your older patients years about such symptoms, since this condition is more prevalent in both men and women who are older than 40 years. A quick history focused on these OAB symptoms can usually suggest the diagnosis.

With increasing drug choices, physicians can relieve the agony of many elderly patients who are enduring a condition that could most of the time be controlled. The recent FDA approval of 3 new oral medications adds to the therapeutic options and may increase the number of patients that could be treated successfully (Table). If one agent fails, try another one, until the best agent is found for the individual patient; as in any medications, there are individual differences in response to its therapeutic efficacy.

The 3 New Drug Options

Trospium

Approved in the United States in May 2004 for the treatment of OAB, trospium (Sanctura; Indevus/Odyssey)—an anticholinergic with predominantly peripheral nonselective antimuscarinic activity—has been available in Europe for more than a decade. In clinical trials, trospium has demonstrated sustained, long-term efficacy by by reducing the symptoms associated with OAB and improving a patient’s quality of life. Trospium works by relaxing smooth muscle tissue in the bladder, thereby reducing bladder contractions. Overactive or unstable detrusor muscle function is assumed to be the cause of OAB, although this has yet to be proven.

In a 12-week, phase 3, multicenter, parallel, double-blind, placebo-controlled study of 523 patients who were equally randomized to 20 mg trospium twice daily or placebo (J Urology. 2004;171:2311-2315), trospium was found safe and sustained efficacy by the end of week 1, including reduced number of voids and urge incontinence episodes and increased volume per void—all of which enhanced the patients’ quality of life.

The results of a 9-month, open-label follow up period of 407 of patients were presented last July at the American Urogynecological Society annual meeting in San Diego, which showed that patients who received trospium for 1 year maintained comparable and continued efficacy for the entire treatment period. At 12 months, the mean decline in void frequency for all patients ranged from 18 to 21 voids per week, and the mean decline in urge incontinence episodes ranged from 64% to 72% daily, compared with baseline. All patients experienced a rise of 27 to 28 mL in volume voided at the end of the study period.

Darifenacin

Darifenacin extended release (Enablex; Novartis), a tertiary amines metabolized through the cytochrome (CY) P3A4 pathway, was approved in December 2004. It works by blocking the M₃ receptor, which is principally responsible for bladder muscle contractions. In clinical studies, darifenacin reduced frequency of incontinence and urination episodes, increased bladder capacity, and decreased feelings of urgency.

In a 12-week, multicenter, placebo-controlled trial (J Urol. 2004;45:420-429), 561 patients with OAB symptoms for >6 months and some patients with previous exposure to antimuscarinic agents were randomized to once-daily oral darifenacin, 7.5 or 15 mg, or matching placebo. Results showed that darifenacin 7.5 and 15 mg had a rapid onset of effect, with significant improvement compared with placebo seen for most parameters at week 2, and sustained through week 12. At week 12, the number of incontinence episodes per week was reduced from baseline by 67.7% with the 7.5 mg of darifenacin and by 72.8% with the 15 mg dosage in contrast to 55.9% with placebo.

Solifenacin

Solifenacin (Vesicare; GlaxoSmithKline/Yamanouchi), also a tertiary amines metabolized through the CYP3A4 pathway, was approved in January 2005 for the treatment of OAB with symptoms of urgency, frequency, and urge incontinence based on data demonstrating that solifenacin 5 and 10 mg resulted in significant improvements in all these OAB symptoms. Solifenacin works by selectively blocking the muscarinic receptors, thereby causing the detrusor muscle to relax and diminish the symptoms associated with OAB.

In a 12-week, placebo-controlled study of solifenacin (J Urol. 2004;172:1919-1924) that included 827 patients with OAB, patients were randomized to once daily treatment with solifenacin 5 or 10 mg, or placebo. The primary efficacy variable was changed from baseline to study end point in mean number of micturitions per 24 hours.

Results showed that micturitions per 24 hours were decreased with solifenacin 5 mg (-2.37; P = .018) and solifenacin 10 mg (-2.81; P = .001) compared with placebo. The number of urge incontinence was reduced with the 2 solifenacin doses compared with placebo (5 mg, P = .014; 10 mg, P = .042); the number of episodes of urgency were also reduced compared with placebo: solifenacin 5 mg (-2.84, -51%; P = .003) and solifenacin 10 mg (-2.90, -52%; P = .002).

Dosing considerations for the 3 drugs

• Trospium: to be taken on an empty stomach; in patients with severe renal impairment or those ³70 years, reduce dose to 20 mg/day.
• Darifenacin: if dosage is well tolerated, could be titrated up to 15 mg/day after 2 weeks.
• Solifenacin: if dosage well tolerated, could be titrated to 10 mg/day.

All 3 drugs are contraindicated in patients with urinary retention, gastric retention, or uncontrolled narrow-angle glaucoma. The most common adverse event for all these agents is dry mouth

Impact of OAB

With increased options, OAB may be finally changing from a condition that is endured to one that can be cured—or at least managed effectively.

With the aging of the baby boomers, the number of people affected by OAB can be expected to increase. Those who suffer from OAB will have a decreased quality of life, and the condition exacts a toll on the person’s social and personal life. Pharmacologic therapy is a mainstay of treatment. The majority of patients can be helped by such therapy and some even cured of this incapacitating condition.