Pharmacology Update

Tolterodine: New Treatment for Incontinence

By William T. Elliott, MD, and James Chan, PharmD, PhD

The fda has approved a new antimuscarinic medication to treat urinary incontinence. Tolterodine is being released by Pharmacia & Upjohn under the trade name Detrol. Antimuscarinic drugs have been the mainstay in managing this disorder for years, but older drugs such as oxybutinin have been burdened by anticholinergic side effects such as dry mouth. Tolterodine appears to be as efficacious as oxybutinin, but it has increased tissue-selectivity for the bladder receptors and, therefore, fewer side effects.

Tolterodine is a competitive muscarinic receptor antagonist. Tolterodine and its active metabolite, 5-hydroxymethyl derivative, have been shown in vitro and in animal studies to be significantly more potent in inhibiting urinary bladder contraction and less potent in inhibiting salivation.1

The drug is indicated for the treatment of overactive bladder symptoms, including urinary frequency, urgency, or urge incontinence. Frequency is defined as urination that occurs more than eight times in 24 hours. The symptoms are common, particularly in older women, in whom the symptoms can be debilitating-causing disruption in social activities, work, sleep patterns, and sexual activity.

Indications

Tolterodine is indicated for the treatment of patients with an overactive bladder with symptoms of urinary frequency, urgency, or urge incontinence.

Potential Advantages

Comparative clinical data indicate that tolterodine is better tolerated than oxybutinin in terms of dry mouth, study withdrawal, and dose reductions.3 Dry mouth was the most frequently reported side effect. The reporting was significantly higher in the oxybutinin group compared to tolterodine or placebo. Moderate or severe dry mouth was reported in 60% of patients in the oxybutinin (5 mg tid) group compared to 17% in the tolterodine 2 mg bid group, 4% in the tolterodine 1 mg bid group, and 6% for placebo (P < 0.001). Twenty-seven percent of patients randomized to oxybutinin withdrew from the studies compared to 13% for tolterodine 2 mg. Dose reduction was reported in 32% of oxybutinin patients compared to 9% of tolterodine (2 mg) patients (P < 0.001). Patients on reduced dose of oxybutinin still reported higher overall frequency of adverse events compared to those on tolterodine 2 mg twice daily (66% vs 50%).7

Potential Disadvantages

Dry mouth is still the most common side effect of tolterodine, with about 40% of patients reporting it in trials.1,2 The efficacy of the drug appears to be modest. Three placebo-controlled trials (n = 339) showed statistical difference in median change from baseline between tolterodine (2 mg bid) and placebo in volume voided per micturition (27-34 mL vs 5-10 mL). Two out of three reported statistical difference in median change from baseline in the number of micturitions/24 hours (-1.6 to -2.2 vs -1.1 to -1.2). However, no statistical difference was reported between tolterodine and placebo in the median change from baseline in the number of incontinence episodes per 24 hours (-1.2 to -1.5 vs -0.8 to -1.1).2

Dosing Information

Tolterodine is available as 1 mg and 2 mg tablets. The initial recommended dose is 2 mg twice daily. The dose may be lowered to 1 mg twice daily based on individual response or tolerability. A lower dose is recommended for patients with hepatic dysfunction, renal dysfunction, or who are taking drugs that are inhibitors of cytochrome P450 3A4 (e.g., ketoconazole, erythromycin). While food increases the bioavailability of tolterodine (about 53%), the manufacturer does not make any specific recommendation regarding taking the drug with food.2

Comments

Tolterodine is a new competitive muscarinic receptor blocker similar to oxybutinin. These drugs are indicated for incontinence due to detrusor muscle overactivity and improve symptoms by relaxing the bladder and increasing bladder capacity. Pooled data from four randomized, parallel, multicenter comparative 12-week trials ( n = 1120) have been published.3 Results indicate that tolterodine 2 mg twice daily and oxybutinin 5 mg three times daily reduce mean daily micturition frequency by about 20%, reduce mean incontinence episodes by 40-60%, and increase mean volume voided per micturition by 18-28% compared to baseline. These data also suggest that tolterodine (2 mg bid) and oxybutinin (5 mg tid) are equivalent, although 5 mg bid was not tested.

Tolterodine does appear to be better tolerated in terms of the most frequently reported side effect, dry mouth. In vitro studies indicate that tolterodine and oxybutinin are equipotent in blocking bladder muscarinic receptors, but tolterodine is eight times less potent than oxybutinin at blocking parotid gland muscarinic receptors.1

Clinical Implications

Urinary incontinence is a common disorder. While it is not associated with increased mortality, it can significantly affect the quality of life. The prevalence is 1.5-5% in men and 10-30% in women between the ages of 15 and 64. Prevalence is over 50% in homebound or institutionalized elderly.4 In 1995, the cost to society of urinary incontinence was estimated to be $26.3 million. Incontinence is classified as stress, urge, or mixed. Detrusor instability results in urge incontinence. Pharmacologic treatment of detrusor overactivity involves blocking muscarinic receptors with drugs such as propantheline and oxybutinin. Unfortunately, the effectiveness of these drugs is limited by anticholinergic side effects such as dry mouth, blurred vision, constipation, and tachycardia. The percent of patients who continue their medication in excess of six months has been reported to be less than 20%.6

Tolterodine offers an antimuscarinic agent with comparable efficacy to oxybutinin but better tissue selectivity for the bladder over the salivary gland. This should improve tolerability and adherence to the treatment regimen, leading to better effectiveness. The wholesale cost for tolterodine 2 mg twice daily is about $1.50 per day.

References

    1. Nilvebrant L, et al. Life Sci 1997;60:1129-1136.

    2. Detrol Product Information. Pharmacia & Upjohn Company. March 1998.

    3. Appell RA. Urology 1997;50(suppl 6A):90-96.

    4. Fantl JA, et al. AHCPR Pub no. 96-0686. 1996.

    5. Wagner TH, et al. Urology 1998;51:355-361.

    6. Kelleher CJ, et al. Br J Obstet Gynaecol 1997;104: 988-993.

    7. Hills CJ, et al. Drugs 1998;55(6):813-820.