Tolterodin

Additional information

Anticholinergic drugs reduce the bladder detrusor muscle contractions and are used to treat urgency incontinence and symptoms of overactive bladder. Due to sex differences in etiology of these symptoms, drug therapy differs as urinary retention must be ruled out before starting treatment with anticholinergic drugs. In women,anticholinergic drugs are commonly used when non-pharmacological treatments such as bladder training are insufficient. In men, benign prostate hyperplasia is a common cause of urgency symptoms. Non-anticholinergic drugs, primarily alpha-1 blockers, are therefore often used as first-line treatment in men even though anticholinergic drugs are used in addition or as monotherapy [1-3].

The baseline symptoms described in studies differ between men and women regarding prevalence of incontinence episodes and frequency of urgency episodes [4, 5]. Treatment effects on these parameters are common outcomes in clinical studies and differences in treatment effect between men and women need to be interpreted in relation to differences at baseline. The placebo effect seen in clinical studies of overactive bladder treatment is relatively high. According to a meta-analysis, 41% of the patients in placebo groups report cure or symptom improvement [6]. Two other meta-analysis report that changes from baseline with placebo treatment are significant for mean micturitions, mean incontinence episodes and mean voided volume [7, 8].

It should be noted that most studies include more women than men, and the low number of men included can affect the ability to make statistically significant analysis.

Pharmacokinetics and dosing

Three studies (37 men, 30 women) conducted by the manufacturer show no significant differences in pharmacokinetic parameters for tolterodine or the active metabolite DD 01 between men and women after a single 2 mg dose. No sex differentiation in dosing has been recommended by the manufacturer [10, 11].

Effects

Efficacy and tolerability of extended release tolterodine in patients with overactive bladder was evaluated in two randomized placebo-controlled studies (745 men, 953 women).  At baseline, 73% of the men and 57% of the women were continent. There were differences in number of micturitions, both total and related to overactive bladder, and number of incontinence episodes between men and women at baseline. In both men and women tolterodine compared to placebo reduced total micturitions, both those related to urgency and severe overactive bladder micturitions [13].

Urgency perception in patients with overactive bladder was analyzed in a placebo-controlled double-blind study (123 men, 649 women). Notably, men in both tolterodine and placebo groups experienced similar improvements in urgency perception, whereas in women the effect was better in the tolterodine group. For perceived effect on bladder symptoms, the difference in effect between tolterodine and placebo was only significant in women [15].An observational post-marketing surveillance study in Germany (520 men, 1730 women) found no difference between men and women regarding voiding frequency or urgency. However, men had a higher likelihood of successful treatment of incontinence but less favorable rating of global efficacy [14].

The speed of onset of treatment effect of tolterodine did not differ between men and women with overactive bladder, when comparing patients with or without previous treatment (302 men, 836 women) [16].

Pooled data from two randomized double-blind studies compared the effect of fesoterodine, tolterodine extended release, or placebo for 12 weeks in patients with urinary incontinence or urgency (673 men, 3435 women). In women tolterodine treatment gave significant improvement in diary dry rate and all bladder diary variables except nocturnal micturations compared to placebo. Both men and women had good effect of the treatment even though the improvement differed between parameters [17]. In another analysis based on the same material (643 men, 3191 women) women had generally larger improvements in outcome in symptom bother, health-related quality of life, reduction of urgency episodes and micturitions [18]. 

In one open label study on patient reported treatment effect on their most bothersome symptom (155 men, 708 women) no difference between men and women was found after 12 weeks of treatment [19].

Adverse effects

In an analysis from two studies of extended release tolterodine the levels of total adverse effect, dry mouth (10.8% in men, 11.7% in women) and constipation (2.2% in men 3.4% in women) was comparable between men and women. The incidence of headache was higher in women (1.1% in men 3.6% in women), however it was not different from the level in the placebo group (1.3% in men 4.0% in women) [13].

Reported adverse events in a  post-marketing surveillance study in Germany (520 men, 1730 women) were low and no analysis of influence of sex differences was done on specific symptoms. Instead an analysis of global tolerability was performed that revealed no association with patient sex [14].

In a retrospective register study of patient reported but not evaluated adverse reactions on anticholinergic medication (11296 men, 21839 women, of which 11670 patients used tolterodin) men were more likely to report of cardiovascular or cerebrovascular side effects of varying severity  [20].

Reproductive health issues

Regarding teratogenic aspects, please consult the Drugs and Birth Defects Database (in Swedish, Janusmed fosterpåverkan).

Other information

Patient satisfaction with anticholinergic treatment was evaluated in a survey study in Japanese patients with overactive bladder syndrome (in total 514 men, 455 women). In the entire study one third of all patients were satisfied and one third dissatisfied with their treatment, men were overall less satisfied than women. Dissatisfaction was commonly influenced by poor efficacy or adverse effects, mainly constipation [9].In a Swedish register study of the prescription of potentially inappropriate drugs in elderly patients, women were more likely to be prescribed anticholinergic drugs then men [10].A German database study (26,834 patients, 1814 treated with tolterodin) evaluated discontinuation rate of anticholinergic drugs in patients with urinary incontinence. Discontinuation rate for all drugs was 75% in women and 78% in men in the first year and 86% in women and 88% in men within three years. After adjusting for demographic and clinical variables, the risk of discontinuation was higher in men [21]. In contrast to this, another retrospective study of persistence with first line anticholinergic treatment in treatment naïve patients (52 men, 325 women, 9 patients treated with tolterodine) the persistence was 27% after 12 months without any difference between men and women [22].In a database study of medication adherence for tolterodine and oxybutynin for treatment of overactive bladder (2357 men, 5501 women in all of which 5708 were treated with tolterodine) no difference was seen between men and women for non-persistence or switch rate. Men had higher median medication possession ratio, defined as total days of medication dispensed except for last refill divided by number of days between first dispense and last refill, for all medications [23].