Fesoterodine

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

In the manufacturer’s report to FDA no sex differences in the pharmacokinetics of fesoterodine are reported from the Phase I studies [11].In a randomized study (12 young men, 12 elderly men, 12 elderly women) no clinically relevant differences in pharmacokinetics between men and women was seen. Residual urinary volume was higher in men than in women eight hours after dosing (elderly men 85 ml, young men 55 ml, elderly women 29 ml) [12].Pooled results from 10 pharmacokinetic studies and 3 efficacy/safety studies showed a 10% lower apparent oral clearance of the active fesoterodine metabolite 5-hydroxymethyl tolterodine in women. This was considered not to be clinically significant [13].

Despite the pharmacokinetic differences of fesoterodine, the clinical studies have shown effect with similar doses in men and women, and no sex differentiation in dosing has been suggested [11].

Effects

In a post hoc analysis of two open label extension studies long term safety, efficacy and tolerability of fesoterodine treatment was compared in men and women (185 men, 705 women). In both groups improvement in number of micturation episodes, urgency episodes and urgency incontinence episodes were found up to 24 months. However, only 45% of the men and 50% of the women continued the treatment for >24 months. The majority of patients who continued with treatment remained at the higher dose of 8 mg throughout the study [14].

Data from two open label extension studies (182 men, 682 women) was analyzed for effect of long term (24 months) treatment with fesoterodine. Women had better outcome in the scales in the KHQ (Kings Health Questionnaire) for emotion, severity/coping and in ICIQ-SF (International Consultation on Incontinence Questionnaire–Short Form) scores than men [15].

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 [16].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 [17].

Adverse effects

Pooled data from two double-blinded studies [16] shows that total adverse effects were slightly higher in women, but treatment discontinuation due to adverse effects were similar. Also the levels of the most common anticholinergic-associated adverse effects, dry mouth and constipation were similar between men and women.

Reproductive health issues

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (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 registry study (in all 26 834 patients, 811 treated with fesoterodine) 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 [18]. In contrast to this, another retrospective study of persistence with first line anticholinergic treatment in treatment naïve patients (52 men, 325 women, 90 patients treated with fesoterodin) the persistence was 27% after 12 months without any difference between men and women [19].

In an open label study in patients with overactive bladder symptoms treated with fesoterodine for 12 weeks (starting dose 4 mg with the option for dose escalation) (68 men, 263 women) no association between patient sex and dose escalation was seen [20]. In contrast to this, a post hoc analysis of data from a 12 week randomized placebo controlled study of the effect of fesoterodine in patients over 65 years (249 men, 536 women), male sex was shown to be associated with a greater change in dose escalation at week 4 [21].