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 [1]. 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 [2-5].The baseline symptoms described in studies differ between men and women regarding prevalence of incontinence episodes and frequency of urgency episodes [6, 7]. 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 [8]. Two other meta-analyses report that changes from baseline with placebo treatment are significant for mean micturitions, mean incontinence episodes and mean voided volume [9, 10].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 analyses.

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 were 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 compared to men. This was not considered to be clinically significant [13].espite the small 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, 14].

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 of micturations, 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 these patients remained at the higher dose of 8 mg throughout the study [15].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 [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, fesoterodine 8 mg  significantly improved urgency episodes and diary dry rates compared to tolterodine or placebo. In men, 8 mg fesoterodine significantly improved severe urgency episodes and OAB-q scores compared with tolterodine, and micturations, urgency episodes, severe urgency episodes, frequency–urgency sum and PPBC scores compared with placebo [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].

Adverse effects

Pooled data from two double-blinded studies [17] shows that total adverse reactions were slightly higher in women, but treatment discontinuation due to adverse reactions were similar. Also, the levels of the most common anticholinergic-associated adverse reactions, dry mouth and constipation were similar between men and women.The risk of dementia among anticholinergic (overactive bladder medication) users (21058 men, 26266 women) compared to beta-3 agonist users (10529 men, 13133 women) was increased in men (HR 1.41; 95%CI 1.23-1.62) but not in women (HR 1.08; 95%CI 0.95-1.23) [19].

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 [20].

Patterns of adherence and persistence, and the need for dose escalation of anticholinergic drugs depend on the population studied and type of study [21-27].