Data reveal a dose-response relationship.


MILAN—New data demonstrate that the investigational agent fesoterodine, at both the 4 or 8 mg per day dose, is associated with significant improvements in overactive bladder (OAB) symptoms.

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“The finding that both doses are effective allows for flexibility and treatment individualization in men and women with OAB,” the researchers led by Vic Khullar, MD, concluded. They reported their findings here at the European Association of Urology’s 23rd annual congress. Dr. Khullar is a consultant urogynecologist at St. Mary’s Hospital in London.


The new data are from a pooled analysis of 1,674 patients with frequency and urgency or urgency urinary incontinence who had been randomized to fesoterodine 8 mg/day, fesoterodine 4 mg/day, or placebo for 12 weeks in two phase III trials. 


Fesoterodine is a nonselective oral antimuscarinic agent that has been shown to improve OAB symptoms. The agent is rapidly hydrolyzed by nonspecific esterases to the active metabolite 5-hydroxymethyl tolterodine. After oral dosing, the parent compound is not detectable in plasma.

It has been unclear whether high doses of antimuscarinic agents produce increased efficacy, so dose escalation has not become routine in clinical practice, Dr. Khullar’s group pointed out. One reason may be that earlier fixed-dose studies with some antimuscarinic agents did not show a clear efficacy dose-response in parallel dosing studies. Another reason is concern about the potential for increased adverse events.


Participants in the two trials were at least 18 years of age and had OAB syndrome for at least six months. OAB syndrome referred to urinary frequency (at least eight micturitions over 24 hours) and urinary urgency (at least six episodes during the three-day diary period) or urgency urinary incontinence (UUI), defined as at least three episodes during the three-day diary period.


Subjects also had moderate bladder problems confirmed on a six-point Likert scale. In each trial, subjects completed three-day bladder diaries at baseline and two and 12 weeks after starting treatment. The primary efficacy end points included diary variables and treatment response based on a four-point Treatment Benefit scale.


By the second week, reductions in UUI episodes, micturition frequency, mean volume voided, urgency epi-sodes, and continent days per week were significantly improved compared with placebo with both doses of fesoterodine.  


Similarly, by the end of treatment, both fesoterodine doses were associated with statistically significant improvements in all efficacy end points compared with placebo. Median percent reductions in UUI episodes for incontinent patients were 58%, 43%, and 23% for the 8-mg,

4-mg, and placebo groups, respectively.


High dose more effective

As regards a dose-response relationship, higher-dose fesoterodine was significantly more effective than lower-dose fesoterodine in improving many important diary variables, including UUI episodes (58% vs. 43%, 8 mg vs. 4 mg, respectively), increases in mean voided volume (33.6% vs. 22.2%, 8 mg vs. 4 mg, respectively, and improvement in continent days per week (3.1 vs. 2.6, 8 mg vs. 4 mg, respectively).  


The most frequent treatment-related adverse events with fesoterodine 4 mg included dry mouth in 19% of patients and constipation in 4%. In the 8 mg group, dry mouth occurred in 35% of patients and constipation occurred in 6%. The figures for placebo-treated patients were 7% and 2%, respectively. Most instances of dry mouth and constipation were mild to moderate in all patients who reported these side effects.


“These data are important in that for the first time an antimuscarinic has demonstrated a definite dose-response relationship in the relief of OAB symptoms,” said coauthor Eric Rovner, MD, associate professor of urology at the Medical University of South Carolina in Charleston.