A review and additional post-hoc analyses of the incidence and impact of constipation observed in darifenacin clinical trials

Abstract

Background: Constipation is a common side effect of antimuscarinic treatment for overactive bladder (OAB). This review evaluates the incidence and impact of constipation on the lives of patients with OAB being treated with darifenacin.

Methods: Constipation data from published Phase III and Phase IIIb/IV darifenacin studies were reviewed and analyzed. Over 4000 patients with OAB (aged 18-89 years; ≥80% female) enrolled in nine studies (three Phase III [data from these fixed-dose studies were pooled and provide the primary focus for this review], three Phase IIIb, and three Phase IV). The impact of constipation was assessed by discontinuations, use of concomitant laxatives, patient-reported perception of treatment, and a bowel habit questionnaire.

Results: In the pooled Phase III trials, 14.8% (50/337) of patients on darifenacin 7.5 mg/day and 21.3% (71/334) on 15 mg/day experienced constipation compared with 12.6% (28/223) and 6.2% (24/388) with tolterodine and placebo, respectively. In addition, a few patients discontinued treatment due to constipation (0.6% [2/337], 1.2% [4/334], 1.8% [4/223], and 0.3% [1/388] in the darifenacin 7.5 mg/day or 15 mg/day, tolterodine, and placebo groups, respectively), or required concomitant laxatives (3.3% [11/337], 6.6% [22/334], 7.2% [16/223], and 1.5% [6/388] in the darifenacin 7.5 mg/day or 15 mg/day, tolterodine, and placebo groups, respectively). Patient-reported perception of treatment quality was observed to be similar between patients who experienced constipation and those who did not. During the long-term extension study, a bowel habit questionnaire showed only small numerical changes over time in frequency of bowel movements, straining to empty bowels, or number of days with hard stools.

Conclusion: While constipation associated with darifenacin was reported in ≤21% of the patient population, it only led to concomitant laxative use in approximately one-third of these patients and a low incidence of treatment discontinuation. These data suggest that constipation did not impact patient perception of treatment quality.

Keywords: antimuscarinics; overactive bladder; tolerability.

Figure 1

Incidences of constipation (all-causality), new-onset use of constipation remedies and discontinuations resulting from constipation during 12 weeks’ treatment with darifenacin 7.5 mg/day or 15 mg/day, tolterodine 4 mg/day or placebo in patients with overactive bladder. Note: ^†Laxatives, stool softeners or fiber supplements.

Figure 2

Proportion of new cases of all-causality constipation reported at different time points during treatment with darifenacin 7.5 mg/day or 15 mg/day, tolterodine 4 mg/day or placebo.

Figure 3

Patient perception of quality of treatment in fixed-dose Phase III studies in overactive bladder patients. (A) Patient satisfaction with drug; (B) Patient preference for study drug over previous therapy; (C) patient willingness to re-use study drug.

Figure 4

(A) Summary of bowel habit questionnaire responses in patients in a long-term 2-year study; (B) Summary of bowel habit questionnaire responses in patients aged ≥65 years; results relate to the last 2 weeks of treatment. Note: “Feeder study” refers to last visit or last observation carried forward from the feeder study. Abbreviations: BL, baseline; BM, bowel movements; EOS, end of study.