Oxybutynin (Page 4 of 5)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

A 24 month study in rats at dosages of oxybutynin chloride of 20, 80, and 160 mg/kg/day showed no evidence of carcinogenicity. These doses are approximately 6, 25, and 50 times the maximum human exposure, based on a human equivalent dose taking into account normalizationof body surface area.

Mutagenesis

Oxybutynin chloride showed no increase of mutagenic activity when tested in Schizosaccharomyces pompholiciformis, Sacchar omyces cerevisiae, and Salmonella typhimurium test systems.

Impairment of Fertility

No impairment of fertility was seen in rats at dosages up to 75 mg/kg/day (24 times the MRHD on a mg/m2 basis) when administered for 2 weeks prior to mating in females and for 9 weeks prior to mating in males.

14 CLINICAL STUDIES

Oxybutynin chloride extended-release tablets were evaluated for the treatment of patients with overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency in three controlled efficacy studies. The majority of patients were Caucasian (89%) and female (91.9%) with a mean age of 59 years (range, 18 to 98 years). Entry criteria required that patients have urge or mixed incontinence (with a predominance of urge) as evidenced by ≥ 6 urge incontinence episodes per week and ≥ 10 micturitions per day. Study 1 was a fixed-dose escalation design, whereas the other two studies used a dose-adjustment design in which each patient’s final dose was adjusted to a balance between improvement of incontinence symptoms and tolerability of side effects. All three studies included patients known to be responsive to oxybutynin or other anticholinergic medications, and these patients were maintained on a final dose for up to 2 weeks.

The efficacy results for the three controlled trials are presented in the following Tables 4, 5, and 6 and Figures 3, 4, and 5.

Table 4 Number of Urge Urinary Incontinence Episodes Per Week (Study 1)

* The difference between oxybutynin chloride extended-release tablets and placebo was statistically significant.

Covariate adjusted mean with missing observations set to baseline values.

Study 1 n Oxybutynin Chloride Extended-Release Tablets n Placebo
Mean Baseline 34 15.9 16 20.9
Mean (SD) Change from Baseline 34 -15.8 (8.9) 16 -7.6 (8.6)
95% Confidence Interval for Difference (Oxybutynin chloride extended-release Tablets -Placebo) (-13.6, -2.8)*

Figure 3

Mean Change (±SD) in Urge Urinary Incontinence Episodes Per Week from Baseline (Study 1)

Study 1
(click image for full-size original)

*The difference between oxybutynin chloride extended-release tablets and placebo was statistically significant.

Table 5 Number of Urge Urinary Incontinence Episodes Per Week (Study 2)

Covariate adjusted mean with missing observations set to baseline values

Study 2 n Oxybutynin Chloride Extended-Release Tablets n Oxybutynin
Mean Baseline 53 27.6 52 23.0
Mean (SD) Change from Baseline 53 -17.6 (11.9) 52 -19.4 (11.9)
95% Confidence Interval for Difference (Oxybutynin chloride extended-release tablets – oxybutynin) (-2.8, 6.5)

Figure 4

Mean Change (±SD) in Urge Urinary Incontinence Episodes Per Week from Baseline (Study 2)

Study 2
(click image for full-size original)
Table 6 Number of Urge Urinary Incontinence Episodes Per Week (Study 3)

** The difference between oxybutynin chloride extended-release tablets and oxybutynin fulfilled the criteria for comparable efficacy.

Convariate adjusted mean with missing observations set to baseline values

Study 3 n Oxybutynin Chloride Extended-Release Tablets n Oxybutynin
Mean Baseline 111 18.9 115 19.5
Mean (SD) Change from Baseline 111 -14.5 (8.7) 115 -13.8 (8.6)
95% Confidence Interval for Difference (Oxybutynin chloride Extended-release tablets – oxybutynin) (-3.0, 1.6)**

Figure 5

Mean Change (±SD) in Urge Urinary Incontinence Episodes Per Week from Baseline (Study 3)

Study 3
(click image for full-size original)

**The difference between oxybutynin chloride extended-release tablets and oxybutynin fulfilled the criteria for comparable efficacy.

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