Oxybutynin Chloride Extended Release (Page 4 of 5)

Food Effects

The rate and extent of absorption and metabolism of oxybutynin are similar under fed and fasted conditions.

Distribution

Oxybutynin is widely distributed in body tissues following systemic absorption. The volume of distribution is 193 L after intravenous administration of 5 mg oxybutynin chloride. Both enantiomers of oxybutynin are highly bound (>99%) to plasma proteins. Both enantiomers of N-desethyloxybutynin are also highly bound (>97%) to plasma proteins. The major binding protein is alpha-1 acid glycoprotein.

Metabolism

Oxybutynin is metabolized primarily by the cytochrome P450 enzyme systems, particularly CYP3A4 found mostly in the liver and gut wall. Its metabolic products include phenylcyclohexylglycolic acid, which is pharmacologically inactive, and desethyloxybutynin, which is pharmacologically active. Following Oxybutynin chloride extended-release tablets administration, plasma concentrations of R- and S-desethyloxybutynin are 73% and 92%, respectively, of concentrations observed with oxybutynin.

Excretion

Oxybutynin is extensively metabolized by the liver, with less than 0.1% of the administered dose excreted unchanged in the urine. Also, less than 0.1% of the administered dose is excreted as the metabolite desethyloxybutynin.

Dose Proportionality

Pharmacokinetic parameters of oxybutynin and desethyloxybutynin (Cmax and AUC) following administration of 5 to 20 mg of Oxybutynin chloride extended-release tablets are dose proportional.

Use in Specific Populations

Pediatric

The pharmacokinetics of Oxybutynin chloride extended-release tablets were evaluated in 19 children aged 5 to 15 years with detrusor overactivity associated with a neurological condition (e.g., spina bifida). The pharmacokinetics of Oxybutynin chloride extended-release tablets in these pediatric patients were consistent with those reported for adults (see Tables 2 and 3, and Figures 1 and 2 above).

Gender

There are no significant differences in the pharmacokinetics of oxybutynin in healthy male and female volunteers following administration of Oxybutynin chloride extended-release tablets.

Race

Available data suggest that there are no significant differences in the pharmacokinetics of oxybutynin based on race in healthy volunteers following administration of Oxybutynin chloride extended-release tablets.

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 normalization of body surface area.

Mutagenesis

Oxybutynin chloride showed no increase of mutagenic activity when tested in Schizosaccharomyces pompholiciformis, Saccharomyces 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 (89.0%) 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

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

(-13.6, -2.8)*

(Oxybutynin chloride extended-release tablets- Placebo)

* The difference between Oxybutynin chloride extended-release tablets and placebo was statistically significant.
Covariate adjusted mean with missing observations set to baseline values

Figure 3: Mean Change (±SD) in Urge Incontinence Episodes Per Week from Baseline (Study 1)

figure 3
(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)

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

(-2.8, 6.5)

(Oxybutynin chloride extended-release tablets- oxybutynin)

Covariate adjusted mean with missing observations set to baseline values

Figure 4: Mean Change (±SD) in Urge Urinary Incontinence Episodes Per Week from Baseline (Study 2)

figure 4
(click image for full-size original)

Table 6: Number of Urge Urinary Incontinence Episodes Per Week (Study 3)

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

(-3.0, 1.6)**

(Oxybutynin chloride extended-release tablets- oxybutynin)

** The difference between Oxybutynin chloride extended-release tablets and oxybutynin fulfilled the criteria for comparable efficacy.
Covariate adjusted mean with missing observations set to baseline values

Figure 5: Mean Change (±SD) in Urge Urinary Incontinence Episodes Per Week from Baseline (Study 3)

figure 5
(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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