Mechanism of Action
Oxybutynin is a racemic (50:50) mixture of R- and S- isomers. Antimuscarinic activity resides predominantly with the R-isomer. Oxybutynin acts as a competitive antagonist of acetylcholine at postganglionic muscarinic receptors, resulting in relaxation of bladder smooth muscle. The active metabolite, N-desethyloxybutynin, has pharmacological activity on the human detrusor muscle that is similar to that of oxybutynin in in vitro studies. In patients with conditions characterized by involuntary detrusor contractions, cystometric studies have demonstrated that oxybutynin increases maximum urinary bladder capacity and increases the volume to first detrusor contraction.
Oxybutynin is transported across intact skin and into the systemic circulation by passive diffusion across the stratum corneum. Steady-state concentrations are achieved within 3 days of continuous dosing.
Absorption of oxybutynin is similar when ANTUROL is applied to the abdomen, upper arm/shoulders or thighs. The pharmacokinetic parameters and mean plasma concentrations during a randomized, crossover study of the three recommended application sites in 25 healthy men and women are shown in Table 2 and Figure 1, respectively.
Table 2: Pharmacokinetic Parameters (mean values) for Oxybutynin
(84 mg/day) 3% gel.
|Application Site|| AUC0-t
Figure 1: Mean (including SD) plasma oxybutynin concentrations
versus time after application of ANTUROL to the abdomen (Site A), thigh (Site
B), and upper arm/shoulder (Site C) (N=25).
Oxybutynin is widely distributed in body tissues following systemic absorption. The volume of distribution was estimated to be 193 L after intravenous administration of 5 mg oxybutynin chloride.
Oxybutynin is metabolized primarily by the cytochrome P450 enzyme systems, particularly CYP3A4, found mostly in the liver and gut wall. Metabolites include N-desethyloxybutynin (DEO), which is pharmacologically active and phenylcyclohexylglycolic acid, which is pharmacologically inactive.
Transdermal administration of oxybutynin bypasses the first-pass gastrointestinal and hepatic metabolism, reducing the formation of the N-desethyloxybutynin metabolite. Only small amounts of CYP3A4 are found in skin, limiting pre-systemic metabolism during transdermal absorption. The AUC ratio of N-desethyloxybutynin metabolite to parent compound following multiple transdermal applications is approximately 1:1 for ANTUROL. The apparent half-life was approximately 30 hours.
Oxybutynin undergoes extensive hepatic metabolism, with less than 0.1% of the administered dose excreted unchanged in the urine. Less than 0.1% of the administered dose is excreted as the metabolite N-desethyloxybutynin.
The potential for dermal transfer of oxybutynin from a treated person to an untreated person was evaluated in a single-dose study where subjects dosed with ANTUROL engaged in vigorous contact with an untreated partner for 15 minutes, either with (N=14 couples) or without (N=14 couples) clothing covering the application area. The untreated partners not protected by clothing demonstrated low detectable plasma concentrations of oxybutynin (mean Cmax = 0.65 ng/mL). Only one of the 14 untreated subjects participating in the clothing-to-skin contact regimen had very low measurable oxybutynin plasma concentrations (Cmax = 0.06 ng/mL) during the 24 hours following contact with treated subjects; oxybutynin was not detectable with the remaining 13 untreated subjects. Regardless of the low exposure observed in this study, patients should avoid skin-to-skin contact with partners after applying the gel.
Use of Sunscreen
The effect of sunscreen on the absorption of oxybutynin when applied 30 minutes before or 30 minutes after ANTUROL application was evaluated in a single-dose randomized crossover study (N=20). Concomitant application of sunscreen, either before or after ANTUROL application, had no effect on the systemic exposure of oxybutynin.
The effect of showering on the absorption of oxybutynin was evaluated in a randomized, steady-state crossover study under conditions of no shower, or showering 1, 2 or 6 hours after ANTUROL application (N=22). The results of the study indicate that showering one hour after administration does not affect the overall systemic exposure to oxybutynin.
The effect of race on the pharmacokinetics of ANTUROL has not been studied.
Available data suggest that there are no significant differences in the pharmacokinetics of oxybutynin based on geriatric status in patients following administration of ANTUROL [see Use In Specific Populations].
The pharmacokinetics of oxybutynin and N-desethyloxybutynin following application of ANTUROL has not been evaluated in individuals younger than 18 years of age [see Use In Specific Populations].
Available data suggest that there are no significant differences in the pharmacokinetics of oxybutynin based on gender in healthy volunteers following administration of ANTUROL.
There is limited experience with the use of ANTUROL in patients with renal insufficiency [see Use In Specific Populations].
There is limited experience with the use of ANTUROL in patients with hepatic insufficiency [see Use In Specific Populations].
The efficacy and safety of ANTUROL was evaluated in a single randomized, double-blind, placebo-controlled, multicenter 12-week study in patients with urinary frequency and urge and mixed urinary incontinence with a predominance of urge incontinence episodes. This was followed by an open-label safety extension. Key entry criteria included adults with overactive bladder (OAB) symptoms for at least 3 months who were either treatment-naive or had demonstrated a beneficial response to anticholinergic treatment for OAB. Subjects were randomly assigned to receive 84mg/day oxybutynin, 56mg/day oxybutynin, or placebo. A total of 214 patients received 84mg/day oxybutynin, 210 patients received 56 mg/day oxybutynin, and 202 patients received placebo gel. The majority of patients were Caucasian (87%) and female (87%), with a mean age of 59 years (range: 19 to 89 years). The primary efficacy endpoint was the change from baseline to week 12 in the number of urinary incontinence episodes (UIE) per week, as determined from a 3-day patient daily diary.
Patients treated with ANTUROL (84 mg) experienced a statistically significant decrease in the number of urinary incontinence episodes per week from baseline to endpoint (the primary efficacy endpoint) compared with placebo (p=0.0445) and patients treated with the 56 mg dose did not show statistically significant efficacy. Statistically significant improvements in daily urinary frequency (p=0.0010) and urinary void volume (p < 0.0001) were also seen with ANTUROL (84 mg) relative to placebo. The mean difference from placebo for ANTUROL (84 mg) was -2.3 for urinary incontinence episodes per week in a group of patients with a mean of greater than 40 incontinence episodes per week at baseline. Mean and median change from baseline in weekly incontinence episodes (primary endpoint), daily urinary frequency, and urinary void volume (secondary endpoints) between placebo and ANTUROL are summarized in Table 3.
Table 3: Mean (SD) and median change from baseline to Week
12 in incontinence episodes, urinary frequency, and urinary void volume: Intent-To-Treat
| Anturol Gel (84 mg/day)
|Mean (SD)||Median||Mean (SD)||Median|
|Weekly Urinary Incontinence Episodes|
|Baseline||45.8 (31.87)||40.9||43.6 (27.90)||37.3|
|Reduction||-18.1 (28.81)||-14.0||-20.4 (24.39)||-16.4|
|Mean difference [Anturol - placebo] (SE)||-2.3 (2.65)|
|P-value† vs. placebo||0.0445a|
|Daily Urinary Frequency|
|Baseline||11.5 (3.34)||11.0||11.3 (2.87)||10.7|
|Mean difference [Anturol - placebo] (SE)||-0.7 (0.30)|
|P-value† vs. placebo||0.0010b|
|Urinary Void Volume (mL)|
|Baseline||184.5 (85.71)||173.4||196.9 (88.11)||189.2|
|Increase||9.8 (64.98)||5.7||32.7 (77.25)||26.6|
|Mean difference [Anturol - placebo] (SE)||23.0 (7.24)|
|P-value† vs. placebo||< 0.0001b|
for missing data
†p-value is based on ANCOVA analysis on rank-transformed data
a Comparison is significant if p ≤ 0.05
b Comparison is significant if p ≤ 0.0125, adjusting for multiplicity
Last reviewed on RxList: 1/3/2012
This monograph has been modified to include the generic and brand name in many instances.
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