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Mechanism of Action
Oxybutynin acts as a competitive antagonist of acetylcholine at postganglionic muscarinic receptors, resulting in relaxation of bladder smooth muscle. Oxybutynin is a racemic (50:50) mixture of R- and S- isomers. Antimuscarinic activity resides predominantly with the R- isomer. The active metabolite, Ndesethyloxybutynin, has pharmacological activity on the human detrusor muscle that is similar to that of oxybutynin in in vitro studies.
Oxybutynin is transported across intact skin and into the systemic circulation by passive diffusion across the stratum corneum. Steady-state concentrations are achieved within 7 days of continuous dosing. Absorption of oxybutynin is similar when GELNIQUE is applied to the abdomen, upper arm/shoulders or thighs. Mean plasma concentrations during a randomized, crossover study of the three recommended application sites in 39 healthy men and women are shown in Figure 1.
Figure 1: Mean (+ SD) plasma oxybutynin concentrations
during steady-state application of GELNIQUE to the abdomen, upper arm/shoulder
and thigh (N=39).
Average steady-state plasma oxybutynin concentrations were 4.7, 5.2, and 5.5 ng/mL for the abdomen, upper arm/shoulder and thigh application sites, respectively (Table 2).
Table 2: Mean (SD) steady-state pharmacokinetic
parameters for oxybutynin following GELNIQUE application to the abdomen, upper arm/shoulder
and thigh (N=39).
|Application Site||AUC0-24 (ng•hr/mL)||Cmax (ng/mL)||Cavg (ng/mL)|
|Abdomen||112.7 (58.00)||6.8 (3.93)||4.7 (2.39)|
|Upper Arm/Shoulder||133.8 (81.58)||8.3 (5.97)||5.5 (3.37)|
|Thigh||125.1 (84.67)||7.0 (4.95)||5.2 (3.50)|
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 phenylcyclohexylglycolic acid, which is pharmacologically inactive, and N-desethyloxybutynin (DEO), which is pharmacologically active.
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 GELNIQUE.
Following intravenous administration, the elimination half-life of oxybutynin is approximately 2 hours. After the final steady-state dose of GELNIQUE, oxybutynin and N-desethyloxybutynin demonstrated biphasic elimination with plasma concentrations beginning to decrease 24 hours after dosing. Elimination was more rapid between 24 and 48 hours after dosing, during which time plasma concentrations of oxybutynin and Ndesethyloxybutynin declined by about one-half. This rapid elimination phase was followed by a more prolonged terminal elimination phase. The apparent elimination half-lives including the terminal elimination phase were 64 hours and 82 hours for oxybutynin and DEO, respectively.
Oxybutynin is extensively metabolized by the liver, 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 Ndesethyloxybutynin.
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 GELNIQUE engaged in vigorous contact with an untreated partner for 15 minutes, either with (N=14 couples) or without (N=12 couples) clothing covering the application area. The untreated partners not protected by clothing demonstrated detectable plasma concentrations of oxybutynin (mean Cmax = 0.94 ng/mL). Two of the 14 untreated subjects participating in the clothing-to-skin contact regimen had measurable oxybutynin plasma concentrations (Cmax < 0.1 ng/mL) during the 48 hours following contact with treated subjects; oxybutynin was not detectable with the remaining 12 untreated subjects.
Use of Sunscreen
The effect of sunscreen on the absorption of oxybutynin when applied 30 minutes before or 30 minutes after GELNIQUE application was evaluated in a single-dose randomized crossover study (N=16). Concomitant application of sunscreen, either before or after GELNIQUE 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 GELNIQUE application (N=20). The results of the study indicate that showering after one hour does not affect the overall systemic exposure to oxybutynin.
The effect of race on the pharmacokinetics of GELNIQUE has not been studied.
Geriatric: Available data suggest that there are no significant differences in the pharmacokinetics of oxybutynin based on geriatric status in patients following administration of GELNIQUE [see Use in Specific Populations].
Pediatric: The pharmacokinetics of oxybutynin and N-desethyloxybutynin have not been evaluated in individuals younger than 18 years of age [see Use In Specific Populations].
Gender: Available data suggest that there are no significant differences in the pharmacokinetics of oxybutynin based on gender in healthy volunteers following administration of GELNIQUE.
Renal Impairment: The effect of renal impairment on the pharmacokinetics of GELNIQUE has not been studied.
Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of GELNIQUE has not been studied.
The efficacy and safety of GELNIQUE were evaluated in a single randomized, double-blind, placebo-controlled, parallel group 12-week study for the treatment of overactive bladder with symptoms of urge incontinence, urgency and frequency. Key entry criteria included adults with symptomatic overactive bladder with an average of ≥ 4 incontinence episodes in a 3-day period and at least 8 micturitions per day. Patients were randomized to daily applications of GELNIQUE 1 gram or matching placebo gel. A total of 389 patients received GELNIQUE and 400 patients received placebo gel. The majority of patients were Caucasian (86.3%) and female (89.2%), with a mean age of 59.4 years (range: 18 to 88 years). The average duration of urinary incontinence was approximately 8.5 years and approximately 75% of patients had no prior pharmacological treatment for urinary incontinence.
Patients treated with GELNIQUE experienced a statistically significant decrease in the number of urinary incontinence episodes per day from baseline to endpoint compared with placebo (p < 0.0001) as well as a decrease in the average daily urinary frequency (p=0.0017) and an increase in the average urine volume per void (p=0.0018).
Mean and median change from baseline in daily incontinence episodes (primary endpoint), urinary frequency, and urinary void volume (secondary endpoints) between placebo and GELNIQUE are summarized in Table 3.
Table 3: Mean and median change from baseline for
incontinence episodes, urinary frequency, and urinary void volume at Week 12
|GELNIQUE 1 gram
|Mean (SD)||Median||Mean (SD)||Median|
|Daily Incontinence Episodes|
|Baseline||5.4 (3.26)||4.7||5.4 (3.28)||4.7|
|Change from baseline||-3.0 (2.73)||-2.7||-2.5 (3.06)||-2.0|
|Mean difference [GELNIQUE – placebo] (95% CI)||-0.5 (-0.14, -0.87)|
|P-value vs. placebo||< 0.0001|
|Daily Urinary Frequency|
|Baseline||12.4 (3.34)||11.7||12.2 (3.32)||11.3|
|Change from baseline||-2.7 (3.21)||-2.7||-2.0 (2.82)||-1.7|
|P-value vs. placebo||0.0017|
|Urinary Void Volume (mL)|
|Baseline||163.4 (65.85)||160.1||167.9 (68.40)||160.6|
|Change from Baseline||21.0 (65.33)||11.5||3.8 (53.79)||0.0|
|P-value vs. placebo||0.0018|
|*Last-Observation-Carried-Forward statistical imputation for missing data|
Last reviewed on RxList: 10/18/2012
This monograph has been modified to include the generic and brand name in many instances.
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