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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. 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 a racemic (50:50) mixture of R- and S- isomers. Antimuscarinic activity resides predominantly with the R-isomer. The active metabolite, N-desethyloxybutynin, has pharmacological activity on the human detrusor muscle that is similar to that of oxybutynin in in vitro studies.

Pharmacokinetics

Absorption

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 (oxybutynin chloride 10 % gel) 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 (oxybutynin chloride 10 % gel) 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 (oxybutynin chloride 10 % gel) application to the abdomen, upper arm/shoulder and thigh (N=39).

Distribution

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.

Metabolism

Oxybutynin is metabolized primarily by the cytochrome P450 enzyme systems, particularly CYP3 A4, 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 (oxybutynin chloride 10 % gel) .

Following intravenous administration, the elimination half-life of oxybutynin is approximately 2 hours. After the final steady-state dose of GELNIQUE (oxybutynin chloride 10 % gel) , 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 N-desethyloxybutynin 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.

Excretion

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 N-desethyloxybutynin.

Person-to-Person Transference

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 (oxybutynin chloride 10 % gel) 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 (oxybutynin chloride 10 % gel) application was evaluated in a single-dose randomized crossover study (N=16). Concomitant application of sunscreen, either before or after GELNIQUE (oxybutynin chloride 10 % gel) application, had no effect on the systemic exposure of oxybutynin.

Showering

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 (oxybutynin chloride 10 % gel) application (N=20). The results of the study indicate that showering after one hour does not affect the overall systemic exposure to oxybutynin.

Race

The effect of race on the pharmacokinetics of GELNIQUE (oxybutynin chloride 10 % gel) has not been studied.

Geriatric Patients

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 Patients

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 (oxybutynin chloride 10 % gel) .

Renal Impairment

There is no experience with the use of GELNIQUE (oxybutynin chloride 10 % gel) in patients with renal insufficiency.

Hepatic Impairment

There is no experience with the use of GELNIQUE (oxybutynin chloride 10 % gel) in patients with hepatic insufficiency.

Clinical Studies

The efficacy and safety of GELNIQUE (oxybutynin chloride 10 % gel) 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 (oxybutynin chloride 10 % gel) 1 gram or matching placebo gel. A total of 389 patients received GELNIQUE (oxybutynin chloride 10 % gel) 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 (oxybutynin chloride 10 % gel) experienced a statistically significant decrease in the number of urinary incontinence episodes per day from baseline to endpoint (the primary efficacy 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 (oxybutynin chloride 10 % gel) 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 (LOCF*).

Last reviewed on RxList: 3/28/2011
This monograph has been modified to include the generic and brand name in many instances.