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The free base form of oxybutynin is pharmacologically equivalent to oxybutynin hydrochloride. 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 thus decreases urinary urgency and the frequency of both incontinence episodes and voluntary urination.

Oxybutynin is a racemic (50:50) mixture of R- and S-isomers. Antimuscarinic activity resides predominantly in 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. The average daily dose of oxybutynin absorbed from the 39 cm² OXYTROL (oxybutynin transdermal) system is 3.9 mg. The average (SD) nominal dose, 0.10 (0.02) mg oxybutynin per cm² surface area, was obtained from analysis of residual oxybutynin content of systems worn over a continuous 4-day period during 303 separate occasions in 76 healthy volunteers. Following application of the first OXYTROL 3.9 mg/day system, oxybutynin plasma concentration increases for approximately 24 to 48 hours, reaching average maximum concentrations of 3 to 4 ng/mL. Thereafter, steady concentrations are maintained for up to 96 hours. Absorption of oxybutynin is bioequivalent when OXYTROL (oxybutynin transdermal) is applied to the abdomen, buttocks, or hip. Average plasma concentrations measured during a randomized, crossover study of the three recommended application sites in 24 healthy men and women are shown in Figure 2.

Figure 2: Average plasma oxybutynin concentrations (Cp) in 24 healthy male and female volunteers during single-dose application of OXYTROL (oxybutynin transdermal) 3.9 mg/day to the abdomen, buttock, and hip (System removal at 96 hours).

Steady-state conditions are reached during the second OXYTROL (oxybutynin transdermal) application. Average steady-state plasma concentrations were 3.1 ng/mL for oxybutynin and 3.8 ng/mL for Ndesethyloxybutynin (Figure 3). Table 1 provides a summary of pharmacokinetic parameters of oxybutynin in healthy volunteers after single and multiple applications of OXYTROL (oxybutynin transdermal) .

Figure 3: Average (SEM) steady-state oxybutynin and N-desethyloxybutynin plasma concentrations (Cp) measured in 13 healthy volunteers following the second transdermal system application in a multiple-dose, randomized, crossover study.

Table 1: Mean (SD) oxybutynin pharmacokinetic parameters from single and multiple dose studies in healthy men and women volunteers after application of OXYTROL (oxybutynin transdermal) on the abdomen.

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 CYP3A4, found mostly in the liver and gut wall. Metabolites include phenylcyclohexylglycolic acid, which is pharmacologically inactive, and Ndesethyloxybutynin, which is pharmacologically active.

After oral administration of oxybutynin, pre-systemic first-pass metabolism results in an oral bioavailability of approximately 6% and higher plasma concentration of the Ndesethyl metabolite compared to oxybutynin (see Figure 4). The plasma concentration AUC ratio of N-desethyl metabolite to parent compound following a single 5 mg oral dose of oxybutynin chloride was 11.9:1.

Transdermal administration of oxybutynin bypasses the first-pass gastrointestinal and hepatic metabolism, reducing the formation of the N-desethyl metabolite (see Figure 4). Only small amounts of CYP3A4 are found in skin, limiting pre-systemic metabolism during transdermal absorption. The resulting plasma concentration AUC ratio of Ndesethyl metabolite to parent compound following multiple OXYTROL (oxybutynin transdermal) applications was 1.3:1.

Figure 4: Average plasma concentrations (Cp) measured after a single, 96-hour application of the OXYTROL (oxybutynin transdermal) 3.9 mg/day system (AUCinf/96) and a single, 5 mg, oral immediate-release dose of oxybutynin chloride (AUCinf/8) in 16 healthy male and female volunteers.

Following intravenous administration, the elimination half-life of oxybutynin is approximately 2 hours. Following removal of OXYTROL, plasma concentrations of oxybutynin and N-desethyloxybutynin decline with an apparent half-life of approximately 7 to 8 hours.

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 N-desethyloxybutynin.

Special Populations

Geriatric: The pharmacokinetics of oxybutynin and N-desethyloxybutynin were similar in all patients studied.

Pediatric: The pharmacokinetics of oxybutynin and N-desethyloxybutynin were not evaluated in individuals younger than 18 years of age. See PRECAUTIONS: Pediatric Use.

Gender: There were no significant differences in the pharmacokinetics of oxybutynin in healthy male and female volunteers following application of OXYTROL (oxybutynin transdermal) .

Race: Available data suggest that there are no significant differences in the pharmacokinetics of oxybutynin based on race in healthy volunteers following administration of OXYTROL (oxybutynin transdermal) . Japanese volunteers demonstrated a somewhat lower metabolism of oxybutynin to N-desethyloxybutynin compared to Caucasian volunteers.

Renal Insufficiency: There is no experience with the use of OXYTROL (oxybutynin transdermal) in patients with renal insufficiency.

Hepatic Insufficiency: There is no experience with the use of OXYTROL (oxybutynin transdermal) in patients with hepatic insufficiency.

Drug-Drug Interactions: See PRECAUTIONS: DRUG INTERACTIONS.

Adhesion

Adhesion was periodically evaluated during the Phase 3 studies. Of the 4,746 OXYTROL (oxybutynin transdermal) evaluations in the Phase 3 trials, 20 (0.4%) were observed at clinic visits to have become completely detached and 35 (0.7%) became partially detached during routine clinic use. Similar to the pharmacokinetic studies, > 98% of the systems evaluated in the Phase 3 studies were assessed as being ≥ 75% attached and thus would be expected to perform as anticipated.

Clinical Studies

The efficacy and safety of OXYTROL (oxybutynin transdermal) were evaluated in patients with urge urinary incontinence in two Phase 3 controlled studies and one open-label extension. Study 1 was a Phase 3, placebo controlled study, comparing the safety and efficacy of OXYTROL (oxybutynin transdermal) at dose levels of 1.3, 2.6, and 3.9 mg/day to placebo in 520 patients. Open-label treatment was available for patients completing the study. Study 2 was a Phase 3 study, comparing the safety and efficacy of OXYTROL (oxybutynin transdermal) 3.9 mg/day versus active and placebo controls in 361 patients.

Study 1 was a randomized, double-blind, placebo-controlled, parallel group study of three dose levels of OXYTROL (oxybutynin transdermal) conducted in 520 patients. The 12-week double-blind treatment included OXYTROL (oxybutynin transdermal) doses of 1.3, 2.6, and 3.9 mg/day with matching placebo. An open-label, dose titration treatment extension allowed continued treatment for up to an additional 40 weeks for patients completing the double-blind period. The majority of patients were Caucasian (91%) and female (92%) with a mean age of 61 years (range, 20 to 88 years). Entry criteria required that patients have urge or mixed incontinence (with a predominance of urge), urge incontinence episodes of ≥ 10 per week, and ≥ 8 micturitions per day. The patient's medical history and a urinary diary during the treatment-free baseline period confirmed the diagnosis of urge incontinence. Approximately 80% of patients had no prior pharmacological treatment for incontinence. Reductions in weekly incontinence episodes, urinary frequency, and urinary void volume between placebo and active treatment groups are summarized in Table 2.

Table 2: Mean and median change from baseline to end of treatment (Week 12 or last observation carried forward) in incontinence episodes, urinary frequency, and urinary void volume in patients treated with OXYTROL (oxybutynin transdermal) 3.9 mg/day or placebo for 12 weeks (Study 1).

Study 2 was a randomized, double-blind, double-dummy, study of OXYTROL (oxybutynin transdermal) 3.9 mg/day versus active and placebo controls conducted in 361 patients. The 12-week double-blind treatment included an OXYTROL (oxybutynin transdermal) dose of 3.9 mg/day, an active comparator, and placebo. The majority of patients were Caucasian (95%) and female (93%) with a mean age of 64 years (range, 18 to 89 years). Entry criteria required that all patients have urge or mixed incontinence (with a predominance of urge) and had achieved a beneficial response from the anticholinergic treatment they were using at the time of study entry. The average duration of prior pharmacological treatment was greater than 2 years. The patient's medical history and a urinary diary during the treatment-free baseline period confirmed the diagnosis of urge incontinence. Reductions in daily incontinence episodes, urinary frequency, and urinary void volume between placebo and active treatment groups are summarized in Table 3.

Table 3: Mean and median change from baseline to end of treatment (Week 12 or last observation carried forward) in incontinence episodes, urinary frequency, and urinary void volume in patients treated with OXYTROL (oxybutynin transdermal) 3.9 mg/day or placebo for 12 weeks (Study 2).

Last reviewed on RxList: 3/18/2011
This monograph has been modified to include the generic and brand name in many instances.