OXYTROL Oxybutynin 3.9 mg/d Patch — NDC 0023-6153-08 (Billing 00023-6153-08)

12 CLINICAL PHARMACOLOGY Figure 2: Average plasma oxybutynin concentrations (Cp) in 24 healthy male and female volunteers during single-dose application of OXYTROL 3.9 mg/day to the abdomen, buttock, and hip (Transdermal System removal at 96 hours). 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. Figure 4: Average plasma concentrations (Cp) measured after a single, 96-hour application of the OXYTROL 3.9 mg/day transdermal system (AUCinf/96) and a single, 5 mg, oral immediate-release dose of oxybutynin chloride (AUCinf/8) in 16 healthy male and female volunteers.

12.1Mechanism of Action 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 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.

12.3Pharmacokinetics 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 cm 2 OXYTROL transdermal system is 3.9 mg. The average (SD) nominal dose, 0.10 (0.02) mg oxybutynin per cm 2 surface area, was obtained from analysis of residual oxybutynin content of transdermal 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 transdermal system, oxybutynin plasma concentrations increase 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 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 3.9 mg/day to the abdomen, buttock, and hip ( Transdermal System removal at 96 hours). Steady-state conditions are reached during the second OXYTROL application.

Average steady-state plasma concentrations were 3.1 ng/mL for oxybutynin and 3.8 ng/mL for N-desethyloxybutynin (Figure 3). Table 3 provides a summary of pharmacokinetic parameters of oxybutynin in healthy volunteers after single and multiple applications of OXYTROL. 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 3: Mean (SD) oxybutynin pharmacokinetic parameters from single and multiple dose studies in healthy men and women volunteers after application of OXYTROL on the abdomen. Dosing Oxybutynin C max (SD) (ng/mL) T max 1 (hr) C avg (SD) (ng/mL) AUC (SD) (ng/mLxh) Single 3.0 (0.8) 48 - 245 (59) 2 3.4 (1.1) 36 - 279 (99) 2 Multip le 6.6 (2.4) 10 4.2 (1.1) 408 (108) 3 4.2 (1.0) 28 3.1 (0.7) 259 (57) 4 1 T max given as median 2 AUC inf 3 AUC 0-96 4 AUC 0-84 Distribution Oxybutynin is widely distributed in body tissues following systemic absorption.

The volume of distribution was estimate… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action 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 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.

12.3Pharmacokinetics 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 cm 2 OXYTROL transdermal system is 3.9 mg. The average (SD) nominal dose, 0.10 (0.02) mg oxybutynin per cm 2 surface area, was obtained from analysis of residual oxybutynin content of transdermal 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 transdermal system, oxybutynin plasma concentrations increase 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 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 3.9 mg/day to the abdomen, buttock, and hip ( Transdermal System removal at 96 hours). Steady-state conditions are reached during the second OXYTROL application.

Average steady-state plasma concentrations were 3.1 ng/mL for oxybutynin and 3.8 ng/mL for N-desethyloxybutynin (Figure 3). Table 3 provides a summary of pharmacokinetic parameters of oxybutynin in healthy volunteers after single and multiple applications of OXYTROL. 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 3: Mean (SD) oxybutynin pharmacokinetic parameters from single and multiple dose studies in healthy men and women volunteers after application of OXYTROL on the abdomen. Dosing Oxybutynin C max (SD) (ng/mL) T max 1 (hr) C avg (SD) (ng/mL) AUC (SD) (ng/mLxh) Single 3.0 (0.8) 48 - 245 (59) 2 3.4 (1.1) 36 - 279 (99) 2 Multip le 6.6 (2.4) 10 4.2 (1.1) 408 (108) 3 4.2 (1.0) 28 3.1 (0.7) 259 (57) 4 1 T max given as median 2 AUC inf 3 AUC 0-96 4 AUC 0-84 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 N-desethyloxybutynin, 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 N-desethyl metabolite compared to oxybutynin (see Figure 4). The plasma concentration area under the time-concentration curve (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 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 N-desethyl metabolite to parent compound following multiple OXYTROL applications was 1.3:1. Figure 4: Average plasma concentrations (Cp) measured after a single, 96-hour application of the OXYTROL 3.9 mg/day transdermal system (AUC inf /96) and a single, 5 mg, oral immediate-release dose of oxybutynin chloride (AUC inf /8) in 16 healthy male and female volunteers.

Following intravenous administration, the elimination h… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES The efficacy and safety of OXYTROL were evaluated in patients with urge urinary incontinence in two controlled studies and one open-label extension. Study 1 was a placebo controlled study, comparing the safety and efficacy of OXYTROL 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 study comparing the safety and efficacy of OXYTROL 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 conducted in 520 patients. The 12-week double-blind treatment included an OXYTROL dose of 3.9 mg/day or 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. Changes in weekly incontinence episodes, urinary frequency, and urinary void volume between placebo and active treatment groups are summarized in Table 4.

Table 4: 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 3.9 mg/day or placebo for 12 weeks (Study 1). Parameter Placebo (N = 127) OXYTROL 3.9 mg/day (N = 120) Mean (SD) Median Mean (SD) Median Weekly Incontinence Episodes Baseline 37.7 (24.0) 30 34.3 (18.2) 31 Reduction 19.2 (21.4) 15 21.0 (17.1) 19 p value vs. placebo - 0.0265 * Daily Urinary Frequency Baseline 12.3 (3.5) 11 11.8 (3.1) 11 Reduction 1.6 (3.0) 1 2.2 (2.5) 2 p value vs. placebo - 0.0313 * Urinary Void Volume (mL) Baseline 175.9 (69.5) 166.5 171.6 (65.1) 168 Increase 10.5 (56.9) 5.5 31.6 (65.6) 26 p value vs. placebo - 0.0009 ** *Comparison significant if p < 0.05 **Comparison significant if p ≤ 0.0167 Study 2 was a randomized, double-blind, study of OXYTROL 3.9 mg/day versus active and placebo controls conducted in 361 patients.

The 12-week double-blind treatment included an OXYTROL 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. Changes in daily incontinence episodes, urinary frequency, and urinary void volume between placebo and active treatment groups are summarized in Table 5.

Table 5: 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 3.9 mg/day or placebo for 12 weeks (Study 2). Parameter Placebo (N = 117) OXYTROL 3.9 mg/day (N = 121) Mean (SD) Median Mean (SD) Median Daily Incontinence Episodes Baseline 5.0 (3.2) 4 4.7 (2.9) 4 Reduction 2.1 (3.0) 2 2.9 (3.0) 3 p value vs. placebo - 0.0137* Daily Urinary Frequency Baseline 12.3 (3.3) 12 12.4 (2.9) 12 Reduction 1.4 (2.7) 1 1.9 (2.7) 2 p value vs. placebo - 0.1010* Urinary Void Volume (mL)… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility A 24-month study in rats at dosages of oxybutynin chloride of 20, 80 and 160 mg/kg showed no evidence of carcinogenicity. These doses are approximately 6, 25 and 50 times the maximum exposure in humans taking an oral dose based on body surface area. Oxybutynin chloride showed no increase of mutagenic activity when tested in Schizosaccharomyces pompholiciformis, Saccharomyces cerevisiae , and Salmonella typhimurium test systems.

Reproduction studies with oxybutynin chloride in the mouse, rat, hamster, and rabbit showed no definite evidence of impaired fertility.