Administer OXYTROL with caution in patients with clinically significant bladder outflow obstruction because of the risk of urinary retention [see Contraindications (4) ].

Administer OXYTROL with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention [see Contraindications (4) ].

OXYTROL, like other anticholinergic drugs, may decrease gastrointestinal motility and should be used with caution in patients with conditions such as ulcerative colitis or intestinal atony.

OXYTROL should be used with caution in patients who have hiatus hernia/gastroesophageal reflux and/or who are concurrently taking drugs (such as bisphosphonates) that can cause or exacerbate esophagitis.

Products containing oxybutynin are associated with anticholinergic central nervous system (CNS) effects. A variety of CNS anticholinergic effects have been reported, including headache, dizziness, somnolence, confusion and hallucinations [see Adverse Events (6.2) ]. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment. Advise patients not to drive or operate heavy machinery until they know how OXYTROL affects them. If a patient experiences anticholinergic CNS effects, drug discontinuation should be considered.

Angioedema requiring hospitalization and emergency medical treatment has occurred with the first or subsequent doses of oral oxybutynin. In the event of angioedema, OXYTROL should be discontinued and appropriate therapy promptly provided.

Patients who develop skin hypersensitivity to OXYTROL should discontinue drug treatment.

Avoid use of OXYTROL in patients with myasthenia gravis, a disease characterized by decreased cholinergic activity at the neuromuscular junction. If experiencing exacerbation of symptoms of myasthenia gravis, oxybutynin-containing product should be discontinued and appropriate therapy promptly provided.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of OXYTROL was evaluated in a total of 417 patients who participated in two clinical efficacy and safety studies and an open-label extension. Additional safety information was collected in earlier phase trials. In the two pivotal studies, a total of 246 patients received OXYTROL during the 12-week treatment periods. A total of 411 patients entered the open-label extension and of those, 65 patients and 52 patients received OXYTROL for at least 24 weeks and at least 36 weeks, respectively.

No deaths were reported during treatment. No serious adverse events related to treatment were reported.

Adverse reactions reported in the pivotal trials are summarized in Tables 1 and 2 below.

Table 1: Number (%) of adverse reactions occurring in ≥ 2% of OXYTROL-treated patients and greater in the OXYTROL group than in the placebo group (Study 1).
Adverse Reaction	Placebo (N = 132)		OXYTROL (3.9 mg/day) (N = 125)
	N	%	N	%
Application site pruritus	8	6.1%	21	16.8%
Dry mouth	11	8.3%	12	9.6%
Application site erythema	3	2.3%	7	5.6%
Application site vesicles	0	0.0%	4	3.2%
Diarrhea	3	2.3%	4	3.2%
Dysuria	0	0.0%	3	2.4%

Table 2: Number (%) of adverse reactions occurring in ≥ 2% of OXYTROL-treated patients and greater in the OXYTROL group than in the placebo group (Study 2).
Adverse Reaction	Placebo (N = 117)		OXYTROL (3.9 mg/day) (N = 121)
	N	%	N	%
Application site pruritus	5	4.3%	17	14.0%
Application site erythema	2	1.7%	10	8.3%
Dry mouth	2	1.7%	5	4.1%
Constipation	0	0.0%	4	3.3%
Application site rash	1	0.9%	4	3.3%
Application site macules	0	0.0%	3	2.5%
Abnormal vision	0	0.0%	3	2.5%

Most adverse reactions were described as mild or moderate in intensity. Severe application site reactions were reported by 6.4% of OXYTROL-treated patients in Study 1 and by 5.0% of OXYTROL-treated patients in Study 2.

Adverse reactions that resulted in discontinuation were reported by 11.2% of OXYTROL-treated patients in Study 1 and 10.7% of OXYTROL-treated patients in Study 2. Most of these discontinuations were due to application site reaction. In the two pivotal studies, no patient discontinued OXYTROL treatment due to dry mouth.

In the open-label extension, the most common treatment-related adverse reactions were: application site pruritus, application site erythema, and dry mouth.

The following adverse reactions have been identified during post approval use of OXYTROL. Because these reactions are reported voluntarily from  a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Nervous System Disorders: Memory impairment, dizziness, somnolence, confusion

Psychiatric Disorders: Delirium, hallucinations

The concomitant use of OXYTROL with other anticholinergic drugs, or with other agents that produce dry mouth, constipation, somnolence, and/or other anticholinergic-like effects may increase the frequency and/or severity of such effects. Anticholinergic agents may potentially alter the absorption of some concomitantly administered drugs due to anticholinergic effects on gastrointestinal motility.

Pharmacokinetic studies have not been performed with patients concomitantly receiving cytochrome P450 enzyme inhibitors, such as antimycotic agents (e.g., ketoconazole, itraconazole, and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin).

Risk Summary

There are no studies with topical or oral oxybutynin use in pregnant women to inform a drug associated risk for birth defects or miscarriage. No adverse developmental outcomes were observed in animal reproduction studies when oxybutynin chloride was administered to pregnant rats and rabbits during organogenesis at approximately 50 and 1 times, respectively, the maximum human dose based on body surface area (see Data). 

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20% respectively.

Data            

A n i m al Da t a

Subcutaneous administration of oxybutynin chloride to rats at doses up to 25 mg/kg (approximately 50 times the human exposure based on surface area) and to rabbits at doses up to 0.4 mg/kg (approximately 1 times the human exposure based on body surface area) throughout the period of organogenesis revealed no evidence of harm to the fetus.

Risk Summary

There is no information on the presence of oxybutynin in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for OXYTROL and any potential adverse effects on the breastfed child from OXYTROL or from the underlying maternal condition.

The safety and efficacy of OXYTROL in pediatric patients have not been established.

Forty-nine percent of OXYTROL-treated patients in the clinical studies were at least 65 years of age. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in response between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see  Clinical Pharmacology (12.3) ].

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.

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 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 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
1Tmax given as median 2AUCinf 3AUC0-96 4AUC0-84

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 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.

Specific Populations:

Geriatric : The pharmacokinetics of oxybutynin and N-desethyloxybutynin were similar in older and younger patients.

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

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

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. Japanese volunteers demonstrated a somewhat lower metabolism of oxybutynin to N-desethyloxybutynin compared to Caucasian volunteers.

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.