The plasma concentration of oxybutynin declines within 1 to 2 hours after removal of transdermal system(s). Patients should be monitored until symptoms resolve. Overdosage with oxybutynin has been associated with anticholinergic effects including CNS excitation, flushing, fever, dehydration, cardiac arrhythmia, vomiting, and urinary retention. Ingestion of 100 mg oral oxybutynin chloride in association with alcohol has been reported in a 13 year old boy who experienced memory loss, and in a 34 year old woman who developed stupor, followed by disorientation and agitation on awakening, dilated pupils, dry skin, cardiac arrhythmia, and retention of urine. Both patients recovered fully with treatment directed at their symptoms.
The use of OXYTROL is contraindicated in the following conditions:
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.
Postmarketing ExperienceThe 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
OXYTROL is a muscarinic antagonist indicated for the treatment of overactive bladder in men with symptoms of urge urinary incontinence, urgency, and frequency.
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 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 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 (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 Ndesethyloxybutynin (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 | |||
| Cmax (SD) (ng/mL) |
Tmax 1 (hr) |
Cavg (SD) (ng/mL) |
AUC (SD) (ng/mLxh) |
|
| Single | 3.0 (0.8) | 48 | - | 245 (59)2 |
| 3.4 (1.1) | 36 | - | 279 (99)2 | |
| Multiple | 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 Tmax given as median 2 AUCinf 3AUC0-96 4 AUC0-84 |
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.
MetabolismOxybutynin 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 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 Ndesethyloxybutynin decline with an apparent half-life of approximately 7 to 8 hours.
ExcretionOxybutynin 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.
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.
DataAnimal Data
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.
Transdermal System: 3.9 mg/day
Storage And HandlingUnit Dose: Heat sealed pouch containing 1 OXYTROL (oxybutynin transdermal system).
Each 39 cm2 system imprinted with “OXYTROL 3.9 mg/day” contains 36 mg of oxybutynin for nominal delivery of 3.9 mg oxybutynin per day when dosed in a twice weekly regimen.
Patient Calendar Box of 8 Systems (NDC 0023-6153-08)
StorageStore at 20-25°C (68-77°F). Protect from moisture and humidity. Do not store outside the sealed pouch. Apply immediately after removal from the protective pouch. Discard used OXYTROL in household trash in a manner that prevents accidental application or ingestion by children, pets, or others.
Keep out of reach of children.
Distributed By: Allergan USA, Inc. Irvine, CA 92612. Revised: Oct 2017.
Included as part of the "PRECAUTIONS" Section
PRECAUTIONS Urinary RetentionAdminister OXYTROL with caution in patients with clinically significant bladder outflow obstruction because of the risk of urinary retention.
Risks In Patients With Gastrointestinal DisordersAdminister OXYTROL with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention.
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.
Central Nervous System EffectsProducts 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. 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.
AngioedemaAngioedema 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.
Skin HypersensitivityPatients who develop skin hypersensitivity to OXYTROL should discontinue drug treatment.
Exacerbation Of Symptoms Of Myasthenia GravisAvoid 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.
Patient Counseling InformationSee FDA-Approved Patient Labeling (PATIENT INFORMATION and Instructions for Use)
Instructions For UseInform patients that OXYTROL should be applied to dry, intact skin on the abdomen, hip, or buttock and not be applied to areas that have been treated with oils, lotions or powders. The patch should not be exposed to sunlight. Contact with water while bathing, swimming, showering or exercising will not change the effect of OXYTROL.
A new application site should be selected with each new system to avoid re-application to the same site within 7 days. Inform patients to try to change the patch on the same 2 days each week and that the package of OXYTROL has a calendar checklist printed on the back to remind patients of their schedule. Inform patients to avoid rubbing the patch area during bathing, swimming, showering or exercising. Inform patients that details on use of the system are explained in the Patient Information Leaflet.
Inform patients to discard used OXYTROL in household trash in a manner that prevents accidental application or ingestion by children, pets, or others. Inform patients to keep out of reach of children.
Important Anticholinergic Adverse ReactionsPatients should be informed that anticholinergic (antimuscarinic) agents, such as OXYTROL, may produce adverse reactions related to anticholinergic pharmacological activity including:
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.
Use In Specific Populations PregnancyRisk 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.
DataAnimal Data
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.
LactationRisk 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.
Pediatric UseThe safety and efficacy of OXYTROL in pediatric patients have not been established.
Geriatric UseForty-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.
OXYTROL 3.9 mg/day should be applied to dry, intact skin on the abdomen, hip, or buttock twice weekly (every 3 or 4 days). A new application site should be selected with each new system to avoid re-application to the same site within 7 days.
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.
Postmarketing ExperienceThe 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
DRUG INTERACTIONSNo specific drug-drug interaction studies have been performed with OXYTROL.
Other AnticholinergicsThe 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.
Cytochrome P450 InhibitorsPharmacokinetic 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).
