2.1 Adults

The recommended starting dose of oxybutynin chloride extended-release tablets is 5 mg or 10 mg once daily at approximately the same time each day. Dosage may be adjusted in 5-mg increments to achieve a balance of efficacy and tolerability (up to a maximum of 30 mg/day). In general, dosage adjustment may proceed at approximately weekly intervals.

2.2 Pediatric Patients Aged 6 Years of Age and Older

The recommended starting dose of oxybutynin chloride extended-release tablets is 5 mg once daily at approximately the same time each day. Dosage may be adjusted in 5-mg increments to achieve a balance of efficacy and tolerability (up to a maximum of 20 mg/day).

5.1 Angioedema

Angioedema of the face, lips, tongue and/or larynx has been reported with oxybutynin. In some cases, angioedema occurred after the first dose. Angioedema associated with upper airway swelling may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, oxybutynin should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided.

5.2 Central Nervous System Effects

Oxybutynin is associated with anticholinergic central nervous system (CNS) effects [see Adverse Reactions (6)]. A variety of CNS anticholinergic effects have been reported, including hallucinations, agitation, confusion and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly in the first few months after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how oxybutynin chloride extended-release tablets affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.

Oxybutynin chloride extended-release tablets should be used with caution in patients with preexisting dementia treated with cholinesterase inhibitors due to the risk of aggravation of symptoms.

Oxybutynin chloride extended-release tablets should be used with caution in patients with Parkinson’s disease due to the risk of aggravation of symptoms.

5.3 Worsening of Symptoms of Myasthenia Gravis

Oxybutynin chloride extended-release tablets should be used with caution in patients with myasthenia gravis due to the risk of aggravation of symptoms.

5.4 Worsening of Symptoms of Decreased Gastrointestinal Motility in Patients with Autonomic Neuropathy

Oxybutynin chloride extended-release tablets should be used with caution in patients with autonomic neuropathy due to the risk of aggravation of symptoms of decreased gastrointestinal motility.

5.5 Urinary Retention

Oxybutynin chloride extended-release tablets should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention [see Contraindications (4)].

5.6 Gastrointestinal Adverse Reactions

Oxybutynin chloride extended-release tablets should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention [see Contraindications (4)].

Oxybutynin chloride extended-release tablets, like other anticholinergic drugs, may decrease gastrointestinal motility and should be used with caution in patients with conditions such as ulcerative colitis and intestinal atony.

Oxybutynin chloride extended-release tablets should be used with caution in patients who have gastroesophageal reflux and/or who are concurrently taking drugs (such as bisphosphonates) that can cause or exacerbate esophagitis.

As with any other nondeformable material, caution should be used when administering oxybutynin chloride extended-release tablets to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other drugs in nondeformable controlled-release formulations.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the 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 and efficacy of oxybutynin chloride extended-release tablets (5 mg/day to 30 mg/day) was evaluated in 774 adult subjects who participated in five double-blind, controlled clinical trials. In four of the five studies, oxybutynin chloride tablets (5 mg/day to 20 mg/day in 199 subjects) was an active comparator. Adverse reactions reported by greater than or equal to 1% of subjects are shown in Table 1.

Table 1: Adverse Drug Reactions Reported by greater than or equal to 1% ofOxybutynin Chloride Extended-Release Tablets-treated Adult Subjects in Five Double-blind, Controlled Clinical Trials of Oxybutynin Chloride Extended-Release Tablets.

The discontinuation rate due to adverse reactions was 4.4% with oxybutynin chloride extended-release tablets compared to 0% with oxybutynin chloride tablets. The most frequent adverse reaction causing discontinuation of study medication was dry mouth (0.7%).

The following adverse reactions were reported by less than 1% of oxybutynin chloride extended-release tablets-treated patients and at a higher incidence than placebo in clinical trials: Metabolism and Nutrition Disorders: anorexia, fluid retention; Vascular disorders: hot flush; Respiratory, thoracic and mediastinal disorders: dysphonia; Gastrointestinal Disorders: dysphagia,frequent bowel movements; General disorders and administration site conditions: chest discomfort, thirst.

6.2 Postmarketing Experience

The following additional adverse reactions have been reported from worldwide postmarketing experience with oxybutynin chloride extended-release tablets. Because postmarketing 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.

Infections and Infestations: Urinary tract infection; Psychiatric Disorders: psychotic disorder, agitation, confusional state, hallucinations, memory impairment, abnormal behavior; Nervous System Disorders: convulsions; Eye Disorders: glaucoma; Respiratory, Thoracic and Mediastinal Disorders: nasal congestion; Cardiac Disorders: arrhythmia, tachycardia, palpitations; QT interval prolongation;

Vascular Disorders: flushing, hypertension; Skin and Subcutaneous Tissue Disorders: rash; Renal and Urinary Disorders: impotence; General Disorders and Administration Site Conditions: hypersensitivity reactions, including angioedema with airway obstruction, urticaria, and face edema; anaphylactic reactions requiring hospitalization for emergency treatment; Injury, poisoning and procedural complications: fall.

Additional adverse events reported with some other oxybutynin chloride formulations include: cycloplegia, mydriasis, and suppression of lactation. In one reported case, concomitant use of oxybutynin with carbamazepine and dantrolene was associated with adverse events of vomiting, drowsiness, confusion, unsteadiness, slurred speech and nystagmus, suggestive of carbamazepine toxicity.

8.1 Pregnancy

Risk Summary

There are no adequate data on oxybutynin chloride extended-release tablets use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

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

8.2 Lactation

Risk Summary

There are no data on the presence of oxybutynin in human milk, the effects on the breastfed infant, or the effects of oxybutynin chloride extended-release tablets on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for oxybutynin chloride extended-release tablets and any potential adverse effects on the breastfed child from oxybutynin chloride extended-release tablets or from the underlying maternal condition.

8.4 Pediatric Use

The safety and efficacy of oxybutynin chloride extended-release tablets were studied in 60 children in a 24-week, open-label, non-randomized trial. Patients were aged 6-15 years, all had symptoms of detrusor overactivity  in  association  with  a  neurological  condition  (e.g.,  spina  bifida),  all  used clean intermittent catheterization, and all were current users of oxybutynin chloride. Study results demonstrated that administration of oxybutynin chloride extended-release tablets 5 mg/day to 20 mg/day was associated with an increase from baseline in mean urine volume per catheterization from 108 mL to 136 mL, an increase from baseline in mean urine volume after morning awakening from 148 mL to 189 mL, and an increase from baseline in the mean percentage of catheterizations without a leaking episode from 34% to 51%.

Urodynamic results were consistent with clinical results. Administration of oxybutynin chloride extended-release tablets resulted in an increase from baseline in mean maximum cystometric capacity from 185 mL to 254 mL, a decrease from baseline in mean detrusor pressure at maximum cystometric capacity from 44 cm H2O to 33 cm H2O, and a reduction in the percentage of patients demonstrating uninhibited detrusor contractions (of at least 15 cm H2O) from 60% to 28%.

The pharmacokinetics of oxybutynin chloride extended-release tablets in these patients were consistent with those reported for adults [see Clinical Pharmacology (12.3)].

Oxybutynin chloride extended-release tablets are not recommended in pediatric patients who cannot swallow the tablet whole without chewing, dividing, or crushing, or in children under the age of 6.

8.5 Geriatric Use

The rate and severity of anticholinergic effects reported by patients less than 65 years old and those 65 years and older were similar. The pharmacokinetics of oxybutynin chloride extended-release tablets were similar in all patients studied (up to 78 years of age).

8.6 Renal Impairment

There were no studies conducted with oxybutynin chloride extended-release tablets in patients with renal impairment.

8.7 Hepatic Impairment

There were no studies conducted with oxybutynin chloride extended-release tablets in patients with hepatic impairment.

12.1 Mechanism of Action

Oxybutynin relaxes bladder smooth muscle. Oxybutynin chloride exerts a direct antispasmodic effect on smooth muscle and inhibits the muscarinic action of acetylcholine on smooth muscle. No blocking effects occur at skeletal neuromuscular junctions or autonomic ganglia (antinicotinic effects).

Antimuscarinic activity resides predominantly in the R-isomer. A metabolite, desethyloxybutynin, has pharmacological activity similar to that of oxybutynin in in vitro studies.

12.2 Pharmacodynamics

In patients with conditions characterized by involuntary bladder contractions, cystometric studies have demonstrated that oxybutynin increases bladder (vesical) capacity, diminishes the frequency of uninhibited contractions of the detrusor muscle, and delays the initial desire to void.

12.3 Pharmacokinetics

Absorption

Following the first dose of oxybutynin chloride extended-release tablets, oxybutynin plasma concentrations rise for 4 to 6 hours; thereafter steady concentrations are maintained for up to 24 hours, minimizing fluctuations between peak and trough concentrations associated with oxybutynin.

The relative bioavailabilities of R- and S-oxybutynin from oxybutynin chloride extended-release tablets are 156% and 187%, respectively, compared with oxybutynin. The mean pharmacokinetic parameters for R­ and S-oxybutynin are summarized in Table 2. The plasma concentration-time profiles for R- and S-oxybutynin are similar in shape; Figure 1 shows the profile for R-oxybutynin.

Table 2: Mean (SD) R- and S-Oxybutynin Pharmacokinetic Parameters Following a Single Dose of Oxybutynin Chloride Extended-Release Tablets10 mg (n=43)

Figure 1:Mean R-oxybutynin plasma  concentrations following a  single dose of Oxybutynin Chloride Extended-Release Tablets10 mg and oxybutynin 5 mg administered every 8 hours (n=23 for each treatment).

Steady state oxybutynin plasma concentrations are achieved by Day 3 of repeated oxybutynin chloride extended-release tablets dosing, with no observed drug accumulation or change in oxybutynin and desethyloxybutynin pharmacokinetic parameters.

Oxybutynin chloride extended-release tablets steady state pharmacokinetics were studied in 19 children aged 5 to15 years with detrusor overactivity associated with a neurological condition (e.g., spina bifida). The children  were  on  oxybutynin chloride extended-release tablets total  daily  dose  ranging  from  5 mg  to  20  mg  (0.10 mg/kg  to 0.77 mg/kg). Sparse sampling technique was used to obtain serum samples. When all available data are normalized to an equivalent of 5 mg per day of oxybutynin chloride extended-release tablets the mean pharmacokinetic parameters derived for R- and S-oxybutynin and R- and S-desethyloxybutynin are summarized in Table 3. The plasma-time concentration profiles for R- and S-oxybutynin are similar  in  shape;  Figure  2  shows  the  profile  for  R-oxybutynin  when  all  available  data are normalized to an equivalent of 5 mg per day.

Table 3: Mean ± SD R- and S-Oxybutynin and R- and S-Desethyloxybutynin Pharmacokinetic Parameters in Children Aged 5 to 15 Following Administration of 5 to 20 mg Oxybutynin Chloride Extended-Release Tablets Once Daily (n=19), All Available Data Normalized to an Equivalent of Oxybutynin Chloride Extended-Release Tablets 5 mg Once Daily

Figure 2: Mean steady state (± SD) R-oxybutynin plasma concentrations following administration of 5 to 20 mg Oxybutynin Chloride Extended-Release Tablets once daily in children aged 5 to 15. Plot represents all available data normalized to an equivalent of Oxybutynin Chloride Extended-Release Tablets 5 mg once daily.

Food Effects

The rate and extent of absorption and metabolism of oxybutynin are similar under fed and fasted conditions.

Distribution

Oxybutynin is widely distributed in body tissues following systemic absorption. The volume of distribution is 193 L after intravenous administration of 5 mg oxybutynin chloride. Both enantiomers of oxybutynin are highly bound (greater than 99%) to plasma proteins. Both enantiomers of N-desethyloxybutynin are also highly bound (greater than 97%) to plasma proteins. The major binding protein is alpha-1 acid glycoprotein.

Metabolism

Oxybutynin is metabolized primarily by the cytochrome P450 enzyme systems, particularly CYP3A4 found mostly in the liver and gut wall. Its metabolic products include phenylcyclohexylglycolic acid, which is pharmacologically inactive, and desethyloxybutynin, which is pharmacologically active. Following oxybutynin chloride extended-release tabletsadministration, plasma concentrations of R- and S-desethyloxybutynin are 73% and 92%, respectively, of concentrations observed with oxybutynin.

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 desethyloxybutynin.

Dose Proportionality

Pharmacokinetic parameters of oxybutynin and desethyloxybutynin (Cmax and AUC) following administration of 5 mg - 20 mg of oxybutynin chloride extended-release tablets are dose proportional.

Use in Specific Populations

Pediatric

The pharmacokinetics of oxybutynin chloride extended-release tablets were evaluated in 19 children aged 5-15 years with detrusor overactivity associated with a neurological condition (e.g., spina bifida). The pharmacokinetics of oxybutynin chloride extended-release tablets in these pediatric patients were consistent with those reported for adults (see Tables 2 and 3, and Figures 1 and 2 above).

Gender

There are no significant differences in the pharmacokinetics of oxybutynin in healthy male and female volunteers following administration of oxybutynin chloride extended-release tablets.

Race

Available data suggest that there are no significant differences in the pharmacokinetics of oxybutynin based on race in healthy volunteers following administration of oxybutynin chloride extended-release tablets.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

A 24-month study in rats at dosages of oxybutynin chloride of 20 mg/kg/day, 80 mg/kg/day, and 160 mg/kg/day showed no evidence of carcinogenicity. These doses are approximately 6, 25, and 50 times the maximum human exposure, based on a human equivalent dose taking into account normalization of body surface area.

Mutagenesis

Oxybutynin chloride showed no increase of mutagenic activity when tested in Schizosaccharomyces pompholiciformis, Saccharomyces cerevisiae, and Salmonella typhimurium test systems.

Impairment of Fertility

No impairment of fertility was seen in rats at dosages up to 75 mg/kg/day (24 times the MRHD on a mg/m2 basis) when administered for 2 weeks prior to mating in females and for 9 weeks prior to mating in males.