ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most common (incidence >=5%) adverse reactions were dry mouth, constipation, diarrhea, headache, somnolence, and dizziness. (6) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of 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 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 immediate-release tablets (5 to 20 mg/day in 199 subjects) was an active comparator. Adverse reactions reported by >= 1% of subjects are shown in Table 1.Table 1: Adverse Drug Reactions Reported by >= 1% of Oxybutynin Chloride Extended-Release Tablets-treated Adult Subjects in Five Double-blind, Controlled Clinical Trials of Oxybutynin Chloride Extended-Release TabletsSystem/Organ Class Preferred TermOxybutynin Chloride Extended-Release Tablets to 30 mg/day = 774 %Oxybutynin Chloride Immediate-Release Tablets1 to 20 mg/day = 199 %Psychiatric Disorders Insomnia 3.05.5Nervous System Disorders Headache 7.58.0Somnolence 5.614.1Dizziness 5.016.6Dysgeusia 1.61.5Eye Disorders Vision blurred 4.39.6Dry eye 3.12.5Respiratory, Thoracic and Mediastinal Disorders Cough 1.93.0Oropharyngeal pain 1.91.5Dry throat 1.72.5Nasal dryness 1.74.5Gastrointestinal Disorders Dry mouth 34.972.4Constipation 8.715.1Diarrhea 7.96.5Dyspepsia 4.56.0Nausea 4.511.6Abdominal pain 1.62.0Vomiting 1.31.5Flatulence 1.22.5Gastro-esophageal reflux disease 1.00.5Skin and Subcutaneous Tissue Disorders Dry skin 1.82.5Pruritus 1.31.5Renal and Urinary Disorders Dysuria 1.92.0Urinary hesitation 1.98.5Urinary retention 1.23.0General Disorders and Administration Site Conditions Fatigue 2.63.0Investigations Residual urine volume2 2.33.51 IR immediate-release2 The bundled term residual urine volume consists of the preferred terms residual urine volume and residual urine volume increased.The discontinuation rate due to adverse reactions was 4.4% with oxybutynin chloride extended-release tablets compared to 0% with oxybutynin chloride immediate-release tablets. The most frequent adverse reaction causing discontinuation of study medication was dry mouth (0.7%). The following adverse reactions were reported by <1% of oxybutynin chloride extended-release tablets-treated patients and at 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Oxybutynin relaxes bladder smooth muscle. Oxybutynin chloride exerts 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. 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 to 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 shows the profile for R-oxybutynin. Table 2: Mean (SD) R- and S-Oxybutynin Pharmacokinetic Parameters Following Single Dose of Oxybutynin Chloride Extended-Release Tablets 10 mg (n=43)Parameters (units) R-Oxybutynin S-Oxybutynin Cmax (ng/mL) 1.0 (0.6)1.8 (1.0)Tmax (h) 12.7 (5.4)11.8 (5.3)t1/2 (h) 13.2 (6.2)12.4 (6.1)AUC(0-48) (ngoh/mL) 18.4 (10.3)34.2 (16.9)AUCinf (ngoh/mL) 21.3 (12.2)39.5 (21.2)Figure 1: Mean R-oxybutynin plasma concentrations following single dose of oxybutynin chloride extended-release tablets 10 mg and oxybutynin mg administered every hours (n=23 for each treatment).Steady-state oxybutynin plasma concentrations are achieved by Day 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 to 15 years with detrusor overactivity associated with neurological condition (e.g., spina bifida). The children were on oxybutynin chloride extended-release tablets total daily dose ranging from to 20 mg (0.10 to 0.77 mg/kg). Sparse sampling technique was used to obtain serum samples. When all available data are normalized to an equivalent of 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 shows the profile for R-oxybutynin when all available data are normalized to an equivalent of mg per day.Table 3: Mean +- SD R- and S-Oxybutynin and R- and S-Desethyloxybutynin Pharmacokinetic Parameters in Children Aged to 15 Following Administration of 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 mg Once DailyR-OxybutyninS-OxybutyninR-DesethyloxybutyninS-DesethyloxybutyninCmax (ng/mL) 0.7 +- 0.4 1.3 +- 0.8 7.8 +- 3.7 4.2 +- 2.3Tmax (h) 5.0 5.0 5.0 5.0AUC (ngoh/mL)12.8 +- 7.0 23.7 +- 14.4 125.1 +- 66.7 73.6 +- 47.7Figure 2: Mean steady-state (+- SD) R-oxybutynin plasma concentrations following administration of to 20 mg Oxybutynin Chloride Extended-Release Tablets once daily in children aged to 15. Plot represents all available data normalized to an equivalent of Oxybutynin Chloride Extended-Release Tablets 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 after intravenous administration of mg oxybutynin chloride. Both enantiomers of oxybutynin are highly bound (>99%) to plasma proteins. Both enantiomers of N-desethyloxybutynin are also highly bound (>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 tablets administration, 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 mg to 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 to 15 years with detrusor overactivity associated with 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 and 3, and Figures and 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. 1. Figure 2.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Oxybutynin chloride extended-release tablets was evaluated for the treatment of patients with overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency in three controlled efficacy studies. The majority of patients were Caucasian (89.0%) and female (91.9%) with mean age of 59 years (range, 18 to 98 years). Entry criteria required that patients have urge or mixed incontinence (with predominance of urge) as evidenced by >= urge incontinence episodes per week and >= 10 micturitions per day. Study was fixed-dose escalation design, whereas the other two studies used dose-adjustment design in which each patients final dose was adjusted to balance between improvement of incontinence symptoms and tolerability of side effects. All three studies included patients known to be responsive to oxybutynin or other anticholinergic medications, and these patients were maintained on final dose for up to weeks. The efficacy results for the three controlled trials are presented in the following Tables 4, and and Figures 3, and 5.Table 4: Number of Urge Urinary Incontinence Episodes Per Week (Study 1)Study 1nOxybutynin Chloride Extended-Release TabletsnPlaceboMean Baseline3415.91620.9Mean (SD) Change from Baseline+ 34-15.8 (8.9)16-7.6 (8.6)95% Confidence Interval for Difference(-13.6, -2.8)(Oxybutynin Chloride Extended-Release Tablets Placebo) The difference between oxybutynin chloride extended-release tablets and placebo was statistically significant.+ Covariate adjusted mean with missing observations set to baseline values.Figure 3: Mean Change (+-SD) in Urge Urinary Incontinence Episodes Per Week from Baseline (Study 1) The difference between oxybutynin chloride and placebo was statistically significant.Table 5: Number of Urge Urinary Incontinence Episodes Per Week (Study 2)Study 2nOxybutynin Chloride Extended-Release TabletsnOxybutyninMean Baseline5327.65223Mean (SD) Change from Baseline+ 53-17.6 (11.9)52-19.4 (11.9)95% Confidence Interval for Difference(-2.8, 6.5)(Oxybutynin Chloride Extended-Release Tablets Oxybutynin)+ Covariate adjusted mean with missing observations set to baseline values.Figure 4: Mean Change (+-SD) in Urge Urinary Incontinence Episodes Per Week from Baseline (Study 2)Table 6: Number of Urge Urinary Incontinence Episodes Per Week (Study 3)Study 3nOxybutynin Chloride Extended-Release TabletsnOxybutyninMean Baseline11118.911519.5Mean (SD) Change from Baseline+ 111-14.5 (8.7)115-13.8 (8.6)95% Confidence Interval for Difference(-3, 1.6)(Oxybutynin Chloride Extended-Release Tablets Oxybutynin) The difference between oxybutynin chloride extended-release tablets and oxybutynin fulfilled the criteria for comparable efficacy.+ Covariate adjusted mean with missing observations set to baseline values.Figure 5: Mean Change (+-SD) in Urge Urinary Incontinence Episodes Per Week from Baseline (Study 3) The difference between oxybutynin chloride and oxybutynin fulfilled the criteria for comparable efficacy.. 1. 1. 1.

DESCRIPTION SECTION.

11 DESCRIPTION. Oxybutynin chloride, USP is an antispasmodic, muscarinic antagonist. Each oxybutynin chloride extended-release tablet, USP contains mg, 10 mg, or 15 mg of oxybutynin chloride USP, formulated as once-a-day controlled-release tablet for oral administration. Oxybutynin chloride, USP is administered as racemate of R- and S-enantiomers. Chemically, oxybutynin chloride, USP is d,l (racemic) 4-diethylamino-2-butynyl phenylcyclohexylglycolate hydrochloride. The empirical formula of oxybutynin chloride, USP is C22H31NO3oHCl. Its structural formula is:Oxybutynin chloride, USP is white crystalline solid with molecular weight of 393.9. It is readily soluble in water and acids, but relatively insoluble in alkalis. Oxybutynin chloride extended-release tablets, USP also contains the following inert ingredients: hydrogenated vegetable oil, hypromellose, isopropyl alcohol, lactose monohydrate, methacrylic acid copolymer, microcrystalline cellulose, polysorbate 80, sodium lauryl sulfate, talc and triethyl citrate. The mg tablets also contain D&C Red 27 and FD&C Blue 1. The 10 mg tablets also contain FD&C Red 40 and FD&C Yellow 6.Meets USP Dissolution Test 7.System Components and Performance Oxybutynin chloride extended-release tablet, USP uses pH-independent hydrophilic matrix and pH dependent enteric coating to deliver oxybutynin chloride, USP at controlled rate over approximately 24 hours. The oxybutynin chloride extended-release tablet, USP comprises of an inner core made of the drug, rate controlling pH independent polymer and other excipients. The tablet core is then coated with pH dependent enteric coating polymer. When tablets will be exposed to an acidic environment such as the stomach, the drug release will be minimal due to outer enteric coating of the pH dependent polymer. The outer enteric coating upon reaching an environment of pH 5.5 and above will start to dissolve and the polymer in the inner core tablet will hydrate to form gel layer and the drug releases via diffusion process.. 1.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Oxybutynin chloride extended-release tablets must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed. Oxybutynin chloride extended-release tablets may be administered with or without food. Oxybutynin chloride extended-release tablets must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed. Oxybutynin chloride extended-release tablets may be administered with or without food. (2) oAdults: Start with mg or 10 mg, once daily at approximately the same time every day. Dose should not exceed 30 mg per day. (2.1) oPediatric patients (6 years of age or older): Start with mg, once daily at approximately the same time every day. Dose should not exceed 20 mg per day. (2.2) oAdults: Start with mg or 10 mg, once daily at approximately the same time every day. Dose should not exceed 30 mg per day. (2.1) oPediatric patients (6 years of age or older): Start with mg, once daily at approximately the same time every day. Dose should not exceed 20 mg per day. (2.2) 2.1 Adults. The recommended starting dose of oxybutynin chloride extended-release tablets is or 10 mg once daily at approximately the same time each day. Dosage may be adjusted in 5-mg increments to achieve balance of efficacy and tolerability (up to maximum of 30 mg/day). In general, dosage adjustment may proceed at approximately weekly intervals. 2.2 Pediatric Patients Aged Years of Age and Older. The recommended starting dose of oxybutynin chloride extended-release tablets is mg once daily at approximately the same time each day. Dosage may be adjusted in 5-mg increments to achieve balance of efficacy and tolerability (up to maximum of 20 mg/day).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce dry mouth, constipation, somnolence (drowsiness), 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. This may be of concern for drugs with narrow therapeutic index. Anticholinergic agents may also antagonize the effects of prokinetic agents, such as metoclopramide.Mean oxybutynin plasma concentrations were approximately fold higher when oxybutynin chloride extended-release tablets was administered with ketoconazole, potent CYP3A4 inhibitor. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter oxybutynin mean pharmacokinetic parameters (i.e., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. oCo-administration with other anticholinergic drugs may increase the frequency and/or severity of anticholinergic-like effects. (7) oCo-administration with strong cytochrome P450 (CYP) 3A4 inhibitors (e.g., ketoconazole) increases the systemic exposure of oxybutynin. (7) oCo-administration with other anticholinergic drugs may increase the frequency and/or severity of anticholinergic-like effects. (7) oCo-administration with strong cytochrome P450 (CYP) 3A4 inhibitors (e.g., ketoconazole) increases the systemic exposure of oxybutynin. (7).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Oxybutynin chloride extended-release tablets are muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. Oxybutynin chloride extended-release tablets are also indicated for the treatment of pediatric patients aged years and older with symptoms of detrusor overactivity associated with neurological condition (e.g., spina bifida). oOxybutynin chloride extended-release tablets are muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. (1) oOxybutynin chloride extended-release tablets are also indicated for the treatment of pediatric patients aged years and older with symptoms of detrusor overactivity associated with neurological condition (e.g., spina bifida). (1) oOxybutynin chloride extended-release tablets are muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. (1) oOxybutynin chloride extended-release tablets are also indicated for the treatment of pediatric patients aged years and older with symptoms of detrusor overactivity associated with neurological condition (e.g., spina bifida). (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. oPatients should be informed that oxybutynin may produce angioedema that could result in life threatening airway obstruction. Patients should be advised to promptly discontinue oxybutynin therapy and seek immediate medical attention if they experience swelling of the tongue, edema of the laryngopharynx, or difficulty breathing. oPatients should be informed that anticholinergic (antimuscarinic) agents such as oxybutynin chloride extended-release tablets, may produce clinically significant adverse reactions related to anticholinergic activity such as: oUrinary retention and constipation oHeat prostration due to decreased sweating. Heat prostration can occur when anticholinergic medicines are administered in the presence of high environmental temperature. oPatients should be informed that anticholinergic medicines such as oxybutynin chloride extended-release tablets may produce drowsiness (somnolence), dizziness or blurred vision. Patients should be advised to exercise caution in decisions to engage in potentially dangerous activities until oxybutynin chloride extended-release tablets effects have been determined. oPatients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents such as oxybutynin chloride extended-release tablets. oPatients should be informed that oxybutynin chloride extended-release tablets should be swallowed whole with the aid of liquids. Patients should not chew, divide, or crush tablets. The medication is contained within nonabsorbable shell designed to release the drug at controlled rate. The tablet shell is eliminated from the body; patients should not be concerned if they occasionally notice in their stool something that looks like tablet. oOxybutynin chloride extended-release tablets should be taken at approximately the same time each day. For more information call 1-877-835-5472 or visit www.amneal.com Trademarks are the property of their respective owners.Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807Packaged and Distributed by:MAJOR(R) PHARMACEUTICALSIndianapolis, IN 46268 USARefer to package label for Distributors NDC NumberRev. 02-2023-10. oPatients should be informed that oxybutynin may produce angioedema that could result in life threatening airway obstruction. Patients should be advised to promptly discontinue oxybutynin therapy and seek immediate medical attention if they experience swelling of the tongue, edema of the laryngopharynx, or difficulty breathing. oPatients should be informed that anticholinergic (antimuscarinic) agents such as oxybutynin chloride extended-release tablets, may produce clinically significant adverse reactions related to anticholinergic activity such as: oUrinary retention and constipation oHeat prostration due to decreased sweating. Heat prostration can occur when anticholinergic medicines are administered in the presence of high environmental temperature. oUrinary retention and constipation oHeat prostration due to decreased sweating. Heat prostration can occur when anticholinergic medicines are administered in the presence of high environmental temperature. oPatients should be informed that anticholinergic medicines such as oxybutynin chloride extended-release tablets may produce drowsiness (somnolence), dizziness or blurred vision. Patients should be advised to exercise caution in decisions to engage in potentially dangerous activities until oxybutynin chloride extended-release tablets effects have been determined. oPatients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents such as oxybutynin chloride extended-release tablets. oPatients should be informed that oxybutynin chloride extended-release tablets should be swallowed whole with the aid of liquids. Patients should not chew, divide, or crush tablets. The medication is contained within nonabsorbable shell designed to release the drug at controlled rate. The tablet shell is eliminated from the body; patients should not be concerned if they occasionally notice in their stool something that looks like tablet. oOxybutynin chloride extended-release tablets should be taken at approximately the same time each day.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and efficacy of oxybutynin chloride extended-release tablets were studied in 60 children in 24-week, open-label, non-randomized trial. Patients were aged to 15 years, all had symptoms of detrusor overactivity in association with 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 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 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, decrease from baseline in mean detrusor pressure at maximum cystometric capacity from 44 cm H2O to 33 cm H2O, and 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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption Following the first dose of oxybutynin chloride extended-release tablets, oxybutynin plasma concentrations rise for to 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 shows the profile for R-oxybutynin. Table 2: Mean (SD) R- and S-Oxybutynin Pharmacokinetic Parameters Following Single Dose of Oxybutynin Chloride Extended-Release Tablets 10 mg (n=43)Parameters (units) R-Oxybutynin S-Oxybutynin Cmax (ng/mL) 1.0 (0.6)1.8 (1.0)Tmax (h) 12.7 (5.4)11.8 (5.3)t1/2 (h) 13.2 (6.2)12.4 (6.1)AUC(0-48) (ngoh/mL) 18.4 (10.3)34.2 (16.9)AUCinf (ngoh/mL) 21.3 (12.2)39.5 (21.2)Figure 1: Mean R-oxybutynin plasma concentrations following single dose of oxybutynin chloride extended-release tablets 10 mg and oxybutynin mg administered every hours (n=23 for each treatment).Steady-state oxybutynin plasma concentrations are achieved by Day 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 to 15 years with detrusor overactivity associated with neurological condition (e.g., spina bifida). The children were on oxybutynin chloride extended-release tablets total daily dose ranging from to 20 mg (0.10 to 0.77 mg/kg). Sparse sampling technique was used to obtain serum samples. When all available data are normalized to an equivalent of 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 shows the profile for R-oxybutynin when all available data are normalized to an equivalent of mg per day.Table 3: Mean +- SD R- and S-Oxybutynin and R- and S-Desethyloxybutynin Pharmacokinetic Parameters in Children Aged to 15 Following Administration of 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 mg Once DailyR-OxybutyninS-OxybutyninR-DesethyloxybutyninS-DesethyloxybutyninCmax (ng/mL) 0.7 +- 0.4 1.3 +- 0.8 7.8 +- 3.7 4.2 +- 2.3Tmax (h) 5.0 5.0 5.0 5.0AUC (ngoh/mL)12.8 +- 7.0 23.7 +- 14.4 125.1 +- 66.7 73.6 +- 47.7Figure 2: Mean steady-state (+- SD) R-oxybutynin plasma concentrations following administration of to 20 mg Oxybutynin Chloride Extended-Release Tablets once daily in children aged to 15. Plot represents all available data normalized to an equivalent of Oxybutynin Chloride Extended-Release Tablets 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 after intravenous administration of mg oxybutynin chloride. Both enantiomers of oxybutynin are highly bound (>99%) to plasma proteins. Both enantiomers of N-desethyloxybutynin are also highly bound (>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 tablets administration, 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 mg to 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 to 15 years with detrusor overactivity associated with 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 and 3, and Figures and 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. 1. Figure 2.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oPediatric Use: 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 years. (8.4) oRenal or Hepatic Impairment: There have been no studies conducted in patients with renal or hepatic impairment. (8.6, 8.7) oPediatric Use: 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 years. (8.4) oRenal or Hepatic Impairment: There have been no studies conducted in patients with renal or hepatic impairment. (8.6, 8.7) 8.1 Pregnancy. Risk Summary There are no adequate data on oxybutynin chloride extended-release tablets use in pregnant women to evaluate for 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 chlorideextended-release tablets on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for oxybutynin chlorideextended-release tablets and any potential adverse effects on the breastfed child from oxybutynin chlorideextended-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 24-week, open-label, non-randomized trial. Patients were aged to 15 years, all had symptoms of detrusor overactivity in association with 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 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 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, decrease from baseline in mean detrusor pressure at maximum cystometric capacity from 44 cm H2O to 33 cm H2O, and 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oAngioedema: Angioedema has been reported with oxybutynin. If symptoms of angioedema occur, discontinue oxybutynin chloride extended-release tablets immediately and initiate appropriate therapy. (5.1) oCentral Nervous System (CNS) Effects: CNS effects have been reported with oxybutynin. If patient experiences anticholinergic CNS effects, consider dose adjustment or discontinuation of oxybutynin chloride extended-release tablets. (5.2) oUse with caution due to aggravation of symptoms:oPre-existing dementia in patients treated with cholinesterase inhibitors (5.2),oParkinsons disease (5.2),oMyasthenia gravis (5.3), and oDecreased gastrointestinal motility in patients with autonomic neuropathy (5.4). oUrinary Retention: Use with caution in patients with clinically significant bladder outflow obstruction because of the risk of urinary retention. (5.5) oGastrointestinal Adverse Reactions: Use with caution in patients with gastrointestinal obstructive disorders or decreased intestinal motility due to risk of gastric retention. Use with caution in patients with gastroesophageal reflux or in patients concurrently taking drugs that can exacerbate esophagitis. (5.6) oAngioedema: Angioedema has been reported with oxybutynin. If symptoms of angioedema occur, discontinue oxybutynin chloride extended-release tablets immediately and initiate appropriate therapy. (5.1) oCentral Nervous System (CNS) Effects: CNS effects have been reported with oxybutynin. If patient experiences anticholinergic CNS effects, consider dose adjustment or discontinuation of oxybutynin chloride extended-release tablets. (5.2) oUse with caution due to aggravation of symptoms:oPre-existing dementia in patients treated with cholinesterase inhibitors (5.2),oParkinsons disease (5.2),oMyasthenia gravis (5.3), and oDecreased gastrointestinal motility in patients with autonomic neuropathy (5.4). oPre-existing dementia in patients treated with cholinesterase inhibitors (5.2),. oParkinsons disease (5.2),. oMyasthenia gravis (5.3), and oDecreased gastrointestinal motility in patients with autonomic neuropathy (5.4). oUrinary Retention: Use with caution in patients with clinically significant bladder outflow obstruction because of the risk of urinary retention. (5.5) oGastrointestinal Adverse Reactions: Use with caution in patients with gastrointestinal obstructive disorders or decreased intestinal motility due to risk of gastric retention. Use with caution in patients with gastroesophageal reflux or in patients concurrently taking drugs that can exacerbate esophagitis. (5.6) 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 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)]. 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 affect them. If 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 Parkinsons 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.