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 Accord Healthcare Inc. at 1-866-941-7875 or www.accordhealthcare.us 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 IR (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 Term Oxybutynin ER to 30 mg/day = 774 Oxybutynin IR IR immediate release to 20 mg/day = 199 Psychiatric Disorders Insomnia3.05.5Nervous System Disorders Headache7.58.0 Somnolence5.614.1 Dizziness5.016.6 Dysgeusia1.61.5Eye Disorders Vision blurred4.39.6 Dry eye3.12.5Respiratory, Thoracic and Mediastinal Disorders Cough1.93.0 Oropharyngeal pain1.91.5 Dry throat1.72.5 Nasal dryness1.74.5Gastrointestinal Disorders Dry mouth34.972.4 Constipation8.715.1 Diarrhea7.96.5 Dyspepsia4.56.0 Nausea4.511.6 Abdominal pain1.62.0 Vomiting1.31.5 Flatulence1.22.5 Gastro-esophageal reflux disease1.00.5Skin and Subcutaneous Tissue Disorders Dry skin1.82.5 Pruritus1.31.5Renal and Urinary Disorders Dysuria1.92.0 Urinary hesitation1.98.5 Urinary retention1.23.0General Disorders and Administration Site Conditions Fatigue2.63.0Investigations Residual urine volume The bundled term residual urine volume consists of the preferred terms residual urine volume and residual urine volume increased. 2.33.5The discontinuation rate due to adverse reactions was 4.4% with oxybutynin ER compared to 0% with oxybutynin IR. 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. 24-month study in rats at dosages of oxybutynin chloride of 20, 80, 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 human equivalent dose taking into account normalization of 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 evidence of impaired fertility.

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. AbsorptionFollowing 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-OxybutyninS-OxybutyninC max (ng/mL) 1.0(0.6)1.8(1.0)T max (h) 12.7(5.4)11.8(5.3)t 1/2 (h) 13.2(6.2)12.4(6.1)AUC (0-48) (ngh/mL) 18.4(10.3)34.2(16.9)AUC inf (ngh/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- DesethyloxybutyninC max (ng/mL) 0.7 +- 0.41.3 +- 0.87.8 +- 3.74.2 +- 2.3T max (h) 5.05.05.05.0AUC (ngh/mL)12.8 +- 7.023.7 +- 14.4125.1 +- 66.773.6 +- 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.. Figure 1. Figure 2. Food EffectsThe rate and extent of absorption and metabolism of oxybutynin are similar under fed and fasted conditions.. DistributionOxybutynin 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.. MetabolismOxybutynin 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.. 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 desethyloxybutynin.. Dose ProportionalityPharmacokinetic parameters of oxybutynin and desethyloxybutynin (C max and AUC) following administration of to 20 mg of oxybutynin chloride extended-release tablets are dose proportional. Use in Specific Populations. PediatricThe 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). GenderThere are no significant differences in the pharmacokinetics of oxybutynin in healthy male and female volunteers following administration of oxybutynin chloride extended-release tablets.. RaceAvailable 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Oxybutynin chloride extended-release tablets were 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 and figures.Number of Urge Urinary Incontinence Episodes Per WeekStudy 1nOxybutynin ERnPlaceboMean 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 ER- Placebo)The difference between Oxybutynin ER and placebo was statistically significant. +Covariate adjusted mean with missing observations set to baseline values Study 2nOxybutynin ERnoxybutyninMean Baseline5327.65223.0Mean (SD) Change from Baseline 53-17.6 (11.9)52-19.4 (11.9)95% Confidence Interval for Difference(-2.8, 6.5)(Oxybutynin ER oxybutynin)+Covariate adjusted mean with missing observations set to baseline values Study 3nOxybutynin ERnoxybutyninMean Baseline11118.911519.5Mean (SD) Change from Baseline 111-14.5 (8.7)115-13.8 (8.6)95% Confidence Interval for Difference(-3.0, 1.6) (Oxybutynin ER oxybutynin)+Covariate adjusted mean with missing observations set to baseline values> The difference between Oxybutynin ER and oxybutynin fulfilled the criteria for comparable efficacy. Figure 3. Figure 4. Figure 5.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Oxybutynin chloride extended-release tablets are contraindicated in patients with urinary retention, gastric retention and other severe decreased gastrointestinal motility conditions, uncontrolled narrow-angle glaucoma.Oxybutynin chloride extended-release tablets are also contraindicated in patients who have demonstrated hypersensitivity to the drug substance or other components of the product. There have been reports of hypersensitivity reactions, including anaphylaxis and angiodema.. Urinary retention 4) Gastric Retention 4) Uncontrolled narrow angle glaucoma 4) Known hypersensitivity to oxybutynin chloride extended-release tablets, oxybutynin or any component of oxybutynin chloride extended-release tablets 4) Urinary retention 4) Gastric Retention 4) Uncontrolled narrow angle glaucoma 4) Known hypersensitivity to oxybutynin chloride extended-release tablets, oxybutynin or any component of oxybutynin chloride extended-release tablets 4).

DESCRIPTION SECTION.

11 DESCRIPTION. Oxybutynin chloride extended-release tablet, 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 is administered as racemate of R- and S-enantiomers.Chemically, oxybutynin chloride is d,l (racemic) 4-diethylamino-2-butynyl phenylcyclohexylglycolate hydrochloride. The empirical formula of oxybutynin chloride is 22H 31NO 3oHCl. Its structural formula is:Oxybutynin chloride 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 contains the following inert ingredients: colloidal anhydrous silicon dioxide, hypromellose, lactose monohydrate, magnesium stearate, methacrylic acid copolymer type-c, microcrystalline cellulose, polyethylene glycol, sodium bicarbonate, sodium lauryl sulfate, talc, titanium dioxide, triethyl citrate. Coloring agents are ferric oxide yellow (in all strengths), ferric oxide red (in mg and 10 mg only) and ferric oxide black (in 15 mg only).System Components and PerformanceOxybutynin chloride extended-release tablets, USP are formulated to deliver oxybutynin chloride at controlled rate over approximately 24 hours. The dosage form is comprised of hydrophilic cellulose polymer matrix tablet surrounded by an enteric coating system. The enteric coat is insoluble in the low pH environment of the stomach. As the tablet passes through the stomach and enters the higher pH environment of the small intestine, the enteric coating dissolves and/or erodes to expose the polymer matrix tablet which swells and releases drug at controlled rate via diffusion and/or erosion.Oxybutynin chloride extended-release tablets, USP meets USP dissolution test 5.. Chemical Structure.

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) Adults: 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) Pediatric 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) Adults: 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) Pediatric 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 tablet 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 tablet 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).

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Oxybutynin chloride extended-release tablets, USP are available as 5, 10 and 15 mg tablets for oral use:5 mg: Pale yellow colored, round shaped, biconvex coated tablets imprinted with EM1 on one side and plain on other side.10 mg: Pink colored, round shaped, biconvex coated tablets imprinted with EM2 on one side and plain on other side.15 mg: Grey colored, round shaped, biconvex coated tablets imprinted with EM3 on one side and plain on other side.. Extended release tablets mg, 10 mg and 15 mg 3).

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 chloride plasma concentrations were approximately fold higher when oxybutynin chloride extended-release tablet 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., max and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered. Co-administration with other anticholinergic drugs may increase the frequency and/or severity of anticholinergic-like effects. 7) Co-administration with strong cytochrome P450 (CYP) 3A4 inhibitors (e.g., ketoconazole) increases the systemic exposure of oxybutynin. 7) Co-administration with other anticholinergic drugs may increase the frequency and/or severity of anticholinergic-like effects. 7) Co-administration with strong cytochrome P450 (CYP) 3A4 inhibitors (e.g., ketoconazole) increases the systemic exposure of oxybutynin. 7).

GERIATRIC USE SECTION.

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).

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Oxybutynin chloride extended-release tablets, USP are available in three dosage strengths, mg (pale yellow), 10 mg (pink), and 15 mg (grey) and are imprinted on one side with EM1, EM2, or EM3 with black ink. Oxybutynin chloride extended-release tablets, USP are supplied in bottles of 30, 100, 500 and 1,000 tablets. mg 30 count bottle 100 count bottle 500 count bottle 1,000 count bottle NDC 16729-317-10 NDC 16729-317-01 NDC 16729-317-16 NDC 16729-317-17 10 mg30 count bottle 100 count bottle 500 count bottle 1,000 count bottle NDC 16729-318-10 NDC 16729-318-01 NDC 16729-318-16 NDC 16729-318-17 15 mg30 count bottle 100 count bottle 500 count bottle 1,000 count bottle NDC 16729-319-10 NDC 16729-319-01 NDC 16729-319-16 NDC 16729-319-17 StorageStore at 25C (77F); excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature]. Protect from moisture and humidity.Keep out of reach of children.

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).. Oxybutynin chloride extended-release tablets are muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. 1) 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). 1) Oxybutynin chloride extended-release tablets are muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. 1) 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). 1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Patients 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.Patients 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: Urinary retention and constipationHeat prostration due to decreased sweating. Heat prostration can occur when anticholinergic medicines are administered in the presence of high environmental temperature. Patients 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.Patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents such as oxybutynin chloride extended-release tablets.Patients 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.Oxybutynin chloride extended-release tablets should be taken at approximately the same time each day.. Patients 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.. Patients 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: Urinary retention and constipationHeat prostration due to decreased sweating. Heat prostration can occur when anticholinergic medicines are administered in the presence of high environmental temperature. Urinary retention and constipation. Heat prostration due to decreased sweating. Heat prostration can occur when anticholinergic medicines are administered in the presence of high environmental temperature.. Patients 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.. Patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents such as oxybutynin chloride extended-release tablets.. Patients 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.. Oxybutynin chloride extended-release tablets should be taken at approximately the same time each day.

MECHANISM OF ACTION SECTION.

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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. 24-month study in rats at dosages of oxybutynin chloride of 20, 80, 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 human equivalent dose taking into account normalization of 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 evidence of impaired fertility.

NURSING MOTHERS SECTION.

8.3 Nursing Mothers. It is not known whether oxybutynin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when oxybutynin chloride extended-release tablets are administered to nursing woman.

OVERDOSAGE SECTION.

10 OVERDOSAGE. The continuous release of oxybutynin from oxybutynin chloride extended-release tablets should be considered in the treatment of overdosage. Patients should be monitored for at least 24 hours. Treatment should be symptomatic and supportive. cathartic may be administered.Overdosage with oxybutynin chloride has been associated with anticholinergic effects including central nervous system excitation, flushing, fever, dehydration, cardiac arrhythmia, vomiting, and urinary retention.Ingestion of 100 mg oxybutynin chloride in association with alcohol has been reported in 13-year-old boy who experienced memory loss, and 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 fully recovered with symptomatic treatment.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Oxybutynin chloride extended-release tablets. Figure 7. Figure 8. Figure 9.

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 2O to 33 cm 2O, and reduction in the percentage of patients demonstrating uninhibited detrusor contractions (of at least 15 cm 2O) 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.

PHARMACODYNAMICS SECTION.

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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionFollowing 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-OxybutyninS-OxybutyninC max (ng/mL) 1.0(0.6)1.8(1.0)T max (h) 12.7(5.4)11.8(5.3)t 1/2 (h) 13.2(6.2)12.4(6.1)AUC (0-48) (ngh/mL) 18.4(10.3)34.2(16.9)AUC inf (ngh/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- DesethyloxybutyninC max (ng/mL) 0.7 +- 0.41.3 +- 0.87.8 +- 3.74.2 +- 2.3T max (h) 5.05.05.05.0AUC (ngh/mL)12.8 +- 7.023.7 +- 14.4125.1 +- 66.773.6 +- 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.. Figure 1. Figure 2. Food EffectsThe rate and extent of absorption and metabolism of oxybutynin are similar under fed and fasted conditions.. DistributionOxybutynin 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.. MetabolismOxybutynin 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.. 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 desethyloxybutynin.. Dose ProportionalityPharmacokinetic parameters of oxybutynin and desethyloxybutynin (C max and AUC) following administration of to 20 mg of oxybutynin chloride extended-release tablets are dose proportional. Use in Specific Populations. PediatricThe 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). GenderThere are no significant differences in the pharmacokinetics of oxybutynin in healthy male and female volunteers following administration of oxybutynin chloride extended-release tablets.. RaceAvailable 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.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Category B. There are no adequate and well-controlled studies using oxybutynin chloride extended-release tablets in pregnant women. Oxybutynin chloride extended-release tablets should be used during pregnancy only if the potential benefit to the patient outweighs the risk to the patient and fetus. Women who become pregnant during oxybutynin chloride extended-release tablets treatment are encouraged to contact their physician.. Risk SummaryBased on animal data, oxybutynin is predicted to have low probability of increasing the risk of adverse developmental effects above background risk.. Animal DataReproduction studies with oxybutynin chloride in the mouse, rat, hamster, and rabbit showed no evidence of impaired fertility or harm to the animal fetus.

SPL UNCLASSIFIED SECTION.

2.1 Adults. The recommended starting dose of Oxybutynin chloride extended-release tablet 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.

STORAGE AND HANDLING SECTION.

StorageStore at 25C (77F); excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature]. Protect from moisture and humidity.Keep out of reach of children.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pediatric 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) Renal or Hepatic Impairment: There have been no studies conducted in patients with renal or hepatic impairment. 8.6, 8.7) Pediatric 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) Renal or Hepatic Impairment: There have been no studies conducted in patients with renal or hepatic impairment. 8.6, 8.7) 8.1 Pregnancy. Pregnancy Category B. There are no adequate and well-controlled studies using oxybutynin chloride extended-release tablets in pregnant women. Oxybutynin chloride extended-release tablets should be used during pregnancy only if the potential benefit to the patient outweighs the risk to the patient and fetus. Women who become pregnant during oxybutynin chloride extended-release tablets treatment are encouraged to contact their physician.. Risk SummaryBased on animal data, oxybutynin is predicted to have low probability of increasing the risk of adverse developmental effects above background risk.. Animal DataReproduction studies with oxybutynin chloride in the mouse, rat, hamster, and rabbit showed no evidence of impaired fertility or harm to the animal fetus.. 8.3 Nursing Mothers. It is not known whether oxybutynin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when oxybutynin chloride extended-release tablets are administered to nursing woman.. 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 2O to 33 cm 2O, and reduction in the percentage of patients demonstrating uninhibited detrusor contractions (of at least 15 cm 2O) 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. Angioedema: Angioedema has been reported with oxybutynin. If symptoms of angioedema occur, discontinue oxybutynin chloride extended-release tablets immediately and initiate appropriate therapy. 5.1) Central 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) Use with caution due to aggravation of symptoms: Pre-existing dementia in patients treated with cholinesterase inhibitors 5.2), Parkinsons disease 5.2), Myasthenia gravis 5.3), and Decreased gastrointestinal motility in patients with autonomic neuropathy. 5.4). Urinary Retention: Use with caution in patients with clinically significant bladder outflow obstruction because of the risk of urinary retention 5.5) Gastrointestinal 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) Angioedema: Angioedema has been reported with oxybutynin. If symptoms of angioedema occur, discontinue oxybutynin chloride extended-release tablets immediately and initiate appropriate therapy. 5.1) Central 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) Use with caution due to aggravation of symptoms: Pre-existing dementia in patients treated with cholinesterase inhibitors 5.2), Parkinsons disease 5.2), Myasthenia gravis 5.3), and Decreased gastrointestinal motility in patients with autonomic neuropathy. 5.4). Pre-existing dementia in patients treated with cholinesterase inhibitors 5.2), Parkinsons disease 5.2), Myasthenia gravis 5.3), and Decreased gastrointestinal motility in patients with autonomic neuropathy. 5.4). Urinary Retention: Use with caution in patients with clinically significant bladder outflow obstruction because of the risk of urinary retention 5.5) Gastrointestinal 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)] 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 tablet affects 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.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 mothers 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.