oxybutynin

1 INDICATIONS AND USAGE Oxybutynin chloride is a 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 6 years and older with symptoms of detrusor overactivity associated with a neurological condition (e.g., spina bifida). ( 1 ) Oxybutynin chloride extended-release tablets are a 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 6 years and older with symptoms of detrusor overactivity associated with a neurological condition (e.g., spina bifida).

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. ( 2 ) Adults: Start with 5 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 5 mg, once daily at approximately the same time every day.Dose should not exceed 20 mg per day. ( 2.2 ) 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. 2.1 Adults The recommended starting dose of oxybutynin chloride extended-release tablet 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 are 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).

3 DOSAGE FORMS AND STRENGTHS Extended-release tablets 5 mg, 10 mg and 15 mg (3) Oxybutynin chloride extended-release tablets, USP are available as 5 mg, 10 mg and 15 mg tablets for oral use: Oxybutynin chloride extended-release tablets USP, 5 mg are white to off-white, round, beveled-edged, biconvex, coated-tablets debossed on one side with "255" and plain on other side. Oxybutynin chloride extended-release tablets USP, 10 mg are white to off-white, round, beveled-edged, biconvex, coated-tablets debossed on one side with "256" and plain on other side. Oxybutynin chloride extended-release tablets USP, 15 mg are white to off-white, round, beveled-edged, biconvex, coated-tablets debossed on one side with "257" and plain on other side.

4 CONTRAINDICATIONS Urinary retention ( 4 ) Gastric Retention ( 4 ) Uncontrolled narrow angle glaucoma ( 4 ) Known hypersensitivity to oxybutynin chloride or any component of oxybutynin chloride extended-release tablets ( 4 ) 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 angioedema.

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 Zydus Pharmaceuticals USA Inc. at 1-877-993-8779 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 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 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 extended-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 Tablets 2 The bundled term residual urine volume consists of the preferred terms residual urine volume and residual urine volume increased. System/Organ Class Preferred Term Oxybutynin Chloride Extended-Release Tablets 5 to 30 mg/day n = 774 % Oxybutynin Chloride Immediate-Release Tablets 5 to 20 mg/day n = 199 % Psychiatric Disorders Insomnia 3 5.5 Nervous System Disorders Headache 7.5 8 Somnolence 5.6 14.1 Dizziness 5 16.6 Dysgeusia 1.6 1.5 Eye Disorders Vision blurred 4.3 9.6 Dry eye 3.1 2.5 Respiratory, Thoracic and Mediastinal Disorders Cough 1.9 3 Oropharyngeal pain 1.9 1.5 Dry throat 1.7 2.5 Nasal dryness 1.7 4.5 Gastrointestinal Disorders Dry mouth 34.9 72.4 Constipation 8.7 15.1 Diarrhea 7.9 6.5 Dyspepsia 4.5 6 Nausea 4.5 11.6 Abdominal pain 1.6 2 Vomiting 1.3 1.5 Flatulence 1.2 2.5 Gastro-esophageal reflux disease 1 0.5 Skin and Subcutaneous Tissue Disorders Dry skin 1.8 2.5 Pruritus 1.3 1.5 Renal and Urinary Disorders Dysuria 1.9 2 Urinary hesitation 1.9 8.5 Urinary retention 1.2 3 General Disorders and Administration Site Conditions Fatigue 2.6 3 I nvestigations Residual urine volume 2 2.3 3.5 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-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, QT interval prolongation; Vascular Disorders: flushing, hypertension; S kin and Subcutaneous Tissue Disorders: rash; Renal and Urinary Disorders: impotence; General Disorders and Administratio …

7 DRUG INTERACTIONS 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 ) 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 a narrow therapeutic index. Anticholinergic agents may also antagonize the effects of prokinetic agents, such as metoclopramide. Mean oxybutynin plasma concentrations were approximately 2 fold higher when oxybutynin chloride extended-release tablets were administered with ketoconazole, a 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.

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 6 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 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 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 to 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 extended-release tablets. Study results demonstrated that administration of oxybutynin chloride extended-release tablets 5 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 H 2 O to 33 cm H 2 O, and a reduction in the percentage of patients demonstrating uninhibited detrusor contractions (of at least 15 cm H 2 O) from 60% to 28%. The pharmacokinetics of oxybutynin chloride 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.

11 DESCRIPTION Oxybutynin chloride extended-release tablets are an antispasmodic, muscarinic antagonist. Each oxybutynin chloride extended-release tablets contains 5 mg, 10 mg, or 15 mg of oxybutynin chloride USP, formulated as a once-a-day controlled-release tablet for oral administration. Oxybutynin chloride is administered as a 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 C 22 H 31 NO 3 •HCl. Its structural formula is: Oxybutynin chloride, USP is a white crystalline, practically odorless powder with a molecular weight of 393.95. It is freely soluble in water and in alcohol, very soluble in methanol and in chloroform, soluble in acetone, slightly soluble in ether and very slightly soluble in hexane. Oxybutynin chloride extended-release tablet, USP also contains the following inactive ingredients: alginic acid, hydrogenated castor oil, hypromellose, lactose monohydrate, magnesium stearate, methacrylic acid copolymer dispersion, microcrystalline cellulose, povidone, talc and triethyl citrate. The product complies the USP Dissolution Test 8 System Components and Performance Oxybutynin chloride extended-release tablet uses an enteric coated hydrophilic hydrogel matrix to deliver oxybutynin chloride at controlled rate over approximately 24 hours by diffusion mechanism. The system comprises of a core, which contains the drug, rate controlling hydrogel and other excipients. The core is surrounded by a partially or complete pH dependent membrane. Hence, when the drug reaches the acidic medium, in stomach minimal drug release will occur and when it reaches an environment of pH 5.5 and above, the outer membrane will be dissolved exposing the inner core. This inner core will partially hydrate to form a gel layer and the drug release will occur via diffusion mechanism from a gel layer and subsequently through gel erosion. Oxybutynin chloride extended-release tablet

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. A 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 a 13 year old boy who experienced memory loss, and a 34 year old woman who developed stupor, followed by disorientation and agitation on awakening, dilated pupils, dry skin, cardiac arrhythmia, and retention of urine. Both patients fully recovered with symptomatic treatment.

16 HOW SUPPLIED/STORAGE AND HANDLING Oxybutynin Chloride Extended-release Tablets USP, 5 mg are white to off-white, round, beveled-edged, biconvex, coated-tablets debossed on one side with "255" and plain on other side and are supplied as follows: NDC 68382-255-06 in bottle of 30 tablets with child-resistant closure NDC 68382-255-14 in bottle of 60 tablets with child-resistant closure NDC 68382-255-16 in bottle of 90 tablets with child-resistant closure NDC 68382-255-01 in bottle of 100 tablets NDC 68382-255-05 in bottle of 500 tablets NDC 68382-255-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets Oxybutynin Chloride Extended-release Tablets USP, 10 mg are white to off-white, round, beveled-edged, biconvex, coated-tablets debossed on one side with "256" and plain on other side and are supplied as follows: NDC 68382-256-06 in bottle of 30 tablets with child-resistant closure NDC 68382-256-14 in bottle of 60 tablets with child-resistant closure NDC 68382-256-16 in bottle of 90 tablets with child-resistant closure NDC 68382-256-01 in bottle of 100 tablets NDC 68382-256-05 in bottle of 500 tablets NDC 68382-256-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets Oxybutynin Chloride Extended-release Tablets USP, 15 mg are white to off-white, round, beveled-edged, biconvex, coated-tablets debossed on one side with "257" and plain on other side and are supplied as follows: NDC 68382-257-06 in bottle of 30 tablets with child-resistant closure NDC 68382-257-14 in bottle of 60 tablets with child-resistant closure NDC 68382-257-16 in bottle of 90 tablets with child-resistant closure NDC 68382-257-01 in bottle of 100 tablets NDC 68382-257-05 in bottle of 500 tablets NDC 68382-257-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets Storage Store at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature]. Protect from moisture and humidity. Keep out of reach of children.