n pharmacokinetic parameters (i.e., c 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)

isorders 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 a patent airway should be promptly provided. 5.2 central nervous system effects oxybutynin is associated with anticholinergic central nervous system (cns) effects [see adverse reactions (6)] . a variety of cns anticholinergic effects have been reported, including hallucinations, agitation, confusion and somnolence. patients should be monitored for signs of anticholinergic cns effects, particularly in the first few months after beginning treatment or increasing the dose. advise patients not to drive or operate heavy machinery until they know how oxybutynin chloride extended - release tablets affect them. if a patient experiences anticholinergic cns effects, dose reduction or drug discontinuation should be considered. oxybutynin chloride extended - release tablets should be used with caution in patients with preexisting dementia treated with cholinesterase inhibitors due to the risk of aggravation of symptoms. oxybutynin chloride extended - release tablets should be used with caution in patients with parkinson's disease due to the risk of aggravation of symptoms. 5.3 worsening of symptoms of myasthenia gravis oxybutynin chloride extended - release tablets should be used with caution in patients with myasthenia gravis due to the risk of aggravation of symptoms. 5.4 worsening of symptoms of decreased gastrointestinal motility in patients with autonomic neuropathy oxybutynin chloride extended - release tablets should be used with caution in patients with autonomic neuropathy due to the risk of aggravation of symptoms of decreased gastrointestinal motility. 5.5 urinary retention oxybutynin chloride extended - release tablets should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention [see contraindications ( 4 )] . 5.6 gastrointestinal adverse reactions oxybutynin chloride extended - release tablets should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention [see contraindications (4)] . oxybutynin chloride extended - release tablets, like other anticholinergic drugs, may decrease gastrointestinal motility and should be used with caution in patients with conditions such as ulcerative colitis and intestinal atony. oxybutynin chloride extended - release tablets should be used with caution in patients who have gastroesophageal reflux and/or who are concurrently taking drugs (such as bisphosphonates) that can cause or exacerbate esophagitis. as with any other nondeformable material, caution should be used when administering oxybutynin chloride extended - release tablets to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic). there have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other drugs in nondeformable controlled-release formulations.

e of efficacy and tolerability (up to a maximum of 30 mg/day). in general, dosage adjustment may proceed at approximately weekly intervals. 2.2 pediatric patients aged 6 years of age and older the recommended starting dose of oxybutynin chloride extended - release tablets is 5 mg once daily at approximately the same time each day. dosage may be adjusted in 5 mg increments to achieve a balance of efficacy and tolerability (up to a maximum of 20 mg/day).

n 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 system/organ class preferred term oxybutynin chloride extended-release tablets 5 mg/day to 30 mg/day n = 774 % oxybutynin chloride ir ir = immediate release 5 mg/day to 20 mg/day n = 199 % psychiatric disorders insomnia 3.0 5.5 nervous system disorders headache 7.5 8.0 somnolence 5.6 14.1 dizziness 5.0 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 3.0 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 6.0 nausea 4.5 11.6 abdominal pain 1.6 2.0 vomiting 1.3 1.5 flatulence 1.2 2.5 gastro-esophageal reflux disease 1.0 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 2.0 urinary hesitation 1.9 8.5 urinary retention 1.2 3.0 general disorders and administration site conditions fatigue 2.6 3.0 investigations residual urine volume the bundled term residual urine volume consists of the preferred terms residual urine volume and residual urine volume increased. 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 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 a higher incidence than placebo in clinical trials: metabolism and nutrition disorders: anorexia, fluid retention; vascular disorders: hot flush; respiratory, thoracic and mediastinal disorders: dysphonia; gastrointestinal disorders: dysphagia, frequent bowel movements; general disorders and administration site conditions: chest discomfort, thirst. 6.2 postmarketing experience the following additional adverse reactions have been reported from worldwide postmarketing experience with oxybutynin chloride extended-release tablets. because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. infections and infestations: urinary tract infection; psychiatric disorders: psychotic disorder, agitation, confusional state, hallucinations, memory impairment, abnormal behavior; nervous system disorders: convulsions; eye disorders: glaucoma; respiratory, thoracic and mediastinal disorders: nasal congestion; cardiac disorders: arrhythmia, tachycardia, palpitations, qt interval prolongation; vascular disorders: flushing, hypertension; skin and subcutaneous tissue disorders: rash; renal and urinary disorders: impotence; general disorders and administration site conditions: hypersensitivity reactions, including angioedema with airway obstruction, urticaria, and face edema; anaphylactic reactions requiring hospitalization for emergency treatment; injury, poisoning and procedural complications: fall. additional adverse events reported with some other oxybutynin chloride formulations include: cycloplegia, mydriasis, and suppression of lactation. in one reported case, concomitant use of oxybutynin with carbamazepine and dantrolene was associated with adverse events of vomiting, drowsiness, confusion, unsteadiness, slurred speech and nystagmus, suggestive of carbamazepine toxicity.

n pharmacokinetic parameters (i.e., c 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)

s on the breastfed infant, or the effects of oxybutynin chloride extended-release tablets on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for oxybutynin chloride extended-release tablets and any potential adverse effects on the breastfed child from oxybutynin chloride extended-release tablets or from the underlying maternal condition. 8.4 pediatric use the safety and efficacy of oxybutynin chloride extended-release tablets were studied in 60 children in a 24-week, open-label, non-randomized trial. patients were aged 6 years 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. study results demonstrated that administration of oxybutynin chloride extended-release tablets 5 mg/day to 20 mg/day was associated with an increase from baseline in mean urine volume per catheterization from 108 ml to 136 ml, an increase from baseline in mean urine volume after morning awakening from 148 ml to 189 ml, and an increase from baseline in the mean percentage of catheterizations without a leaking episode from 34% to 51%. urodynamic results were consistent with clinical results. administration of oxybutynin chloride extended-release tablets resulted in an increase from baseline in mean maximum cystometric capacity from 185 ml to 254 ml, a decrease from baseline in mean detrusor pressure at maximum cystometric capacity from 44 cm 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 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.

seline 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 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.

hereafter steady concentrations are maintained for up to 24 hours, minimizing fluctuations between peak and trough concentrations associated with oxybutynin. the relative bioavailabilities of r- and s-oxybutynin from oxybutynin chloride extended-release tablets are 156% and 187%, respectively, compared with oxybutynin. the mean pharmacokinetic parameters for r- and s-oxybutynin are summarized in table 2. the plasma concentration-time profiles for r- and s-oxybutynin are similar in shape; figure 1 shows the profile for r-oxybutynin. table 2: mean (sd) r- and s-oxybutynin pharmacokinetic parameters following a single dose of oxybutynin chloride extended-release tablets 10 mg (n = 43) parameters (units) r-oxybutynin s-oxybutynin c 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) (ng∙h/ml) 18.4 (10.3) 34.2 (16.9) auc inf (ng∙h/ml) 21.3 (12.2) 39.5 (21.2) figure 1: mean r-oxybutynin plasma concentrations following a single dose of oxybutynin chloride extended-release tablets 10 mg and oxybutynin 5 mg administered every 8 hours (n = 23 for each treatment). steady state oxybutynin plasma concentrations are achieved by day 3 of repeated oxybutynin chloride extended-release tablets dosing, with no observed drug accumulation or change in oxybutynin and desethyloxybutynin pharmacokinetic parameters. oxybutynin chloride extended-release tablets steady state pharmacokinetics were studied in 19 children aged 5 years to 15 years with detrusor overactivity associated with a neurological condition (e.g., spina bifida). the children were on oxybutynin chloride extended-release tablets total daily dose ranging from 5 mg to 20 mg (0.10 mg/kg to 0.77 mg/kg). sparse sampling technique was used to obtain serum samples. when all available data are normalized to an equivalent of 5 mg per day of oxybutynin chloride extended-release tablets, the mean pharmacokinetic parameters derived for r- and s-oxybutynin and r- and s-desethyloxybutynin are summarized in table 3. the plasma-time concentration profiles for r- and s-oxybutynin are similar in shape; figure 2 shows the profile for r-oxybutynin when all available data are normalized to an equivalent of 5 mg per day. table 3: mean ± sd r- and s-oxybutynin and r- and s-desethyloxybutynin pharmacokinetic parameters in children aged 5 to 15 following administration of 5 mg to 20 mg oxybutynin chloride extended-release tablets once daily (n = 19), all available data normalized to an equivalent of oxybutynin chloride extended-release tablets 5 mg once daily r-oxybutynin s-oxybutynin r-desethyloxybutynin s-desethyloxybutynin c max (ng/ml) 0.7 ± 0.4 1.3 ± 0.8 7.8 ± 3.7 4.2 ± 2.3 t max (h) 5.0 5.0 5.0 5.0 auc(ng∙h/ml) 12.8 ± 7.0 23.7 ± 14.4 125.1 ± 66.7 73.6 ± 47.7 figure 2: mean steady state (± sd) r-oxybutynin plasma concentrations following administration of 5 mg to 20 mg oxybutynin chloride extended-release tablets once daily in children aged 5 to 15. plot represents all available data normalized to an equivalent of oxybutynin chloride extended-release tablets 5 mg once daily. figure 1 figure 2 food effects the rate and extent of absorption and metabolism of oxybutynin are similar under fed and fasted conditions. distribution oxybutynin is widely distributed in body tissues following systemic absorption. the volume of distribution is 193 l after intravenous administration of 5 mg oxybutynin chloride. both enantiomers of oxybutynin are highly bound (> 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 (c max and auc) following administration of 5 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 5 years to 15 years with detrusor overactivity associated with a neurological condition (e.g., spina bifida). the pharmacokinetics of oxybutynin chloride extended - release tablets in these pediatric patients were consistent with those reported for adults (see tables 2 and 3, and figures 1 and 2 above). gender there are no significant differences in the pharmacokinetics of oxybutynin in healthy male and female volunteers following administration of oxybutynin chloride extended - release tablets. race available data suggest that there are no significant differences in the pharmacokinetics of oxybutynin based on race in healthy volunteers following administration of oxybutynin chloride extended - release tablets.

.1) auc (0–48) (ng∙h/ml) 18.4 (10.3) 34.2 (16.9) auc inf (ng∙h/ml) 21.3 (12.2) 39.5 (21.2) figure 1: mean r-oxybutynin plasma concentrations following a single dose of oxybutynin chloride extended-release tablets 10 mg and oxybutynin 5 mg administered every 8 hours (n = 23 for each treatment). steady state oxybutynin plasma concentrations are achieved by day 3 of repeated oxybutynin chloride extended-release tablets dosing, with no observed drug accumulation or change in oxybutynin and desethyloxybutynin pharmacokinetic parameters. oxybutynin chloride extended-release tablets steady state pharmacokinetics were studied in 19 children aged 5 years to 15 years with detrusor overactivity associated with a neurological condition (e.g., spina bifida). the children were on oxybutynin chloride extended-release tablets total daily dose ranging from 5 mg to 20 mg (0.10 mg/kg to 0.77 mg/kg). sparse sampling technique was used to obtain serum samples. when all available data are normalized to an equivalent of 5 mg per day of oxybutynin chloride extended-release tablets, the mean pharmacokinetic parameters derived for r- and s-oxybutynin and r- and s-desethyloxybutynin are summarized in table 3. the plasma-time concentration profiles for r- and s-oxybutynin are similar in shape; figure 2 shows the profile for r-oxybutynin when all available data are normalized to an equivalent of 5 mg per day. table 3: mean ± sd r- and s-oxybutynin and r- and s-desethyloxybutynin pharmacokinetic parameters in children aged 5 to 15 following administration of 5 mg to 20 mg oxybutynin chloride extended-release tablets once daily (n = 19), all available data normalized to an equivalent of oxybutynin chloride extended-release tablets 5 mg once daily r-oxybutynin s-oxybutynin r-desethyloxybutynin s-desethyloxybutynin c max (ng/ml) 0.7 ± 0.4 1.3 ± 0.8 7.8 ± 3.7 4.2 ± 2.3 t max (h) 5.0 5.0 5.0 5.0 auc(ng∙h/ml) 12.8 ± 7.0 23.7 ± 14.4 125.1 ± 66.7 73.6 ± 47.7 figure 2: mean steady state (± sd) r-oxybutynin plasma concentrations following administration of 5 mg to 20 mg oxybutynin chloride extended-release tablets once daily in children aged 5 to 15. plot represents all available data normalized to an equivalent of oxybutynin chloride extended-release tablets 5 mg once daily. figure 1 figure 2 food effects the rate and extent of absorption and metabolism of oxybutynin are similar under fed and fasted conditions. distribution oxybutynin is widely distributed in body tissues following systemic absorption. the volume of distribution is 193 l after intravenous administration of 5 mg oxybutynin chloride. both enantiomers of oxybutynin are highly bound (> 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 (c max and auc) following administration of 5 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 5 years to 15 years with detrusor overactivity associated with a neurological condition (e.g., spina bifida). the pharmacokinetics of oxybutynin chloride extended - release tablets in these pediatric patients were consistent with those reported for adults (see tables 2 and 3, and figures 1 and 2 above). gender there are no significant differences in the pharmacokinetics of oxybutynin in healthy male and female volunteers following administration of oxybutynin chloride extended - release tablets. race available data suggest that there are no significant differences in the pharmacokinetics of oxybutynin based on race in healthy volunteers following administration of oxybutynin chloride extended - release tablets.

y results for the three controlled trials are presented in the following tables 4, 5, and 6 and figures 3, 4, and 5. table 4: number of urge urinary incontinence episodes per week (study 1) study 1 n oxybutynin chloride extended-release tablets n placebo mean baseline 34 15.9 16 20.9 mean (sd) change from baseline covariate adjusted mean with missing observations set to baseline values 34 -15.8 (8.9) 16 -7.6 (8.6) 95% confidence interval for difference (-13.6, -2.8) the difference between oxybutynin chloride extended-release tablets and placebo was statistically significant. (oxybutynin chloride extended-release tablets - placebo) figure 3: mean change (±sd) in urge urinary incontinence episodes per week from baseline (study 1) * the difference between oxybutynin chloride extended-release tablets and placebo was statistically significant. table 5: number of urge urinary incontinence episodes per week (study 2) study 2 n oxybutynin chloride extended-release tablets n oxybutynin mean baseline 53 27.6 52 23.0 mean (sd) change from baseline covariate adjusted mean with missing observations set to baseline values 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) 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 3 n oxybutynin chloride extended-release tablets n oxybutynin mean baseline 111 18.9 115 19.5 mean (sd) change from baseline covariate adjusted mean with missing observations set to baseline values 111 -14.5 (8.7) 115 -13.8 (8.6) 95% confidence interval for difference (-3.0, 1.6) the difference between oxybutynin chloride extended-release tablets and oxybutynin fulfilled the criteria for comparable efficacy. (oxybutynin chloride extended-release tablets- oxybutynin) figure 5: mean change (±sd) in urge urinary incontinence episodes per week from baseline (study 3) ** the difference between oxybutynin chloride extended-release tablets and oxybutynin fulfilled the criteria for comparable efficacy. figure 5 figure 4 figure 3

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. the hydrated polymer system of the tablet is not rigid and is expected to be broken up by normal peristalsis in the gi tract. the biologically inert components of the tablet may occasionally remain intact during gi transit and will be eliminated in the feces as a soft, hydrated mass. oxybutynin chloride extended-release tablets should be taken at approximately the same time each day. for more information call 1-888-235-bion or 1-888-235-2466. distributed by: bionpharma inc. 600 alexander road, princeton, nj 08540 made in india fda-07