OXYBUTYNIN CHLORIDE
EXTENDED-RELEASE
TABLETS
5 mg and 10 mg

Oxybutynin chloride is an antispasmodic, anticholinergic agent. Each oxybutynin chloride extended-release tablet contains 5 mg or 10 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 molecular formula of oxybutynin chloride is C₂₂H₃₁NO₃ • HCl.

Its structural formula is:

Oxybutynin chloride is a white crystalline solid with a molecular weight of 393.9. It is readily soluble in water and acids, but relatively insoluble in alkalis.

Oxybutynin chloride extended-release tablets contain the following inactive ingredients: colloidal silicon dioxide, dibasic calcium phosphate (anhydrous), hypromellose, magnesium stearate, methacrylic acid copolymer dispersion, polydextrose, polyethylene glycol, polysorbate 80, povidone, sodium hydroxide, talc, titanium dioxide, triacetin and triethyl citrate. The 5 mg strength also contains D&C Yellow No. 10 aluminum lake, FD&C Blue No. 1 aluminum lake and FD&C Red No. 40 aluminum lake; and the 10 mg strength also contains D&C Yellow No. 6 aluminum lake.

In addition, oxybutynin extended-release tablets may also contain imprinting ink consisting of either black pigment and natural resin or black iron oxide and propylene glycol.

Oxybutynin chloride extended-release tablets are formulated to deliver oxybutynin chloride at a controlled rate over approximately 24 hours. The dosage form is comprised of a 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 a controlled rate via diffusion and/or erosion.

Oxybutynin chloride exerts a direct antispasmodic effect on smooth muscle and inhibits the muscarinic action of acetylcholine on smooth muscle. Oxybutynin chloride exhibits only one-fifth of the anticholinergic activity of atropine on the rabbit detrusor muscle, but four to ten times the antispasmodic activity. No blocking effects occur at skeletal neuromuscular junctions or autonomic ganglia (antinicotinic effects).

Oxybutynin chloride relaxes bladder smooth muscle. 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. Oxybutynin thus decreases urgency and the frequency of both incontinent episodes and voluntary urination.

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

Oxybutynin chloride extended-release was evaluated for the treatment of patients with overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency in three controlled studies and one open label study. The majority of patients were Caucasian (89%) and female (91.9%) with a mean age of 59 years (range, 18 to 98 years). Entry criteria required that patients have urge or mixed incontinence (with a predominance of urge) as evidenced by ≥ 6 urge incontinence episodes per week and ≥ 10 micturitions per day. Study 1 was a forced dose escalation design, whereas the other studies used a dose adjustment design in which each patient's final dose was adjusted to a balance between improvement of incontinence symptoms and tolerability of side effects. Controlled studies included patients known to be responsive to oxybutynin or other anticholinergic medications, and these patients were maintained on a final dose for up to 2 weeks.

The efficacy results for the three controlled trials are presented in the following tables and figures.

Number of Urge Urinary Incontinence Episodes Per Week

Study 1	N	Oxybutynin Chloride ER	N	Placebo
Mean Baseline	34	15.9	16	20.9
Mean (SD) Change from BaselineCovariate adjusted mean with missing observations set to baseline values	34	-15.8 (8.9)	16	-7.6 (8.6)
95% Confidence Interval for Difference (oxybutynin chloride ER - Placebo)		(-13.6, -2.8)The difference between oxybutynin chloride ER and placebo was statistically significant.

Study 2	N	Oxybutynin Chloride ER	N	oxybutynin
Mean Baseline	53	27.6	52	23.0
Mean (SD) Change from BaselineCovariate adjusted mean with missing observations set to baseline values	53	-17.6 (11.9)	52	-19.4 (11.9)
95% Confidence Interval for Difference (oxybutynin chloride ER - oxybutynin)		(-2.8, 6.5)

Study 3	N	Oxybutynin Chloride ER	N	oxybutynin
Mean Baseline	111	18.9	115	19.5
Mean (SD) Change from BaselineCovariate adjusted mean with missing observations set to baseline values	111	-14.5 (8.7)	115	-13.8 (8.6)
95% Confidence Interval for Difference (oxybutynin chloride ER - oxybutynin)		(-3.0, 1.6)The difference between oxybutynin chloride ER and oxybutynin fulfilled the criteria for comparable efficacy.

Oxybutynin chloride extended-release tablets are once-daily controlled-release tablets indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.

Pediatric use information for the treatment of patients aged 6 years and older with symptoms of detrusor overactivity associated with a neurological condition (e.g., spina bifida) is approved for Alza Corporation's oxybutynin extended-release tablets. However, due to Alza Corporation's marketing exclusivity rights, this drug product is not labeled for pediatric use.

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 and in patients who are at risk for these conditions.

Oxybutynin chloride extended-release is also contraindicated in patients who have demonstrated hypersensitivity to the drug substance or other components of the product.

Oxybutynin chloride extended-release should be used with caution in patients with hepatic or renal impairment and in patients with myasthenia gravis due to the risk of symptom aggravation.

Patients should be informed that heat prostration (fever and heat stroke due to decreased sweating) can occur when anticholinergics such as oxybutynin chloride are administered in the presence of high environmental temperature.

Because anticholinergic agents such as oxybutynin may produce drowsiness (somnolence) or blurred vision, patients should be advised to exercise caution.

Patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents such as oxybutynin.

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.

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.

Mean oxybutynin chloride 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., C_max and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are coadministered.

Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin.

A 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 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 definite evidence of impaired fertility.

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 is administered to a nursing woman.

Clinical study information for pediatric patients 6 to 15 years of age with symptoms of detrusor overactivity in association with a neurological condition (e.g., spina bifida) is approved for Alza Corporation's oxybutynin chloride extended-release tablets. However, due to Alza Corporation's marketing exclusivity rights, this drug product is not labeled for 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.

The rate and severity of anticholinergic effects reported by patients less than 65 years old and those 65 years and older were similar (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations: Gender).

The safety and efficacy of oxybutynin chloride was evaluated in a total of 580 participants who received oxybutynin chloride extended-release tablets in four clinical trials (429 patients, 151 healthy volunteers). These participants were treated with 5 to 30 mg/day for up to 4.5 months. Three of these studies allowed dose adjustments based on efficacy and adverse events and one was a fixed dose escalation design. Safety information is provided for 429 patients from these three controlled clinical studies and one open label study in the first column of Table 2 below. Adverse events from two additional fixed dose, active controlled, 12 week treatment duration, post-marketing studies, in which 576 patients were treated with oxybutynin chloride extended-release tablets 10 mg/day, are also uled in Table 2 (second column). The adverse events are reported regardless of causality.

The most common adverse events reported by patients receiving 5 to 30 mg/day oxybutynin chloride extended-release tablets were the expected side effects of anticholinergic agents. The incidence of dry mouth was dose related.

The discontinuation rate for all adverse events was 6.8% in the 429 patients from the four studies of efficacy and safety who received 5 to 30 mg/day. The most frequent adverse event causing early discontinuation of study medication was nausea (1.9%), while discontinuation due to dry mouth was 1.2%.

In addition, the following adverse events were reported by 2 to < 5% of the 429 patients who received 5 to 30 mg/day of oxybutynin chloride extended-release tablets in the four efficacy and safety studies. General: abdominal pain, dry nasal and sinus mucous membranes, accidental injury, back pain, flu syndrome; Cardiovascular: hypertension, palpitation, vasodilatation; Digestive: flatulence, gastroesophageal reflux; Musculoskeletal: arthritis; Nervous: insomnia, nervousness, confusion; Respiratory: upper respiratory tract infection, cough, sinusitis, bronchitis, pharyngitis; Skin: dry skin, rash; Urogenital: impaired urination (hesitancy), increased post void residual volume, urinary retention, cystitis.

Additional rare adverse events reported from worldwide post-marketing experience with oxybutynin chloride extended-release tablets include: peripheral edema, cardiac arrhythmia, tachycardia, hallucinations, convulsions, and impotence.

Additional adverse events reported with some other oxybutynin chloride formulations include: cycloplegia, mydriasis, and suppression of lactation.

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. Activated charcoal as well as 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.

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.

The recommended starting dose of oxybutynin chloride extended-release tablets is 5 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.

Dosing information for pediatric patients aged 6 years and older is approved for Alza Corporation's oxybutynin chloride extended-release tablets. However, due to Alza Corporation's marketing exclusivity rights, this drug product is not labeled for pediatric use.

Oxybutynin chloride extended-release tablets are available containing 5 mg or 10 mg of oxybutynin chloride, USP.

The 5 mg tablets are light green film coated, round, unscored tablets with M over O 5 imprinted in black ink on one side of the tablet and blank on the other side. They are available as follows:

NDC 0378-6605-01
bottles of 100 tablets

NDC 0378-6605-05
bottles of 500 tablets

The 10 mg tablets are peach film coated, round, unscored tablets with M over O 10 imprinted in black ink on one side of the tablet and blank on the other side. They are available as follows:

NDC 0378-6610-01
bottles of 100 tablets

NDC 0378-6610-05
bottles of 500 tablets