DESCRIPTION

DITROPAN XL® (oxybutynin chloride) is an antispasmodic, anticholinergic agent. Each DITROPAN XL Extended Release Tablet contains 5 mg, 10 mg, or 15 mg ofoxybutynin 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 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.

DITROPAN XL also contains the following inert ingredients: cellulose acetate, hypromellose, lactose, magnesium stearate, polyethylene glycol, polyethylene oxide, synthetic iron oxides, titanium dioxide, polysorbate 80, sodium chloride, and butylated hydroxytoluene.

System Components and Performance

DITROPAN XL uses osmotic pressure to deliver oxybutynin chloride at a controlled rate over approximately 24 hours. The system, which resembles a conventional tablet in appearance, comprises an osmotically active bilayer core surrounded by a semipermeable membrane. The bilayer core is composed of a drug layer containing the drug and excipients, and a push layer containing osmotically active components. There is a precision-laser drilled orifice in the semipermeable membrane on the drug-layer side of the tablet. In an aqueous environment, such as the gastrointestinal tract, water permeates through the membrane into the tablet core, causing the drug to go into suspension and the push layer to expand. This expansion pushes the suspended drug out through the orifice. The semipermeable membrane controls the rate at which water permeates into the tablet core, which in turn controls the rate of drug delivery. The controlled rate of drug delivery into the gastrointestinal lumen is thus independent of pH or gastrointestinal motility. The function of DITROPAN XL depends on the existence of an osmotic gradient between the contents of the bilayer core and the fluid in the gastrointestinal tract. Since the osmotic gradient remains constant, drug delivery remains essentially constant. The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the feces as an insoluble shell.

CLINICAL PHARMACOLOGY

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.

Pharmacokinetics

Absorption

Following the first dose of DITROPAN XL® (oxybutynin chloride), oxybutynin plasma concentrations rise for 4 to 6 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 DITROPAN XL are 156% and 187%, respectively, compared with oxybutynin. The mean pharmacokinetic parameters for R- and S-oxybutynin are summarized in Table 1. The plasma concentration-time profiles for R- and S-oxybutynin are similar in shape; Figure 1 shows the profile for R-oxybutynin.

Steady-state oxybutynin plasma concentrations are achieved by Day 3 of repeated DITROPAN XL dosing, with no observed drug accumulation or change in oxybutynin and desethyloxybutynin pharmacokinetic parameters.

DITROPAN XL steady-state pharmacokinetics was studied in 19 children aged 5-15 years with detrusor overactivity associated with a neurological condition (e.g., spina bifida). The children were on DITROPAN XL total daily dose ranging from 5 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 5 mg per day DITROPAN XL, the mean pharmacokinetic parameters derived for R- and S-oxybutynin and R- and S-desethyloxybutynin are summarized in Table 2. 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.

Food Effects

The rate and extent of absorption and metabolism of oxybutynin are similar under fed and fasted conditions.

Distribution

Plasma concentrations of oxybutynin decline biexponentially following intravenous or oral administration. The volume of distribution is 193 L after intravenous administration of 5 mg oxybutynin chloride.

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 DITROPAN XL 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 5-20 mg of DITROPAN XL are dose proportional.

Special Populations

Geriatric:    The pharmacokinetics of DITROPAN XL were similar in all patients studied (up to 78 years of age).

Pediatric:    The pharmacokinetics of DITROPAN XL were evaluated in 19 children aged 5-15 years with detrusor overactivity associated with a neurological condition (e.g., spina bifida). The pharmacokinetics of DITROPAN XL in these pediatric patients were consistent with those reported for adults (see Tables 1 and 2, 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 DITROPAN XL.

Race:    Available data suggest that there are no significant differences in the pharmacokinetics of oxybutynin based on race in healthy volunteers following administration of DITROPAN XL.

Renal Insufficiency:    There is no experience with the use of DITROPAN XL in patients with renal insufficiency.

Hepatic Insufficiency:    There is no experience with the use of DITROPAN XL in patients with hepatic insufficiency.

Drug-Drug Interactions:    See PRECAUTIONS: Drug Interactions.

CLINICAL STUDIES

DITROPAN XL® (oxybutynin chloride) 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 (89.0%) 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 fixed 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.

INDICATIONS AND USAGE

DITROPAN XL® (oxybutynin chloride) is a once-daily controlled-release tablet indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.

DITROPAN XL is also indicated in the treatment of pediatric patients aged 6 years and older with symptoms of detrusor overactivity associated with a neurological condition (e.g., spina bifida).

CONTRAINDICATIONS

DITROPAN XL® (oxybutynin chloride) is 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.

DITROPAN XL is also contraindicated in patients who have demonstrated hypersensitivity to the drug substance or other components of the product.

PRECAUTIONS

General

DITROPAN XL® (oxybutynin chloride) 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.

Urinary Retention

DITROPAN XL should be administered with caution to patients with clinically significant bladder outflow obstruct-ion because of the risk of urinary retention (see CONTRAINDICATIONS ).

Gastrointestinal Disorders

DITROPAN XL should be administered with caution to patients with gastrointestinal obstructive disorders be-cause of the risk of gastric retention (see CONTRAINDICATIONS ).

DITROPAN XL, 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.

DITROPAN XL should be used with caution in patients who have gastro-esophageal 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 DITROPAN XL 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.

Information for Patients

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 DITROPAN XL should be swallowed whole with the aid of liquids. Patients should not chew, divide, or crush tablets. The medication is contained within a nonabsorbable shell designed to release the drug at a controlled rate. The tablet shell is eliminated from the body; patients should not be concerned if they occasionally notice in their stool something that looks like a tablet.

DITROPAN XL should be taken at approximately the same time each day.

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 anti-cholinergic 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 DITROPAN XL was 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 co-administered.

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

Pregnancy: Teratogenic Effects

Pregnancy Category B

Reproduction studies with oxybutynin chloride in the mouse, rat, hamster, and rabbit showed no definite evidence of impaired fertility or harm to the animal fetus. The safety of DITROPAN XL administration to women who are or who may become pregnant has not been established. Therefore, DITROPAN XL should not be given to pregnant women unless, in the judgment of the physician, the probable clinical benefits outweigh the possible hazards.

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 DITROPAN XL is administered to a nursing woman.

Pediatric Use

The safety and efficacy of DITROPAN XL were studied in 60 children in a 24-week, open-label trial. Patients were aged 6-15 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 DITROPAN XL 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 DITROPAN XL 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%.

DITROPAN XL is not recommended in pediatric patients who can not swallow the tablet whole without chewing, dividing, or crushing, or in children under the age of 6 (See DOSAGE AND ADMINISTRATION ).

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 (see CLINICAL PHARMACOLOGY , Pharmacokinetics , Special Populations: Gender ).

ADVERSE REACTIONS

Adverse Events with DITROPAN XL

The safety and efficacy of DITROPAN XL® (oxybutynin chloride) was evaluated in a total of 580 participants who received DITROPAN XL in 4 clinical trials (429 patients, 151 healthy volunteers). These participants were treated with 5-30 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 3 below. Adverse events from two additional fixed dose, active controlled, 12 week treatment duration, postmarketing studies, in which 576 patients were treated with DITROPAN XL 10 mg/day, are also listed in Table 3 (second column). The adverse events are reported regardless of causality.

The most common adverse events reported by patients receiving 5-30 mg/day DITROPAN XL 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 4 studies of efficacy and safety who received 5-30 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 5-30 mg/day of DITROPAN XL in the 4 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 postmarketing experience with DITROPAN XL 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.

OVERDOSAGE

The continuous release of oxybutynin from DITROPAN XL® (oxybutynin chloride) 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.

DOSAGE AND ADMINISTRATION

DITROPAN XL® (oxybutynin chloride) must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed.

DITROPAN XL may be administered with or without food.

Adults:    The recommended starting dose of DITROPAN XL 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.

Pediatric patients aged 6 years of age and older:    The recommended starting dose of DITROPAN XL is 5 mg once daily. Dosage may be adjusted in 5-mg increments to achieve a balance of efficacy and tolerability (up to a maximum of 20 mg/day).

HOW SUPPLIED

DITROPAN XL® (oxybutynin chloride) Extended Release Tablets are available in three dosage strengths, 5 mg (pale yellow), 10 mg (pink), and 15 mg (gray) and are imprinted with "5 XL", "10 XL", or "15 XL". DITROPAN XL Extended Release Tablets are supplied in bottles of 100 tablets.

Storage

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from moisture and humidity.

Rx Only

For more information call 1-888-395-1232 or visit www.DITROPANXL.com

Manufactured by Alza Corporation, Mountain View, CA 94043

An ALZA OROS®

Technology Product

DITROPAN XL® and OROS® are registered trademarks of Alza Corporation.

Distributed and Marketed by Ortho-Mcneil Pharmaceutical, Inc., Raritan, NJ 08869.

Ortho-Mcneil

631-10-800-2        Revised June 2004