DITROPAN XL® (oxybutynin chloride) is an antispasmodic, anticholinergic agent. Each DITROPAN XL® Extended Release Tablet 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 phenylcyclohexyl-glycolate 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, hydroxypropyl methylcellulose, lactose, magnesium stearate, polyethylene glycol, polyethylene oxide, synthetic iron oxides, titanium dioxide, polysorbate 80, sodium chloride, and butylated hydroxytoluene.
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.
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.
Following the first dose of DITROPAN XL®, 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.
The rate and extent of absorption and metabolism of oxybutynin are similar under fed and fasted conditions.
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.
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.
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.
Pharmacokinetic parameters of oxybutynin and desethyloxybutynin (C max and AUC) following administration of 5-20 mg of DITROPAN XL® are dose proportional.
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 not evaluated in individuals younger than 18 years of age. See PRECAUTIONS : Pediatric Use .
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 .
DITROPAN XL® 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 forced dose escalation design, whereas the other studies used a dose adjustment design in which each patient' 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.
DITROPAN XL® 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 contraindicated in patients with urinary retention, gastric retention, or 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.
DITROPAN XL® should be used with caution in patients with hepatic or renal impairment.
DITROPAN XL® should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention (see CONTRAINDICATIONS ).
DITROPAN XL® should be administered with caution to patients with gastrointestinal obstructive disorders because 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, intestinal atony, and myasthenia gravis.
DITROPAN XL® 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 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.
Patients should be informed that heat prostration (fever and heat stroke due to decreased sweating) can occur when anticholinergics such as oxybutyin 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.
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.
Pharmacokinetic studies with patients concomitantly receiving cytochrome P450 enzyme inhibitors, such as antimycotic agents (e.g. ketoconazole, itraconazole, and miconazole) or macrolide antibiotics (e.g. erythromycin and clarithromycin), have not been performed.
No specific drug-drug interaction studies have been performed with DITROPAN XL®.
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 on 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.
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.
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.
The safety and efficacy of DITROPAN XL® in pediatric patients have not been established.
The rate and severity of anticholinergic effects reported by patients less than 65 years old and those 65 years and older were similar (See , , Special Populations : Gender ).
The safety and efficacy of DITROPAN XL® was evaluated in a total of 580 participants who received DITROPAN XL® in clinical trials (429 patients, 151 healthy volunteers). These participants were treated with 5-30 mg/day for up to 4.5 months. Safety information is provided for 429 patients from three controlled clinical studies and one open label study (Table 2). 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%. 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 patients using DITROPAN XL® (5-30 mg/day) in all 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.
Other adverse events have been reported with oxybutynin chloride: tachycardia, hallucinations, cycloplegia, mydriasis, impotence, and suppression of lactation.
The continuous release of oxybutynin from DITROPAN XL® 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 has been associated with anticholinergic effects including CNS 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.
DITROPAN XL® 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.
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 30 mg/day). In general dosage adjustment may proceed at approximately weekly intervals.
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® (oxybutynin chloride) Extended Release Tablets are supplied in bottles of 100 tablets.
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.
For more information call 1-888-395-1232 or visit www.DitropanXL.com
Manufactured, distributed, and marketed by
ALZA Corporation, Mountain View, CA 94043.
UCB Pharma, Inc., Smyrna, GA 30080.
00096531 Edition: 7/99