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.

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.

Table 1 Mean (SD) R- and S-Oxybutynin Pharmacokinetic Parameters Following a Single Dose of DITROPAN XL® 10 mg (n=43)

Parameters (units)	R-Oxybutynin		S-Oxybutynin
Cmax (ng/mL)	1.0	(0.6)	1.8	(1.0)
Tmax (h)	12.7	(5.4)	11.8	(5.3)
t1/2 (h)	13.2	(6.2)	12.4	(6.1)
AUC (0–48) (ng∙h/mL)	18.4	(10.3)	34.2	(16.9)
AUCinf (ng∙h/mL)	21.3	(12.2)	39.5	(21.2)

Figure 1. Mean R-oxybutynin plasma concentrations following a single dose of DITROPAN XL® 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 DITROPAN XL® dosing, with no observed drug accumulation or change in oxybutynin and desethyloxybutynin pharmacokinetic parameters.

DITROPAN XL® steady state pharmacokinetics were 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.

Table 2 Mean ± SD R- and S-Oxybutynin and R- and S-Desethyloxybutynin Pharmacokinetic Parameters in Children Aged 5–15 Following Administration of 5 to 20 mg DITROPAN XL® Once Daily (n=19), All Available Data Normalized to an Equivalent of DITROPAN XL® 5 mg Once Daily

	R-Oxybutynin	S-Oxybutynin	R- Desethyloxybutynin	S- Desethyloxybutynin
Cmax (ng/mL)	0.7 ± 0.4	1.3 ± 0.8	7.8 ± 3.7	4.2 ± 2.3
Tmax (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 to 20 mg DITROPAN XL® once daily in children aged 5–15. Plot represents all available data normalized to an equivalent of DITROPAN XL® 5 mg once daily.

Food Effects

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

Central Nervous System Effects

Oxybutynin is associated with anticholinergic central nervous system (CNS) effects (see ADVERSE REACTIONS). 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. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.

DITROPAN XL® should be used with caution in patients with preexisting dementia treated with cholinesterase inhibitors due to the risk of aggravation of symptoms.

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 obstruction because of the risk of urinary retention (see CONTRAINDICATIONS).

Gastrointestinal Disorders

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 and intestinal atony.

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.

Information for Patients

Patients should be informed that oxybutynin may produce angioedema that could result in life-threatening airway obstruction. Patients should be advised to promptly discontinue oxybutynin therapy and seek immediate medical attention if they experience edema of the tongue, edema of the laryngopharynx, or difficulty breathing.

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 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 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., Cmax and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered.

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

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 H2O to 33 cm H2O, and a reduction in the percentage of patients demonstrating uninhibited detrusor contractions (of at least 15 cm H2O) from 60% to 28%.

DITROPAN XL® is not recommended in pediatric patients who cannot 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: Geriatric).

Adverse Events with DITROPAN XL®

The safety and efficacy of DITROPAN XL® (oxybutynin chloride) were evaluated in a total of 580 participants who received DITROPAN XL® in 4 clinical trials (429 patients) and four pharmacokinetic studies (151 healthy volunteers). The 429 patients were treated with 5–30 mg/day for up to 4.5 months. Three of the 4 clinical trials 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 the 429 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 ≥ 1 to < 5% of all patients who received DITROPAN XL® in the 6 adjustable and fixed-dose efficacy and safety studies. Infections and infestations: nasopharyngitis, upper respiratory tract infection, sinusitis, bronchitis, cystitis; Psychiatric disorders: insomnia, depression, nervousness, confusional state; Nervous System Disorders: dysgeusia; Cardiac disorders: palpitations; Vascular disorders: hypertension; Respiratory, thoracic and mediastinal disorders: nasal dryness, cough, pharyngolaryngeal pain, dry throat; Gastrointestinal Disorders: gastroesophageal reflux disease, abdominal pain, loose stools, flatulence, vomiting; Skin and subcutaneous tissue disorders: dry skin, pruritis; Musculoskeletal and connective tissue disorders: back pain, arthralgia, pain in extremity; Renal and urinary disorders: urinary retention, urinary hesitation, dysuria; General disorders and administration site conditions: fatigue, edema peripheral, asthenia, chest pain; Investigations: blood pressure increased.

Postmarketing Surveillance

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. The following additional adverse drug reactions have been reported from worldwide postmarketing experience with DITROPAN XL®: Psychiatric Disorders: psychotic disorder, agitation, hallucinations, memory impairment; Nervous System Disorders: convulsions; Eye Disorders: glaucoma; Cardiac Disorders: arrhythmia, tachycardia, QT interval prolongation; Vascular Disorders: flushing; 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; rare 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.

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 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).

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.

Relabeling and Repackaging by:
Physicians Total Care, Inc.
Tulsa, Oklahoma      74146