OXYBUTYNIN CHLORIDE
DESCRIPTION
TROPAN XL® (oxybutynin chloride) is an antispasmodic, anticholinergic agent. 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.
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.
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
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 TROPAN 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 TROPAN XL® are dose proportional.
Special Populations
Geriatric The pharmacokinetics of TROPAN XL® were similar in all patients studied (up to 78 years of age).
Pediatric The pharmacokinetics of TROPAN 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 TROPAN 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 TROPAN XL®.
Renal Insufficiency: There is no experience with the use of TROPAN XL® in patients with renal insufficiency.
Hepatic Insufficiency: There is no experience with the use of TROPAN XL® in patients with hepatic insufficiency.
Drug-Drug Interactions: See PRECAUTIONS : Drug Interactions .
Clinical Studies
TROPAN 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.
INDICATIONS AND USAGE
TROPAN XL® is a once-daily controlled-release tablet indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.
CONTRAINDICATIONS
TROPAN 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.
TROPAN XL® is also contraindicated in patients who have demonstrated hypersensitivity to the drug substance or other components of the product.
PRECAUTIONS
General
TROPAN XL® should be used with caution in patients with hepatic or renal impairment.
Urinary Retention:
TROPAN 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:
TROPAN XL® should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention (see CONTRAINDICATIONS ).
TROPAN 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.
TROPAN 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 TROPAN 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 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 TROPAN 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.
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.
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 TROPAN XL®.
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 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.
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 TROPAN XL® administration to women who are or who may become pregnant has not been established. Therefore, TROPAN 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 TROPAN XL® is administered to a nursing woman.
Pediatric Use
The safety and efficacy of TROPAN XL® in pediatric patients have not been established.
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 TROPAN XL®
The safety and efficacy of TROPAN XL® was evaluated in a total of 580 participants who received TROPAN 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.
Table 2
Incidence (%) of Adverse Events Reported by >/=5% of
Patients Using TROPAN XL® (5-30 mg/day) Body System Adverse Event TROPAN XL®
5-30 mg/day
(n=429)
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General headache 9.8
asthenia 6.8
pain 6.8
Digestivedry mouth 60.8
constipation 13.1
diarrhea 9.1
nausea 8.9
dyspepsia 6.8
Nervoussomnolence 11.9
dizziness 6.3
Respiratoryrhinitis 5.6
Special senses blurred vision 7.7
dry eyes 6.1
Urogenitalurinary tract infection 5.1
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The most common adverse events reported by patients receiving 5-30 mg/day TROPAN 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 TROPAN 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.
Adverse Events with Oxybutynin Chloride
Other adverse events have been reported with oxybutynin chloride: tachycardia, hallucinations, cycloplegia, mydriasis, impotence, and suppression of lactation.
OVERDOSAGE
The continuous release of oxybutynin from TROPAN 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.
DOSAGE AND ADMINISTRATION
TROPAN XL® must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed.
TROPAN XL® may be administered with or without food.
The recommended starting dose of TROPAN 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.