VA Class:GU201

ATC Class:G04BD04

AHFS Class:

• Antimuscarinics 86:12.04

Generic Name(s):

• Oxybutynin Chloride

Oxybutynin, a synthetic tertiary amine, is a genitourinary antispasmodic agent.

Overactive Bladder

Oxybutynin and oxybutynin chloride are used in the treatment of overactive bladder for the relief of symptoms associated with voiding (e.g., urge urinary incontinence, urgency, frequency, urinary leakage, dysuria).100,116,119,120

Oxybutynin chloride (as extended-release tablets) also is used for the relief of symptoms of detrusor overactivity associated with a neurologic condition (e.g., spina bifida) in pediatric patients 6 years of age and older.116

According to the International Continence Society (ICS), overactive bladder disorder is characterized by involuntary destrusor contractions that may occur spontaneously or may be provoked (by rapid filling, alterations of posture, coughing, walking, jumping).108 An overactive bladder of neurogenic origin usually has been referred to as an unstable disorder.102,107,108 The hyperflexic overactive bladder disorder usually involves a neurologic disorder.102,105,108

The diagnosis of neurogenic bladder should be confirmed by cystometry and other appropriate diagnostic procedures before therapy with oxybutynin is initiated. In addition, the patient's response to therapy should be periodically evaluated by cystometry. Appropriate antibacterial therapy should be administered whenever urinary tract infection is present. In limited clinical studies, oxybutynin was more effective than placebo in relieving urinary symptoms associated with neurogenic bladder; however, the drug was not superior to a standard antimuscarinic agent such as propantheline bromide. In one uncontrolled study, oxybutynin was reported to relieve mild to moderate urinary tract discomfort resulting from prostatectomy, radiation therapy, or infection.

Results of one clinical study in patients with overactive bladder indicate that therapy with extended-release oxybutynin chloride tablets (15 mg daily) was substantially more effective than placebo in decreasing the number of urge incontinence episodes.116,119 Two randomized, double-blind clinical studies have been conducted to evaluate the comparative efficacy and safety of extended-release oxybutynin tablets and conventional oxybutynin tablets; dosage of both formulations was individualized to balance efficacy and tolerability.116,119 When decreases in the number of episodes of urge incontinence were compared, one study indicated that the formulations were comparable; although comparable efficacy was not demonstrated according to predetermined criteria in the second study, there was no substantial difference between the formulations.116,119 Efficacy of extended-release oxybutynin tablets was maintained after 12 weeks of therapy in one study.119

Therapy with the oxybutynin transdermal system was more effective than placebo in reducing symptoms of overactive bladder.120 In 2 randomized, double-blind, controlled studies in patients with urge urinary incontinence, treatment with the oxybutynin transdermal system (delivering 3.9 mg of oxybutynin daily) for at least 12 weeks substantially reduced the number of weekly incontinence episodes and increased urinary void volumes compared with placebo.120 In 1 of the 2 studies, treatment with oxybutynin also substantially reduced the daily micturition frequency compared with placebo.120

In one randomized, double-blind, placebo-controlled study of 12 weeks' duration evaluating the comparative efficacy and safety of oxybutynin chloride (5 mg 3 times daily) and tolterodine tartrate (2 mg twice daily) in patients with overactive bladder, efficacy of the 2 drugs appeared to be similar in reducing urinary symptoms of the disorder.103,109 Administration of oxybutynin, tolterodine tartrate, or placebo was associated with decreased number of micturitions per 24 hours in 19.5, 21, or 10.5% of patients, respectively, while the mean number of episodes of incontinence decreased by 71, 47, or 19%, respectively.109 In addition, increases in the volume of urine voided per micturition were similar in patients receiving oxybutynin (mean increase of 31%) and tolterodine (mean increase of 27%) compared with a 7% increase in patients receiving placebo.109 It appears that tolterodine was better tolerated than oxybutynin; tolterodine was associated with a lower incidence of dry mouth than oxybutinin.102,103,109,110,111 (See Cautions.) Analysis of pooled data from other comparative studies of 12 weeks' duration using the same dosages of oxybutynin and tolterodine tartrate also indicate that efficacy of tolterodine is similar to that of oxybutynin in decreasing the mean number of micturitions per 24 hours and the mean number of episodes of incontinence;102,103,105,107,111,112 although both drugs increased the mean volume voided per micturition, such increases were greater with oxybutynin than with tolterodine.102,111,112 Some clinicians, however, consider tolterodine to be less effective but better tolerated than older agents (e.g., oxybutynin) in the management of overactive bladder.110

The efficacy of oral oxybutynin chloride (as conventional tablets, oral solution, or extended-release tablets) for the relief of symptoms of detrusor overactivity associated with a neurologic condition (e.g., spina bifida) in pediatric patients was evaluated in pediatric patients 5-15 years of age in a 24-week, open-label trial.100,116,122 All patients had symptoms of detrusor overactivity in association with a neurologic condition (e.g., spina bifida), used clean intermittent catheterization, and already were users of oxybutynin chloride (at total daily dosages of 10 or 15 mg) at the time of the study.100,116,122 During the study, patients received total daily dosages of oxybutynin chloride ranging from 5-15 mg as conventional tablets, 5-30 mg as oral solution, or 5-20 mg as extended-release tablets.100,116,122 In these patients, oxybutynin chloride therapy was associated with increased mean urine volume per catheterization, increased mean urine volume after morning awakening, and an increase in the mean percentage of catheterizations without a leaking episode.116,122 Improvements in bladder function were consistent across all 3 formulations.122

Other Uses

Oxybutynin has been used in children for the treatment of primary nocturnal enuresis†.101 In one study in children with a history of nocturnal (but not daytime) enuresis and normal bladders, there was no significant difference in the frequency of nocturnal enuresis when the children were receiving oxybutynin compared to when they were receiving placebo.101

Oxybutynin has been used as an antispasmodic in the symptomatic treatment of various GI disorders† without conclusive evidence of efficacy.

Administration

Oxybutynin chloride is administered orally,100,116 and oxybutynin is administered percutaneously by topical application of a transdermal system.120 Like other antimuscarinic agents, oxybutynin should probably be discontinued periodically to determine whether or not the patient can manage without the drug and to minimize any tendency for the patient to become resistant to the drug.

Oxybutynin chloride extended-release tablets should be swallowed intact with liquid, and should not be chewed, crushed, or broken.116 The extended-release preparation of the drug may be administered without regard to meals.116,117,118 Patients should be advised that the tablet shell does not dissolve and may be passed in the stool.116

Patients receiving transdermal oxybutynin therapy should be carefully instructed in the use of the transdermal system.120 To obtain optimum results, patients also should be given a copy of the patient instructions provided by the manufacturer.120 Prior to application, the oxybutynin transdermal system should be removed from the protective pouch.120 The transdermal system should then be applied immediately to dry, intact skin on the abdomen, hip, or buttock.120 A new application site should be selected with each new system to avoid reapplication to the same site within 7 days.120 The used system should be discarded in a manner that prevents accidental application or ingestion by children, pets, or others.120

Dosage

For the treatment of overactive bladder, the usual adult dosage of oxybutynin chloride (as conventional tablets or oral solution) is 5 mg 2 or 3 times daily with a maximum of 5 mg 4 times daily.100 A lower initial dosage (2.5 mg 2 or 3 times daily) is recommended for frail geriatric patients.100 The usual dosage in children older than 5 years of age is 5 mg twice daily with a maximum of 5 mg 3 times daily.100

The usual initial adult dosage of oxybutynin chloride (as extended-release tablets [Ditropan^® XL]) for the treatment of overactive bladder is 5 or 10 mg once daily, administered at approximately the same time each day.116 In pediatric patients 6 years of age and older, the usual initial dosage of extended-release oxybutynin chloride for the relief of symptoms of detrusor overactivity associated with a neurologic condition (e.g., spina bifida) is 5 mg once daily.116 Dosage of the drug should be adjusted according to the patient's response and tolerance.116 Generally, dosage is increased gradually at 7-day intervals in increments of 5 mg up to a maximum dosage of 30 mg daily (in adults) or 20 mg daily (in pediatric patients 6 years of age and older).116

The usual initial adult dosage of oxybutynin (as the transdermal system [Oxytrol^®]) for the treatment of overactive bladder is 1 transdermal system (delivering 3.9 mg per day) applied twice weekly (every 3-4 days).120

Adverse Effects

Adverse effects of oxybutynin chloride are typical of those produced by antimuscarinic agents and are occasionally severe enough to require discontinuance of the drug.100,116

Adverse effects considered at least possibly related to oxybutynin therapy and reported in 5% or more of patients receiving oxybutynin chloride (as conventional or extended-release tablets or as an oral solution) include dry mouth, dizziness, constipation, somnolence, impaired urination, nausea, blurred vision, dyspepsia, asthenia, pain, abdominal pain, headache, rhinitis, dry eyes, diarrhea, increased postvoid residual volume, and urinary tract infection.100 Adverse effects reported in 2-5% of patients receiving oral oxybutynin chloride include dry nasal and sinus mucous membranes, hypertension, palpitation, vasodilation, peripheral edema, insomnia, nervousness, confusion, dry skin, dry eyes, taste perversion, accidental injury, back pain, flu syndrome, flatulence, GI reflux, arthritis, upper respiratory infection, cough, sinusitis, bronchitis, pharyngitis, urinary retention, and cystitis.100,116 Other adverse effects reported include tachycardia, hallucinations, cycloplegia, mydriasis, impotence, suppression of lactation, rash, decreased GI motility, seizures, and decreased sweating.100,116

Adverse effects occurring in 2% or more of patients receiving the oxybutynin transdermal system and at an incidence greater than that reported with placebo include local reactions (i.e., pruritus, erythema, vesicles, rash, or macules at the application site), dry mouth, diarrhea, constipation, dysuria, and abnormal vision.120 Other adverse effects considered at least possibly related to oxybutynin therapy and reported in more than 1% of patients receiving the oxybutynin transdermal system include abdominal pain, nausea, flatulence, fatigue, somnolence, headache, flushing, rash, burning at the application site, and back pain.120

Severe allergic reactions including rash, urticaria, and other dermatologic reactions have occurred with other antimuscarinic agents and presumably might occur in susceptible individuals following oxybutynin administration. Antimuscarinic agents may also produce signs of CNS stimulation when administered in high dosage. (See Acute Toxicity: Manifestations.)

When oxybutynin was compared with tolterodine tartrate (another antimuscarinic agent used for overactive bladder), dry mouth was reported in about 78 or 40% of patients receiving oxybutynin chloride (5 mg 3 times daily) or tolterodine tartrate (2 mg twice daily), respectively.102,107,110,111,115 Dry mouth has been reported in approximately 61% of patients receiving 5-30 mg of extended-release oxybutynin chloride tablets in clinical studies, and 1.2% of patients discontinued therapy because of dry mouth.116 In addition, 1.9% of patients in clinical studies discontinued therapy because of nausea, which was the most frequently reported cause of discontinuance of extended-release oxybutynin chloride tablets.116

Precautions and Contraindications

Patients should be warned that oxybutynin may cause drowsiness or blurred vision and may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle). Alcohol or other sedative drugs may enhance drowsiness caused by oxybutynin.100 Administration of oxybutynin during hot weather can cause heat prostration (i.e., fever and heat stroke secondary to suppression of sweating).100 Since diarrhea may be a symptom of partial intestinal obstruction, especially in patients with ileostomies or colostomies, the possibility of intestinal obstruction should be excluded before oxybutynin is administered to patients with diarrhea.

Oxybutynin should be used with caution in frail geriatric patients, in patients with hepatic or renal impairment, and in patients with myasthenia gravis.100,116,120 The possibility that oxybutynin may aggravate the symptoms of hyperthyroidism, coronary heart disease, congestive heart failure, cardiac arrhythmias, hiatal hernia, tachycardia, hypertension, myasthenia gravis, or prostatic hypertrophy should be considered. 100

Oxybutynin may increase the risk of urinary or gastric retention; therefore, the drug should be used with caution in patients with clinically important bladder outflow obstruction or in those with GI obstructive disorders.100,116,120 Like other antimuscarinic agents, oxybutynin may decrease GI motility;100,116,120 in patients with ulcerative colitis, the drug may suppress intestinal motility to the point of producing a paralytic ileus and precipitate or aggravate toxic megacolon, a serious complication of the disease.100 Therefore, oxybutynin should be used with caution in patients with GI disorders such as ulcerative colitis or intestinal atony.100,116,120 Oxybutynin also should be used with caution in patients with gastroesophageal reflux and/or in patients receiving oxybutynin concomitantly with drugs that can cause or exacerbate esophagitis (e.g., bisphosphonates).100,116,120

As with other nondeformable material, extended-release oxybutynin chloride tablets should be used with caution in patients with preexisting severe GI narrowing (pathologic or iatrogenic) since obstruction may occur.116 Because extended-release tablets are designed to remain intact and slowly release oxybutynin from a nonabsorbable shell during passage through the GI tract, patients should be advised not to become alarmed if they notice a tablet-like substance in their stools.116

Oxybutynin is contraindicated in patients with urinary retention, gastric retention and/or other severely decreased GI motility conditions, or uncontrolled angle-closure glaucoma; the drug also is contraindicated in patients at increased risk for these conditions.100,116,120

Oxybutynin is contraindicated in patients hypersensitive to the drug or any ingredient in the formulations.100,116,120

Pediatric Precautions

Pending further accumulation of clinical data on the use of oxybutynin chloride in young children, conventional tablets or oral solutions of the drug should not be administered to children younger than 5 years of age.100 The manufacturer states that use of oxybutynin chloride extended-release tablets is not recommended in pediatric patients who cannot swallow the tablet whole (i.e., without chewing, dividing, or crushing) or in pediatric patients younger than 6 years of age.116 Safety and efficacy of the oxybutynin transdermal system have not been established in pediatric patients.120

Geriatric Precautions

No overall differences in safety or efficacy of oxybutynin were observed between geriatric individuals (65 years of age and older) and younger adults in clinical studies, and other clinical experience has not revealed evidence of age-related differences.100,116,120 Following administration of oxybutynin chloride extended-release tablets, the pharmacokinetics of the drug were found to be similar in patients of all ages (including geriatric patients up to 78 years of age), and the incidence and severity of anticholinergic effects were similar among geriatric and younger patients.116 However, the possibility that some older patients may exhibit increased sensitivity to oxybutynin cannot be ruled out.120 Therefore, the manufacturer of oxybutynin conventional tablets and oral solution states that dosage in geriatric patients should be selected with caution, usually initiating therapy at the low end of the dosage range, since decreased hepatic, renal, or cardiac function and concomitant disease and drug therapy occur more frequently in these patients.100 A lower initial dosage (2.5 mg 2 or 3 times daily) is recommended for frail geriatric patients because of the reported prolongation of elimination half-life of the drug (from 2-3 hours to 5 hours) in such patients.100

Mutagenicity and Carcinogenicity

Oxybutynin chloride was not mutagenic when tested in Schizosaccharomyces pompholiciformis , Saccharomyces cerevisiae , and Salmonella typhimurium test systems.100 There was no evidence of carcinogenicity when the drug was given to rats for 24 months at dosages up to approximately 50 times the maximum human exposure (based on surface area).100,116,120

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in hamsters, mice, rabbits, and rats using oxybutynin have not revealed evidence of harm to the fetus.100,116,120 Safe use of oxybutynin during pregnancy has not been established, and the drug should be used in pregnant women or women who may become pregnant only when the potential benefits to the patient outweigh the possible risks to the fetus.100,116,120

Fertility

Reproduction studies in hamsters, mice, rabbits, and rats using oxybutynin have not revealed evidence of impaired fertility.100,116,120

Lactation

Since it is not known whether oxybutynin chloride is distributed into human milk, the drug should be used with caution in nursing women.100,116,120

The manufacturer states that specific drug interaction studies with the oxybutynin transdermal system have not been conducted to date.120

Anticholinergic Agents

Concomitant administration of oxybutynin chloride with other drugs having anticholinergic effects may increase the frequency and/or severity of adverse anticholinergic effects (e.g., dry mouth, constipation, somnolence).100,116,120 By inhibiting the motility of the GI tract, anticholinergic agents (e.g., oxybutynin) may alter GI absorption of some concomitantly administered drugs; this may be of concern for drugs with a narrow therapeutic index.100,116,120

Drugs Affecting Hepatic Microsomal Enzymes

Concomitant oral administration of oxybutynin chloride with ketoconazole (a potent inhibitor of cytochrome P-450 [CYP] microsomal isoenzyme 3A4 resulted in a 2- to 4-fold increase in plasma oxybutynin concentrations.100,116 Other CYP3A4 inhibitors (e.g., clarithromycin, erythromycin, itraconazole, miconazole) also may alter oxybutynin plasma concentrations; however, the clinical relevance of such potential interactions is not known.100,116 The manufacturer of oral oxybutynin preparations states that caution should be exercised when the drug is used concomitantly with CYP3A4 inhibitors.100,116

Antacids

Concomitant administration of oxybutynin extended-release tablets with 20 mL of an antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone did not substantially alter plasma concentrations of oxybutynin or desethyloxybutynin (an active metabolite of oxybutynin).116

Other Drugs

Oral oxybutynin preparations should be used with caution in patients concurrently receiving drugs that can cause or exacerbate esophagitis (e.g., bisphosphonates).100,116

Acute Toxicity

Manifestations

Oxybutynin chloride overdosage has been associated with anticholinergic effects including CNS excitation (e.g., restlessness, tremor, irritability, seizures, delirium, hallucinations), flushing, fever, dehydration, cardiac arrhythmia, vomiting, and urinary retention.100,116,120 Other manifestations include hypotension or hypertension, respiratory failure, paralysis, and coma.100

Ingestion of 100 mg of 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 experienced symptoms of stupor, followed by disorientation and agitation upon awakening, mydriasis, dry skin, cardiac arrhythmia, and urinary retention.100,116,120 Both patients fully recovered with symptomatic treatment.100,116,120

Treatment

Treatment of oxybutynin chloride overdosage generally involves symptomatic and supportive care.100 Activated charcoal as well as a cathartic may be administered following overdosage with oral oxybutynin chloride preparations.100,116 If overdosage of the extended-release tablets occurs, the continuous release of oxybutynin from this formulation should be considered, and patients should be monitored for at least 24 hours.116 IV administration of 0.5-2 mg of physostigmine salicylate may be used to counteract CNS disturbances. The dose of physostigmine may be repeated as needed up to a maximum total dosage of 5 mg. Fever may be treated with ice packs or other cold applications and alcohol sponging.121 In patients with severe intoxication, slow, carefully titrated IV administration of a 2% solution of thiopental sodium (no longer commercially available in the US) or rectal infusion of 100-200 mL of a 2% solution of chloral hydrate may be necessary to combat extreme excitement. Respiration should be maintained;121 artificial respiration may be required if paralysis of respiratory muscles occurs.

Following overdosage with the oxybutynin transdermal system(s), the system(s) should be removed, and patients should be monitored until manifestations have resolved.120 Plasma concentration of oxybutynin declines within 1-2 hours after removal of the transdermal system(s).120

Pharmacology

Oxybutynin and oxybutynin chloride exert a direct spasmolytic (papaverine-like) action and an antimuscarinic (atropine-like) action on smooth muscle.100,116,120 Oxybutynin does not appear to exhibit antinicotinic effects (i.e., block acetylcholine effects at skeletal myoneural junctions or at autonomic ganglia).100,116,120 The spasmolytic effect of the drug has been demonstrated on the detrusor muscle of the bladder, the small intestine, and the colon of various animals. Unlike papaverine, however, oxybutynin appears to have little or no effect on the smooth muscle of blood vessels.

Oxybutynin is a racemic mixture of R - and S -isomers.120 Antimuscarinic activity resides predominantly in the R -isomer.100,116,120 The active metabolite of oxybutynin (desethyloxybutynin) has pharmacologic activity similar to that of oxybutynin in vitro.100,116,120 In in vitro binding studies, oxybutynin demonstrated high binding specificity for M₃/m3 receptors while tolterodine (another antimuscarinic drug used for the management of overactive bladder) demonstrated no specificity for any subtype of muscarinic receptors.102,103,104,105,106 In vitro, the relative binding affinity of oxybutynin at the muscarinic receptors in the bladder is similar to that of tolterodine,102,103,106 while at the muscarinic receptors in the parotid gland the potency of oxybutynin appears to be eightfold greater than that of tolterodine.102,103,104,105,106,107

Oxybutynin relaxes bladder smooth muscle.100,116,120 Cystometric studies in patients with uninhibited neurogenic and reflex neurogenic bladders indicate that oxybutynin chloride increases urinary bladder capacity, diminishes the frequency of uninhibited contractions of the detrusor muscle, and delays the initial desire to void.100,116,120 Oxybutynin, thus, decreases urgency and the frequency of incontinent episodes and voluntary urination.100,116,120 Antimuscarinic effects of oxybutynin were more evident in patients with uninhibited neurogenic bladders than in those with reflex neurogenic bladders. In animal studies, the drug has shown moderate antihistaminic, some local anesthetic, some mild analgesic, and very low mydriatic and antisialagogue activity.

Pharmacokinetics

Pharmacokinetic studies to date have not revealed age-, gender-, or race-related differences in the pharmacokinetics of oxybutynin following administration of the drug as extended-release tablets or as the transdermal system.116,120 However, healthy Japanese individuals demonstrated a somewhat lower metabolism of oxybutynin to desethyloxybutynin compared with Caucasians.120 The pharmacokinetics of oxybutynin were similar in adults up to 78 years of age following administration of extended-release tablets.116

Absorption

Oxybutynin chloride (as conventional tablets or oral solution) appears to be rapidly absorbed from the GI tract100 and undergoes extensive first-pass metabolism following oral administration.120 Following oral administration in adults or pediatric patients 5-15 years of age, the absolute bioavailability of oxybutynin is approximately 6% (with the ratio of desethyloxybutynin to oxybutynin being 11.9:1120 ), and peak plasma concentrations are achieved within 1 hour.100 Wide interindividual variations in pharmacokinetic parameters exist following oral administration of oxybutynin chloride.100 Some data indicate that administration of oxybutynin chloride oral solution with food may delay absorption and increase bioavailability of oxybutynin by 25%.100 However, administration of oxybutynin chloride extended-release tablets with food reportedly does not affect the rate or extent of absorption of the drug.116,117,118

The relative bioavailabilities of R - and S -oxybutynin following oral administration of extended-release oxybutynin chloride tablets are 156 and 187% respectively, compared with conventional oxybutynin formulations.116,119 Following oral administration of a single dose of oxybutynin chloride as extended-release tablets, plasma oxybutynin concentrations increase gradually for 4-6 hours, peak within 12-13 hours, and are maintained for up to 24 hours.116,119 Steady-state concentrations were achieved by the third day, and no accumulation or change in pharmacokinetics of oxybutynin or desethyloxybutynin, its active metabolite, was observed.116 Following oral administration of oxybutynin extended-release tablets (5-20 mg daily) in pediatric patients 5-15 years of age, peak plasma concentrations are achieved within approximately 5 hours.116

Transdermal administration of oxybutynin bypasses first-pass GI and hepatic metabolism; the ratio of desethyloxybutynin to oxybutynin following multiple transdermal applications is 1.3:1.120 Following application of a single transdermal system, plasma oxybutynin concentrations increase gradually for 24-48 hours, peak within 36-48 hours, and are maintained for up to 96 hours.120 Steady-state concentrations are achieved with application of the second transdermal system.120 Following multiple applications of the transdermal system to the abdomen, peak plasma concentrations are achieved within 10-28 hours.120 Absorption of oxybutynin is similar following application of the transdermal system to the abdomen, buttock, or hip.120

The onset of action of oxybutynin occurs within 30-60 minutes, and peak effects occur within 3-6 hours after administration. The antispasmodic action may last 6-10 hours.

Distribution

Limited data are available on the distribution of oxybutynin into human body tissues and fluids. In rats, oxybutynin has been detected in the brain, lungs, kidneys, and liver following oral administration. Following IV administration of a 5-mg dose of oxybutynin chloride, the volume of distribution of oxybutynin is about 193 L.100,116,120

Elimination

Oxybutynin is metabolized principally by the cytochrome P-450 isoenzyme 3A4, which is found mainly in the liver and intestinal wall.100,116,120 The drug is extensively metabolized in the liver.100,116,119,120 Metabolites of oxybutynin include phenylcyclohexylglycolic acid, which is pharmacologically inactive, and desethyloxybutynin, which exhibits antimuscarinic activity similar to that of oxybutynin in in vitro studies.100,116,119 The half-life of oxybutynin is 2-3 hours following administration of conventional tablets or oral solution and 12-13 hours following administration of extended-release tablets.100,116 Following removal of the oxybutynin transdermal system, plasma concentrations of oxybutynin and desethyloxybutynin decline with an apparent half-life of approximately 7-8 hours.120

Less than 0.1% of an administered dose is excreted as unchanged drug in urine.100,116,120 Less than 0.1% of the administered dose is excreted as the metabolite desethyloxybutynin.100,116,120

Chemistry and Stability

Chemistry

Oxybutynin or oxybutynin chloride is a synthetic tertiary amine which is chemically and pharmacologically similar to some anticholinergic, antispasmodic, local anesthetic, and antihistaminic compounds. Oxybutynin chloride occurs as white to off-white crystals and is freely soluble in water and acids, but relatively insoluble in alkalis.100,116 Oxybutynin occurs as a white powder and is soluble in alcohol but relatively insoluble in water.120 The drug has a pK_a of 6.96. The commercially available drug is a racemic mixture of 2 optical isomers.116,120

The commercially available extended-release tablets of oxybutynin chloride (Ditropan^® XL) contain the drug in an oral osmotic delivery system formulation.116 The osmotic delivery system consists of an osmotically active bilayer core (comprised of a layer containing the drug and a push layer containing osmotically active components) surrounded by a semipermeable membrane with a laser-drilled delivery orifice.116 The semipermeable membrane controls the rate at which water permeates into the tablet core.116 As water enters the formulation in the GI tract, the drug becomes suspended; the osmotic layer expands and the drug is pushed out the delivery orifice of the membrane into the GI tract at a constant rate.116 The rate of oxybutynin delivery in the GI tract is independent of GI pH, motility, and presence of food in the GI tract.116 The inert tablet ingredients remain intact and are eliminated in feces.116

The commercially available oxybutynin transdermal system (Oxytrol^®) contains 3 layers.120 Layer 1 (backing film) is a thin flexible polyester/ethylene-vinyl acetate film that provides the system with occlusivity and physical integrity and protects the adhesive/drug layer.120 Layer 2 (adhesive/drug layer) is a cast film of acrylic adhesive containing oxybutynin and triacetin.120 Layer 3 (release liner) is 2 overlapped siliconized polyester strips that are peeled off and discarded by the patient prior to applying the transdermal system.120

Stability

Oxybutynin chloride conventional tablets should be stored in tight, light-resistant containers at 15-30°C100 and have an expiration date of 4 years following the date of manufacture. Oxybutynin chloride oral solution should be stored in tight, light-resistant containers at 15-30°C.100 Oxybutynin chloride extended-release tablets should be stored at a controlled room temperature of 25°C but may be exposed to temperatures ranging from 15-30°C; extended-release tablets should be protected from moisture.116 The oxybutynin transdermal system should be stored inside the sealed pouch at 25°C but may be exposed to temperatures ranging from 15-30°C; the transdermal system should be protected from moisture and humidity.120

Only references cited for selected revisions after 1984 are available electronically.

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111. Van Kerrebroeck PEVA, Serment G, Dreher E. Clinical efficacy and safety of tolterodine compared to oxybutynin in patients with overactive bladder. Neurourol Urodyn . 1997; 16:478-9.

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113. Pharmacia & Upjohn, Kalamazoo, MI: Personal communication on tolterodine.

114. Reviewers' comments (personal observations) on tolterodine.

115. Pharmacia & Upjohn Company. Detrol^® (tolterodine tartrate) tablets prescribing information. Kalamazoo, MI; 1998 Mar.

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