Oxybutynin Chloride

Absorption

Following oral administration of oxybutynin chloride, oxybutynin is rapidly absorbed achieving C_max within an hour, following which plasma concentration decreases with an effective half-life of approximately 2 to 3 hours. The absolute bioavailability of oxybutynin is reported to be about 6% (range 1.6 to 10.9%) for the tablets. Wide interindividual variation in pharmacokinetic parameters is evident following oral administration of 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.

Figure 1. Mean R-oxybutynin plasma concentrations following three doses of oxybutynin chloride 5 mg administered every 8 hours for 1 day in 23 healthy adult volunteers

Oxybutynin chloride steady-state pharmacokinetics were also studied in 11 pediatric patients with detrusor overactivity associated with a neurological condition (e.g., spina bifida). These pediatric patients were on oxybutynin chloride tablets with total daily dose ranging from 7.5 mg to 15 mg (0.22 to 0.53 mg/kg). Overall, most patients (86.9%) were taking a total daily oxybutynin chloride dose between 10 mg and 15 mg. Sparse sampling technique was used to obtain serum samples. When all available data are normalized to an equivalent of 5 mg twice daily oxybutynin chloride, 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 twice daily.

Figure 2. Mean steady-state (±SD) R-oxybutynin plasma concentrations following administration of total daily oxybutynin chloride tablet dose of 7.5 mg to 15 mg (0.22 mg/kg to 0.53 mg/kg) in children 5 to 15 years of age. – Plot represents all available data normalized to the equivalent of oxybutynin chloride 5 mg BID or TID at steady state

Food Effects

Data in the literature suggests that oxybutynin solution co-administered with food resulted in a slight delay in absorption and an increase in its bioavailability by 25% (n=18).¹

Distribution

Oxybutynin is widely distributed in body tissues following systemic absorption. The volume of distribution is 193 L after intravenous administration of 5 mg oxybutynin chloride. Both enantiomers of oxybutynin are highly bound (> 99%) to plasma proteins. Both enantiomers of desethyloxybutynin are also highly bound (> 97%) to plasma proteins. The major binding protein is alpha-1 acid glycoprotein.

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.

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.

Oxybutynin chloride should be used with caution in the frail elderly, in patients with hepatic or renal impairment, and in patients with myasthenia gravis.

Oxybutynin chloride may aggravate the symptoms of hyperthyroidism, coronary heart disease, congestive heart failure, cardiac arrhythmias, hiatal hernia, tachycardia, hypertension, myasthenia gravis, and prostatic hypertrophy.

Urinary Retention

Oxybutynin chloride should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention (see CONTRAINDICATIONS).

Gastrointestinal Disorders

Oxybutynin chloride should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention (see CONTRAINDICATIONS).

Administration of oxybutynin chloride to patients with ulcerative colitis may suppress intestinal motility to the point of producing a paralytic ileus and precipitate or aggravate toxic megacolon, a serious complication of the disease.

Oxybutynin chloride, 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.

Oxybutynin chloride 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.

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.

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 3 to 4 fold higher when oxybutynin chloride 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.

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 using oxybutynin chloride in the hamster, rabbit, rat, and mouse have shown no definite evidence of impaired fertility.

Category B.

Reproduction studies using oxybutynin chloride in the hamster, rabbit, rat, and mouse have shown no definite evidence of impaired fertility or harm to the animal fetus. The safety of oxybutynin chloride administered to women who are or who may become pregnant has not been established. Therefore, oxybutynin chloride 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 this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when oxybutynin chloride is administered to a nursing woman. 

The safety and efficacy of oxybutynin chloride administration have been demonstrated for pediatric patients 5 years of age and older (see DOSAGE AND ADMINISTRATION).

The safety and efficacy of oxybutynin chloride tablets were studied in 30 children in a 24-week, open-label trial. Patients were aged 5 to 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 the administration of oxybutynin chloride was associated with improvement in clinical and urodynamic parameters.

At total daily doses ranging from 5 mg to 15 mg, treatment with oxybutynin chloride tablets was associated with an increase from baseline in mean urine volume per catheterization from 122 mL to 145 mL, an increase from baseline in mean urine volume after morning awakening from 148 mL to 168 mL, and an increase from baseline in the mean percentage of catheterizations without a leaking episode from 43% to 61%. Urodynamic results in these patients were consistent with the clinical results. Treatment with oxybutynin chloride tablets was associated with an increase from baseline in maximum cystometric capacity from 230 mL to 279 mL, a decrease from baseline in mean detrusor pressure at maximum cystometric capacity from 36 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 39% to 20%.

As there is insufficient clinical data for pediatric populations under age 5, oxybutynin chloride is not recommended for this age group.

Clinical studies of oxybutynin chloride did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between healthy elderly and younger patients; however, a lower initial starting dose of 2.5 mg given 2 or 3 times a day has been recommended for the frail elderly due to a prolongation of the elimination half-life from 2 to 3 hours to 5 hours.^2,3,4 In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.