Chemically, oxybutynin chloride is d,l (racemic) 4-diethylamino-2-butynyl phenylcyclohexylglycolate hydrochloride. The empirical formula of oxybutynin chloride is C 22H 31NO 3•HCl. The structural formula appears below:

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.

Each 5 mL, for oral administration, contains 5 mg of oxybutynin chloride. In addition, the following inactive ingredients are present: citric acid, FD&C Green #3, raspberry flavor, glycerin, methylparaben, propylene glycol, sodium citrate, sorbitol solution, sucrose, and water.

Therapeutic Category: Antispasmodic, anticholinergic.

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 chloride increases bladder (vesical) capacity, diminishes the frequency of uninhibited contractions of the detrusor muscle, and delays the initial desire to void. Oxybutynin chloride thus decreases urgency and the frequency of both incontinent episodes and voluntary urination.

Antimuscarinic activity resides predominately in the R-isomer. A metabolite, desethyloxybutynin, has pharmacological activity similar to that of oxybutynin in in vitro studies.

Pharmacokinetics

Absorption

Following oral administration of oxybutynin chloride, oxybutynin is rapidly absorbed achieving Cmax 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 both the tablet and syrup. 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 R-oxybutynin.

Table 1 Mean (SD) R- and S-Oxybutynin Pharmacokinetic Parameters Following Three Doses of Oxybutynin Chloride 5 mg Administered every 8 Hours (n=23)

Parameters (units)	R-Oxybutynin	S-Oxybutynin
C max(ng/mL)	3.6 (2.2)	7.8 (4.1)
T max (h)	0.89 (0.34)	0.65 (0.32)
AUC t(ng • h/mL)	22.6 (11.3)	35.0 (17.3)
AUC  inf(ng • h/mL)	24.3 (12.3)	37.3 (18.7)

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 23 pediatric patients with detrusor overactivity associated with a neurological condition (e.g., spina bifida). These pediatric patients were on oxybutynin chloride tablets (n=11) with total daily dose ranging from 7.5 mg to 15 mg (0.22 to 0.53 mg/kg) or oxybutynin chloride syrup (n=12) with total daily dose ranging from 5 mg to 22.5 mg (0.26 to 0.75 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 2a (for tablet) and Table 2b (for syrup). 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.

Table 2aMean ± SD R- and S-Oxybutynin and R- and S-Desethyloxybutynin Pharmacokinetic Parameters In Children Aged 5-15 Following Administration of 7.5 mg to 15 mg Total Daily Dose of Oxybutynin Chloride Tablets (N=11)

All Available Data Normalized to an Equivalent of Oxybutynin Chloride Tablets 5 mg BID or TID at Steady State

	R-Oxybutynin	S-Oxybutynin	R-Desethyloxybutynin	S-Desethyloxybutynin
C max* (ng/mL)	6.1 ± 3.2	10.1 ± 7.5	55.4 ± 17.9	28.2 ± 10.0
T max(hr)	1.0	1.0	2.0	2.0
AUC** (ng.hr/mL)	19.8 ± 7.4	28.4 ± 12.7	238.8 ± 77.6	119.5 ± 50.7

*Reflects C maxfor pooled data
**AUC 0-end of dosing interval

Table 2bMean ± SD R- and S-Oxybutynin and R- and S-Desethyloxybutynin Pharmacokinetic Parameters In Children Aged 5-15 Following Administration of 5 mg to 22.5 mg Total Daily Dose of Oxybutynin Chloride Syrup (N=12)

All Available Data Normalized to an Equivalent of Oxybutynin Chloride Syrup 5 mg BID or TID at Steady State

	R-Oxybutynin	S-Oxybutynin	R-Desethyloxybutynin	S-Desethyloxybutynin
C max* (ng/mL)	5.7 ± 6.2	7.3 ± 7.3	54.2 ± 34.0	27.8 ± 20.7
T max(hr)	1.0	1.0	1.0	1.0
AUC** (ng.hr/mL)	16.3 ± 17.1	20.2 ± 20.8	209.1 ± 174.2	99.1 ± 87.5

*Reflects C maxfor pooled data
**AUC 0-end of dosing interval

Figure 2.Mean steady-state (±SD) R-oxybutynin plasma concentrations following administration of total daily OXYBUTYNIN CHLORIDE dose of 5 mg to 30 mg (0.21 mg/kg to 0.77 mg/kg) in children 5-15 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
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.

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 was well tolerated in patients administered the drug in controlled studies of 30 days’ duration and in uncontrolled studies in which some of the patients received the drug for 2 years.

Oxybutynin Chloride Syrup is indicated for the relief of symptoms of bladder instability associated with voiding in patients with uninhibited neurogenic or reflex neurogenic bladder (i.e., urgency, frequency, urinary leakage, urge incontinence, dysuria).

Oxybutynin Chloride Syrup is contraindicated in patients with urinary retention, gastric retention and other severe decreased gastrointestinal motility conditions, uncontrolled narrow-angle glaucoma and in patients who are at risk for these conditions.

Oxybutynin chloride is also contraindicated in patients who have demonstrated hypersensitivity to the drug substance or other components of the product.

Angioedema of the face, lips, tongue and/or larynx has been reported with oxybutynin. In some cases, angioedema occurred after the first dose. Angioedema associated with upper airway swelling may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, oxybutynin should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided.

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.

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

General
Oxybutynin Chloride Syrup 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.

The safety and efficacy of Oxybutynin Chloride Syrup was evaluated in a total of 199 patients in three clinical trials comparing oxybutynin chloride with oxybutynin chloride extended release tablets (see Table 3). These participants were treated with oxybutynin chloride 5-20 mg/day for up to 6 weeks. Table 3 shows the incidence of adverse events judged by investigators to be at least possibly related to treatment and reported by at least 5% of patients.

The most common adverse events reported by patients receiving oxybutynin chloride 5-20 mg/day were the expected side effects of anticholinergic agents. The incidence of dry mouth was dose-related.

In addition, the following adverse events were reported by 1 to <5% of patients using oxybutynin chloride (5-20 mg/day) in all studies. Infections and Infestations: nasopharyngitis, upper respiratory tract infection, bronchitis, cystitis, fungal infection; Metabolism and Nutrition Disorders: fluid retention; Psychiatric Disorders: confusional state; Nervous System Disorders: dysgeusia, sinus headache; Eye Disorders: keratoconjunctivitis sicca, eye irritation; Cardiac Disorders: palpitations, sinus arrhythmia; Vascular Disorders: flushing; Respiratory, Thoracic and Mediastinal Disorders: nasal dryness, cough, pharyngolaryngeal pain, dry throat, sinus congestion, hoarseness, asthma, nasal congestion; Gastrointestinal Disorders: diarrhea, abdominal pain, loose stools, flatulence, vomiting, abdominal pain upper, dysphagia, aptyalism, eructation, tongue coated; Skin and Subcutaneous Tissue Disorders: dry skin, pruritis; Musculoskeletal and Connective Tissue Disorders: back pain, arthralgia, pain in extremity, flank pain; Renal and Urinary Disorders: dysuria, pollakiuria; General Disorders and Administration Site Conditions: fatigue, edema peripheral, asthenia, pain, thirst, edema; Investigations: blood pressure increased, blood glucose increased, blood pressure decreased; Injury, Poisoning, and Procedural Complications: fall.

Postmarketing Surveillance

Because postmarketing adverse events 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 events have been reported from worldwide postmarketing experience with oxybutynin chloride: Psychiatric Disorders: psychotic disorder, agitation, hallucinations; memory impairment; Nervous System Disorders: convulsions; Eye disorders: cycloplegia, mydriasis; Cardiac Disorders: tachycardia; QT interval prolongation; Gastrointestinal Disorders: decreased gastrointestinal motility; Skin and Subcutaneous Tissue Disorders: rash, decreased sweating; Renal and Urinary Disorders: impotence; Reproductive system and breast disorders: Suppression of lactation. 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.

Treatment should be symptomatic and supportive. Activated charcoal as well as a cathartic may be administered.

Overdosage with oxybutynin chloride has been associated with anticholinergic effects including central nervous system excitation (e.g., restlessness, tremor, irritability, convulsions, delirium, hallucinations), flushing, fever, dehydration, cardiac arrhythmia, vomiting, and urinary retention. Other symptoms may include hypotension or hypertension, respiratory failure, paralysis, and coma. 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.

Syrup

Adults: The usual dose is one teaspoon (5 mg/5 mL) of syrup two to three times a day. The maximum recommended dose is one teaspoon (5 mg/5 mL) of syrup four times a day. A lower starting dose of 2.5 mg two or three times a day is recommended for the frail elderly. Pediatric patients over 5 years of age: The usual dose is one teaspoon (5 mg/5 mL) of syrup two times a day. The maximum recommended dose is one teaspoon (5 mg/5 mL) of syrup three times a day.

OXYBUTYNIN CHLORIDE SYRUP USP (5 mg/5 mL) is supplied in bottles of one pint (473 mL).

OXYBUTYNIN CHLORIDE SYRUP USP (5 mg/5 mL) is a light bluish-green liquid with a characteristic raspberry flavor.

NDC 54838-510-80

Pharmacist: Dispense in tight, light-resistant container as defined in the USP.

Store at controlled room temperature 59°F to 86°F (15°C to 30°C).

1. Yong C et al. Effect of Food on the Pharmacokinetics of Oxybutynin in normal subjects. Pharm Res. 1991; 8 (Suppl.): S-320.
2. Hughes KM et al. Measurement of oxybutynin and its N-desethyl metabolite in plasma, and its application to pharmacokinetic studies in young, elderly and frail elderly volunteers. Xenobiotica. 1992; 22 (7): 859-869.
3. Ouslander J et al. Pharmacokinetics and Clinical Effects of Oxybutynin in Geriatric Patients. J. Urol. 1988; 140: 47-50.
4. Yarker Y et al. Oxybutynin: A review of its Pharmacodynamic and Pharmacokinetic Properties, and its Therapeutic Use in Detrusor Instability. Drugs & Aging. 1995; 6(3): 243-262.

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DISTRIBUTED BY:

ATLANTIC BIOLOGICALS CORP.

20101 N.E 16TH PLACE

MIAMI, FL 33179

NDC 17856-0149-1

Oxybutynin Chloride Syrup USP

5 mg per 5 mL 

Rx Only