OXYBUTYNIN CHLORIDE (Page 3 of 4)

CONTRAINDICATIONS

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

WARNINGS

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 patient airway should be promptly provided.

PRECAUTIONS

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 extended release tablets 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 extended release tablets 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

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

Oxybutynin chloride extended release tablets, 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 extended release tablets 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 oxybutynin chloride extended release tablets 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 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 oxybutynin chloride extended release tablets should be swallowed whole with the aid of liquids. Patients should not chew, divide, or crush tablets.

Oxybutynin chloride extended release tablets 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 oxybutynin chloride extended release tablets were 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

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 oxybutynin chloride extended release tablet administration to women who are or who may become pregnant has not been established. Therefore, oxybutynin chloride extended release tablets 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 oxybutynin chloride extended release tablets are administered to a nursing woman.

Pediatric Use

Clinical study information for pediatric patients 6 to 15 years of age with symptoms of detrusor overactivity associated with a neurological condition (e.g., spina bifida) is approved for Alza Corporation’s oxybutynin chloride extended release tablets. However, due to Alza Corporation’s marketing exclusivity rights, this drug product is not labeled for pediatric use.

Oxybutynin chloride extended release tablets are not recommended in pediatric patients who cannot swallow the tablet whole without chewing, dividing, or crushing, or in children under the age of 6 years.

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 REACTIONS

Clinical Trials

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety and efficacy of oxybutynin chloride extended-release tablets were evaluated in a total of 580 participants who received oxybutynin chloride extended-release tablets 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 2 below.

Adverse reactions from two additional fixed-dose, activecontrolled, 12-week treatment duration, postmarketing studies, in which 576 patients were treated with oxybutynin chloride extended-release tablets 10 mg/day, are also listed in Table 2 (second column).

Table 2 Incidence (%) of Adverse Reactions Reported by ≥ 5% of Patients Using Oxybutynin Chloride Extended-Release Tablets (5 – 30 mg/day) and % of Corresponding Adverse Reactions in Two Fixed-Dose (10 mg/day) Studies
Body System Adverse Reactions Oxybutynin Chloride ER Tablets Oxybutynin Chloride ER Tablets
5 – 30 mg/day (n = 429) 10 mg/day (n = 576)
General headache 10 6
Digestive dry mouth 61 29
constipation 13 7
diarrhea 9 7
nausea 9 2
dyspepsia 7 5
Nervous somnolence 12 2
dizziness 6 4
Special senses blurred vision 8 1
dry eyes 6 3
Urogenital urinary tract infection 5 5

The most common adverse reactions reported by the 429 patients receiving 5 — 30 mg/day oxybutynin chloride extended-release tablets were the expected side effects of anticholinergic agents. The incidence of dry mouth was dose-related.

The discontinuation rate for all adverse reactions 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 reactions causing early discontinuation of study medication was nausea (1.9%), while discontinuation due to dry mouth was 1.2%.

In addition, the following adverse reactions were reported by ≥ 1 to < 5% of all patients who received oxybutynin chloride extended-release tablets in the 6 adjustable and fixed-dose efficacy and safety studies. Psychiatric disorders: depression, nervousness, insomnia, confusional state; Nervous System Disorders: dysgeusia; Cardiac disorders: palpitations; Vascular disorders: hypertension; Respiratory, thoracic and mediastinal disorders: nasal dryness, cough, oropharyngeal pain, dry throat; Gastrointestinal Disorders: gastroesophageal reflux disease, abdominal pain, flatulence, vomiting; Skin and subcutaneous tissue disorders: dry skin, pruritus; Renal and urinary disorders: urinary retention, urinary hesitation, dysuria; General disorders and administration site conditions: fatigue, edema peripheral, chest pain.

The following adverse reactions were reported by <1% of oxybutynin chloride extended-release tablets-treated patients and at a higher incidence than placebo in clinical trials: Metabolism and Nutrition Disorders: anorexia, fluid retention; Vascular disorders: hot flush; Respiratory, thoracic and mediastinal disorders: dysphonia; Gastrointestinal Disorders: dysphagia, frequent bowel movements; General disorders and administration site conditions: chest discomfort, thirst.

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