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Oxybutynin Chloride

HIGHLIGHTS OF PRESCRIBING INFORMATION Initial U.S. Approval: 1975INDICATIONS AND USAGE •Oxybutynin chloride is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency. (1) •Oxybutynin chloride extended-release tablets are also indicated for the treatment of pediatric patients aged 6 years and older with symptoms of detrusor overactivity associated with a neurological condition (e.g., spina bifida). (1) DOSAGE AND ADMINISTRATIONOxybutynin chloride extended-release tablets must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed. Oxybutynin chloride extended-release tablets may be administered with or without food. (2) •Adults: Start with 5 mg or 10 mg, once daily at approximately the same time every day. Dose should not exceed 30 mg per day. (2.1) •Pediatric patients (6 years of age or older): Start with 5 mg, once daily at approximately the same time every day. Dose should not exceed 20 mg per day. (2.2) DOSAGE FORMS AND STRENGTHSExtended-release tablets 5 mg and 10 mg (3)CONTRAINDICATIONS •Urinary retention (4) •Gastric Retention (4) •Uncontrolled narrow angle glaucoma (4) •Known hypersensitivity to oxybutynin chloride extended-release tablets, oxybutynin or any component of oxybutynin chloride extended-release tablets. (4) WARNINGS AND PRECAUTIONS •Angioedema: Angioedema has been reported with oxybutynin. If symptoms of angioedema occur, discontinue oxybutynin chloride extended-release immediately and initiate appropriate therapy. (5.1) •Central Nervous System (CNS) effects: CNS effects have been reported with oxybutynin. If patient experiences anticholinergic CNS effects, consider dose adjustment or discontinuation of oxybutynin chloride extended-release. (5.2) •Worsening of Myasthenia Gravis: Use with caution in Myasthenia gravis patients due to risk of symptom aggravation. (5.3) •Urinary Retention: Use with caution in patients with clinically significant bladder outflow obstruction because of the risk of urinary retention. (5.4) •Gastrointestinal Adverse Reactions: Use with caution in patients with gastrointestinal obstructive disorders or decreased intestinal motility due to risk of gastric retention. Use with caution in patients with gastroesophageal reflux or in patients concurrently taking drugs that can exacerbate esophagitis. (5.5) Side EffectsThe most common (incidence ≥ 5%) adverse reactions were dry mouth, constipation, somnolence, headache, diarrhea, nausea, blurred vision, dyspepsia, dizziness, dry eyes, and urinary tract infection. (6) To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS •Co-administration with other anticholinergic drugs may increase the frequency and/or severity of anticholinergic-like effects. (7) •Co-administration with strong cytochrome P450 (CYP) 3A4 inhibitors (e.g., ketoconazole) increases the systemic exposure of oxybutynin. (7) USE IN SPECIFIC POPULATIONS •Pediatric Use: Oxybutynin chloride extended-release is 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. (8.4) •Renal or Hepatic Impairment: There have been no studies conducted in patients with renal or hepatic impairment. (8.6, 8.7)

FULL PRESCRIBING INFORMATION: CONTENTS*

1 OXYBUTYNIN CHLORIDE INDICATIONS AND USAGE
2 OXYBUTYNIN CHLORIDE DOSAGE AND ADMINISTRATION
- 2.1 Adults
- 2.2 Pediatric Patients Aged 6 Years of Age and Older
3 DOSAGE FORMS AND STRENGTHS
4 OXYBUTYNIN CHLORIDE CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
6 OXYBUTYNIN CHLORIDE ADVERSE REACTIONS
- 6.1 Clinical Trials Experience
- 6.2 Postmarketing Experience
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
10 OVERDOSAGE
11 OXYBUTYNIN CHLORIDE DESCRIPTION
12 CLINICAL PHARMACOLOGY
13 NONCLINICAL TOXICOLOGY
- 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
- 16.1 Storage
17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Oxybutynin chloride is a muscarinic antagonist indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.

Oxybutynin chloride extended-release tablets are also indicated for the treatment of pediatric patients aged 6 years and older with symptoms of detrusor overactivity associated with a neurological condition (e.g., spina bifida).

2 DOSAGE AND ADMINISTRATION

Oxybutynin chloride extended-release tablets must be swallowed whole with the aid of liquids, and must not be chewed, divided, or crushed.

Oxybutynin chloride extended-release tablets may be administered with or without food.

2.1 Adults

The recommended starting dose of oxybutynin chloride extended-release tablets is 5 mg or 10 mg once daily at approximately the same time each day. 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.

2.2 Pediatric Patients Aged 6 Years of Age and Older

The recommended starting dose of oxybutynin chloride extended-release tablets is 5 mg once daily at approximately the same time each day. Dosage may be adjusted in 5 mg increments to achieve a balance of efficacy and tolerability (up to a maximum of 20 mg/day).

3 DOSAGE FORMS AND STRENGTHS

Oxybutynin extended-release tablets are available as 5 mg and 10 mg tablets for oral use:

The 5 mg tablets are light green film-coated, round, unscored tablets with M over O 5 imprinted in black ink on one side of the tablet and blank on the other side.

The 10 mg tablets are peach film-coated, round, unscored tablets with M over O 10 imprinted in black ink on one side of the tablet and blank on the other side.

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.

Oxybutynin chloride extended-release is also contraindicated in patients who have demonstrated hypersensitivity to the drug substance or other components of the product. There have been reports of hypersensitivity reactions, including anaphylaxis and angiodema.

5 WARNINGS AND PRECAUTIONS

5.1 Angioedema

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.

5.2 Central Nervous System Effects

Oxybutynin is associated with anticholinergic central nervous system (CNS) effects [see Adverse Reactions (6)]. 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. Advise patients not to drive or operate heavy machinery until they know how oxybutynin chloride extended-release affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.

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

5.3 Worsening of Symptoms of Myasthenia Gravis

Oxybutynin chloride extended-release should be used with caution in patients with myasthenia gravis due to the risk of symptom aggravation.

5.4 Urinary Retention

Oxybutynin chloride extended-release should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention [see Contraindications (4)].

5.5 Gastrointestinal Side Effects

Oxybutynin chloride extended-release should be administered with caution to patients with gastrointestinal obstructive disorders because of the risk of gastric retention [see Contraindications (4)].

Oxybutynin chloride extended-release 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 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 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.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

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 (5 to 30 mg/day) was evaluated in 774 adult subjects who participated in five double-blind, controlled clinical trials. In four of the five studies, oxybutynin chloride tablets (5 to 20 mg/day in 199 subjects) was an active comparator. Adverse reactions reported by ≥ 1% of subjects are shown in Table 1.

Table 1: Adverse Drug Reactions Reported by ≥ 1% of Oxybutynin Chloride Extended-release Tablet-Treated Adult Subjects in Five Double-blind, Controlled Clinical Trials of Oxybutynin Chloride Extended-release Tablets

System/Organ Class Preferred Term	Oxybutynin Chloride Extended-release Tablets 5 to 30 mg/day n = 774 %	Oxybutynin Chloride Tablets Immediate-release formulation 5 to 20 mg/day n = 199 %
Psychiatric Disorders
Insomnia	3	5.5
Nervous System Disorders
Headache	7.5	8
Somnolence	5.6	14.1
Dizziness	5	16.6
Dysgeusia	1.6	1.5
Eye Disorders
Vision blurred	4.3	9.6
Dry eye	3.1	2.5
Respiratory, Thoracic and Mediastinal Disorders
Cough	1.9	3
Oropharyngeal pain	1.9	1.5
Dry throat	1.7	2.5
Nasal dryness	1.7	4.5
Gastrointestinal Disorders
Dry mouth	34.9	72.4
Constipation	8.7	15.1
Diarrhea	7.9	6.5
Dyspepsia	4.5	6
Nausea	4.5	11.6
Abdominal pain	1.6	2
Vomiting	1.3	1.5
Flatulence	1.2	2.5
Gastro-esophageal reflux disease	1	0.5
Skin and Subcutaneous Tissue Disorders
Dry skin	1.8	2.5
Pruritus	1.3	1.5
Renal and Urinary Disorders
Dysuria	1.9	2
Urinary hesitation	1.9	8.5
Urinary retention	1.2	3
General Disorders and Administration Site Conditions
Fatigue	2.6	3
Investigations
Residual urine volumeThe bundled term residual urine volume consists of the preferred terms residual urine volume and residual urine volume increased.	2.3	3.5

The discontinuation rate due to adverse reactions was 4.4% with oxybutynin chloride extended-release tablets compared to 0% with oxybutynin chloride tablets. The most frequent adverse reaction causing discontinuation of study medication was dry mouth (0.7%).

The following adverse reactions were reported by < 1% of oxybutynin chloride extended-release tablet-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.

6.2 Postmarketing Experience

The following additional adverse reactions have been reported from worldwide postmarketing experience with oxybutynin chloride extended-release tablets. Because postmarketing reactions 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.

Psychiatric Disorders: psychotic disorder, agitation, hallucinations, memory impairment; Nervous System Disorders: convulsions; Eye Disorders: glaucoma; Cardiac Disorders: arrhythmia, tachycardia, QT interval prolongation; Vascular Disorders: flushing; Skin and Subcutaneous Tissue Disorders: rash; Renal and Urinary Disorders: impotence; General Disorders and Administration Site Conditions: hypersensitivity reactions, including angioedema with airway obstruction, urticaria, and face edema; anaphylactic reactions requiring hospitalization for emergency treatment; Injury, poisoning and procedural complications: fall.

Additional adverse events reported with some other oxybutynin chloride formulations include: cycloplegia, mydriasis, and suppression of lactation.

7 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., C_max and AUC). The clinical relevance of such potential interactions is not known. Caution should be used when such drugs are co-administered.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects. Pregnancy Category B

There are no adequate and well-controlled studies using oxybutynin chloride extended-release in pregnant women. Oxybutynin chloride extended-release should be used during pregnancy only if the potential benefit to the patient outweighs the risk to the patient and fetus. Women who become pregnant during oxybutynin chloride extended-release treatment are encouraged to contact their physician.

Risk Summary

Based on animal data, oxybutynin is predicted to have a low probability of increasing the risk of adverse developmental effects above background risk.

Animal Data

Reproduction studies with oxybutynin chloride in the mouse, rat, hamster, and rabbit showed no evidence of impaired fertility or harm to the animal fetus.

8.3 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 is administered to a nursing woman.

8.4 Pediatric Use

The safety and efficacy of oxybutynin chloride were studied in 60 children in a 24-week, open-label, non-randomized trial. Patients were aged 6 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 administration of oxybutynin chloride extended-release 5 to 20 mg/day was associated with an increase from baseline in mean urine volume per catheterization from 108 mL to 136 mL, an increase from baseline in mean urine volume after morning awakening from 148 mL to 189 mL, and an increase from baseline in the mean percentage of catheterizations without a leaking episode from 34% to 51%.

Urodynamic results were consistent with clinical results. Administration of oxybutynin chloride extended-release resulted in an increase from baseline in mean maximum cystometric capacity from 185 mL to 254 mL, a decrease from baseline in mean detrusor pressure at maximum cystometric capacity from 44 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 60% to 28%.

The pharmacokinetics of oxybutynin chloride extended-release in these patients were consistent with those reported for adults [see Clinical Pharmacology (12.3)].

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

8.5 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. The pharmacokinetics of oxybutynin chloride extended-release were similar in all patients studied (up to 78 years of age).

8.6 Renal Impairment

There were no studies conducted with oxybutynin chloride extended-release in patients with renal impairment.

8.7 Hepatic Impairment

There were no studies conducted with oxybutynin chloride extended-release in patients with hepatic impairment.

10 OVERDOSAGE

The continuous release of oxybutynin from oxybutynin chloride extended-release tablets 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 chloride has been associated with anticholinergic effects including central nervous system 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.

11 DESCRIPTION

Oxybutynin chloride is an antispasmodic, muscarinic antagonist. Each oxybutynin chloride extended-release tablet, USP contains 5 mg or 10 mg of oxybutynin chloride USP, formulated as a once-a-day controlled-release tablet for oral administration. Oxybutynin chloride is administered as a racemate of R-and S-enantiomers.

Chemically, oxybutynin chloride is d,l (racemic) 4-diethylamino-2-butynyl phenyl-cyclohexylglycolate hydrochloride. The molecular formula of oxybutynin chloride is C₂₂H₃₁NO₃•HCl.

Its structural formula is:

Oxybutynin chloride, USP 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.

Oxybutynin chloride extended-release tablets also contain the following inactive ingredients: colloidal silicon dioxide, dibasic calcium phosphate (anhydrous), hypromellose, magnesium stearate, methacrylic acid copolymer dispersion, polydextrose, polyethylene glycol, polysorbate 80, povidone, sodium hydroxide, talc, titanium dioxide, triacetin and triethyl citrate. The 5 mg strength also contains D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake and FD&C Red No. 40 Aluminum Lake; and the 10 mg strength also contains FD&C Yellow No. 6 Aluminum Lake.

In addition, the imprinting ink contains black iron oxide, hypromellose and propylene glycol.

Meets USP Dissolution Test 2.

System Components and Performance

Oxybutynin chloride extended-release tablets are formulated to deliver oxybutynin chloride at a controlled rate over approximately 24 hours. The dosage form is comprised of a hydrophilic cellulose polymer matrix tablet surrounded by an enteric coating system. The enteric coat is insoluble in the low pH environment of the stomach. As the tablet passes through the stomach and enters the higher pH environment of the small intestine, the enteric coating dissolves and/or erodes to expose the polymer matrix tablet which swells and releases drug at a controlled rate via diffusion and/or erosion.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Oxybutynin relaxes bladder smooth muscle. Oxybutynin chloride exerts a direct antispasmodic effect on smooth muscle and inhibits the muscarinic action of acetylcholine on smooth muscle. No blocking effects occur at skeletal neuromuscular junctions or autonomic ganglia (antinicotinic effects).

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

12.2 Pharmacodynamics

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.

12.3 Pharmacokinetics

Absorption

Following the first dose of oxybutynin chloride extended-release tablets, oxybutynin plasma concentrations rise for 4 to 6 hours; thereafter steady concentrations are maintained for up to 24 hours, minimizing fluctuations between peak and trough concentrations associated with oxybutynin.

The relative bioavailabilities of R-and S-oxybutynin from oxybutynin chloride extended-release are 156% and 187%, respectively, compared with oxybutynin. The mean pharmacokinetic parameters for R- and S-oxybutynin are summarized in Table 2. The plasma concentration-time profiles for R- and S-oxybutynin are similar in shape; Figure 1 shows the profile for R-oxybutynin.

Table 2: Mean (SD) R- and S-Oxybutynin Pharmacokinetic Parameters Following a Single Dose of Oxybutynin Chloride Extended-release Tablets 10 mg (n = 43)

Parameters (units)	R-Oxybutynin		S-Oxybutynin
C_max (ng/mL)	1	(0.6)	1.8	(1)
T_max (h)	12.7	(5.4)	11.8	(5.3)
t_1/2 (h)	13.2	(6.2)	12.4	(6.1)
AUC_(0-48) (ng•h/mL)	18.4	(10.3)	34.2	(16.9)
AUC_inf (ng•h/mL)	21.3	(12.2)	39.5	(21.2)

Figure 1: Mean R-Oxybutynin Plasma Concentrations Following a Single Dose of Oxybutynin Chloride Extended-release Tablets 10 mg and Oxybutynin 5 mg Administered Every 8 hours (n = 23 for Each Treatment).

Steady state oxybutynin plasma concentrations are achieved by Day 3 of repeated oxybutynin chloride extended-release dosing, with no observed drug accumulation or change in oxybutynin and desethyloxybutynin pharmacokinetic parameters.

Oxybutynin chloride extended-release steady state pharmacokinetics were studied in 19 children aged 5 to 15 years with detrusor overactivity associated with a neurological condition (e.g., spina bifida). The children were on oxybutynin chloride extended-release total daily dose ranging from 5 mg to 20 mg (0.10 to 0.77 mg/kg). Sparse sampling technique was used to obtain serum samples. When all available data are normalized to an equivalent of 5 mg per day of oxybutynin chloride extended-release, the mean pharmacokinetic parameters derived for R- and S-oxybutynin and R- and S-desethyloxybutynin are summarized in Table 3. 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 per day.

Table 3: Mean ± SD R- and S-Oxybutynin and R- and S-Desethyloxybutynin Pharmacokinetic Parameters in Children Aged 5 to 15 Following Administration of 5 mg to 20 mg Oxybutynin Chloride Extended-release Tablets Once Daily (n = 19), All Available Data Normalized to an Equivalent of Oxybutynin Chloride Extended-release Tablets 5 mg Once Daily

	R-Oxybutynin	S-Oxybutynin	R-Desethyloxybutynin	S-Desethyloxybutynin
C_max (ng/mL)	0.7 ± 0.4	1.3 ± 0.8	7.8 ± 3.7	4.2 ± 2.3
T_max (h)	5	5	5	5
AUC (ng•h/mL)	12.8 ± 7	23.7 ± 14.4	125.1 ± 66.7	73.6 ± 47.7

Figure 2: Mean Steady State (± SD) R-Oxybutynin Plasma Concentrations following Administration of 5 to 20 mg Oxybutynin Chloride Extended-release Tablets Once Daily in Children Aged 5 to 15. Plot Represents All Available Data Normalized to an Equivalent of Oxybutynin Chloride Extended-release Tablets 5 mg Once Daily.

Food Effects

The rate and extent of absorption and metabolism of oxybutynin are similar under fed and fasted conditions.

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 N-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. Following oxybutynin chloride extended-release 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 mg to 20 mg of oxybutynin chloride extended-release tablets are dose proportional.

Use in Specific Populations

Pediatric

The pharmacokinetics of oxybutynin chloride extended-release were evaluated in 19 children aged 5 to 15 years with detrusor overactivity associated with a neurological condition (e.g., spina bifida). The pharmacokinetics of oxybutynin chloride extended-release in these pediatric patients were consistent with those reported for adults (see Tables 2 and 3, and Figures 1 and 2 above).

Gender

There are no significant differences in the pharmacokinetics of oxybutynin in healthy male and female volunteers following administration of oxybutynin chloride extended-release.

Race

Available data suggest that there are no significant differences in the pharmacokinetics of oxybutynin based on race in healthy volunteers following administration of oxybutynin chloride extended-release.

13 NONCLINICAL TOXICOLOGY

13.1 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 a human equivalent dose taking into account normalization of body 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 evidence of impaired fertility.

14 CLINICAL STUDIES

Oxybutynin chloride extended-release was evaluated for the treatment of patients with overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency in three controlled efficacy studies. The majority of patients were Caucasian (89%) 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 fixed-dose escalation design, whereas the other two studies used a dose-adjustment design in which each patient’s final dose was adjusted to a balance between improvement of incontinence symptoms and tolerability of side effects. All three 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.

Number of Urge Incontinence Episodes per Week

16 HOW SUPPLIED/STORAGE AND HANDLING

Oxybutynin Chloride Extended-release Tablets, USP are available containing 5 mg or 10 mg of oxybutynin chloride, USP.

The 5 mg tablets are light green film-coated, round, unscored tablets with M over O 5 imprinted in black ink on one side of the tablet and blank on the other side. They are available as follows:

NDC 0378-6605-01

bottles of 100 tablets

NDC 0378-6605-05

bottles of 500 tablets

The 10 mg tablets are peach film-coated, round, unscored tablets with M over O 10 imprinted in black ink on one side of the tablet and blank on the other side. They are available as follows:

NDC 0378-6610-01

bottles of 100 tablets

NDC 0378-6610-05

bottles of 500 tablets

16.1 Storage

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Protect from moisture and humidity.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

17 PATIENT COUNSELING INFORMATION

•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 swelling of the tongue, edema of the laryngopharynx, or difficulty breathing.
•Patients should be informed that anticholinergic (antimuscarinic) agents such as oxybutynin chloride extended-release tablets, may produce clinically significant adverse reactions related to anticholinergic activity including:
- oUrinary retention and constipation
- oHeat prostration due to decreased sweating. Heat prostration can occur when anticholinergic medicines are administered in the presence of high environmental temperature.
•Patients should be informed that anticholinergic medicines such as oxybutynin chloride extended-release tablets may produce drowsiness (somnolence), dizziness or blurred vision. Patients should be advised to exercise caution in decisions to engage in potentially dangerous activities until oxybutynin chloride extended-release tablets effects have been determined.
•Patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents such as oxybutynin chloride extended-release tablets.
•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.

For more information call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX).

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

REVISED JANUARY 2014
OXBN:R7

PRINCIPAL DISPLAY PANEL - 5 mg

NDC 0378-6605-01

Oxybutynin
Chloride
Extended-release
Tablets, USP
5 mg

Rx only 100 Tablets

Each film-coated tablet contains:
Oxybutynin chloride, USP 5 mg

Dispense in a tight, light-resistant
container as defined in the USP
using a child-resistant closure.

Keep container tightly closed.

Keep this and all medication
out of the reach of children.

Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature.]

Protect from moisture and
humidity.

Usual Dosage: Once daily. See
accompanying prescribing
information.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Mylan.com

RM6605A4

PRINCIPAL DISPLAY PANEL - 10 mg

NDC 0378-6610-01

Oxybutynin
Chloride
Extended-release
Tablets, USP
10 mg

Rx only 100 Tablets

Each film-coated tablet contains:
Oxybutynin chloride, USP 10 mg

Dispense in a tight, light-resistant
container as defined in the USP
using a child-resistant closure.

Keep container tightly closed.

Keep this and all medication
out of the reach of children.

Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature.]

Protect from moisture and
humidity.

Usual Dosage: Once daily. See
accompanying prescribing
information.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Mylan.com

RM6610A5