OXYBUTYNIN CHLORIDE- oxybutynin chloride tablet, extended release

United States - English - NLM (National Library of Medicine)

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Active ingredient:
OXYBUTYNIN CHLORIDE (UNII: L9F3D9RENQ) (OXYBUTYNIN - UNII:K9P6MC7092)
Available from:
KAISER FOUNDATION HOSPITALS
INN (International Name):
OXYBUTYNIN CHLORIDE
Composition:
OXYBUTYNIN CHLORIDE 10 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Oxybutynin chloride extended-release tablets are 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). 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 tablets are 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 angioedema. Pregnancy Category B. There are no adequate and well-controlled studies using oxybutynin chloride extended-relea
Product summary:
Oxybutynin chloride extended-release tablets, 10 mg – Each light pink, film-coated, round convex tablet is debossed with "G 342" on one side and plain on the other side. Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Protect from moisture and humidity. Dispense in a tightly-closed, light-resistant container (USP).
Authorization status:
Abbreviated New Drug Application
Authorization number:
0179-0187-88

OXYBUTYNIN CHLORIDE- oxybutynin chloride tablet, extended release

KAISER FOUNDATION HOSPITALS

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use oxybutynin chloride extended-release

tablets safely and effectively. See full prescribing information for oxybutynin chloride extended-release

tablets.

Oxybutynin Chloride Extended-Release Tablets for oral use

Initial U.S. Approval: 1975

INDICATIONS AND USAGE

Oxybutynin chloride extended-release tablets are 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 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)

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 STRENGTHS

Extended release tablets 5 mg, 10 mg and 15 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 tablets 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

tablets. ( 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)

ADVERSE REACTIONS

The 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 TEVA USA, PHARMACOVIGILANCE at 1-866-832-8537

or drug.safety@tevapharm.com; 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 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. ( 8.4)

Renal or Hepatic Impairment: There have been no studies conducted in patients with renal or hepatic impairment. ( 8.6,

8.7)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 10/2015

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Adults

2.2 Pediatric Patients Aged 6 Years of Age and Older

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Angioedema

5.2 Central Nervous System Effects

5.3 Worsening of Symptoms of Myasthenia Gravis

5.4 Urinary Retention

5.5 Gastrointestinal Adverse Reactions

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

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

Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Oxybutynin chloride extended-release tablets are 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 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 chloride extended-release tablets are available as 5, 10 and 15 mg tablets for oral use:

5 mg:

Light purple, film-coated, round convex tablets, debossed with "G 341" on one side and

plain on the other side.

10 mg:

Light pink, film-coated, round convex tablets, debossed with "G 342" on one side and

plain on the other side.

15 mg:

Off-white, film-coated, round convex tablets, debossed with "G 343" on one side and

plain 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 tablets are 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 angioedema.

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 tablets affect them. 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.

5.3 Worsening of Symptoms of Myasthenia Gravis

Oxybutynin chloride extended-release tablets 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 tablets 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 Adverse Reactions

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 (4)]

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.

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) were

evaluated in 774 adult subjects who participated in five double-blind, controlled clinical trials. In four

of the five studies, oxybutynin chloride immediate release tablets (5 to 20 mg/day in 199 subjects) were

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

Tablets-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 IR

Tablets 5 to 20 mg/day

n = 199

%

Psychiatric Disorders

Insomnia

Nervous System Disorders

Headache

Somnolence

14.1

Dizziness

16.6

Dysgeusia

Eye Disorders

Vision blurred

Dry eye

Respiratory, Thoracic and Mediastinal Disorders

Cough

Oropharyngeal pain

Dry throat

Nasal dryness

Gastrointestinal Disorders

Dry mouth

34.9

72.4

Constipation

15.1

Diarrhea

Dyspepsia

Nausea

11.6

Abdominal pain

Vomiting

Flatulence

Gastro-esophageal reflux

disease

Skin and Subcutaneous Tissue Disorders

Dry skin

Pruritus

Renal and Urinary Disorders

Dysuria

Urinary hesitation

Urinary retention

General Disorders and Administration Site Conditions

Fatigue

*

Inves tigations

Residual urine volume

The discontinuation rate due to adverse reactions was 4.4% with oxybutynin chloride extended-release

tablets compared to 0% with oxybutynin chloride immediate release 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

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.

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

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

Pregnancy Category B. There are no adequate and well-controlled studies using oxybutynin chloride

IR = immediate release

The bundled term residual urine volume consists of the preferred terms residual urine volume and residual urine

volume increased.

extended-release tablets in pregnant women. Oxybutynin chloride extended-release tablets 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 tablets 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 tablets are

administered to a nursing woman.

8.4 Pediatric Use

The safety and efficacy of oxybutynin chloride extended-release tablets 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 tablets 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 tablets 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 H

O to 33 cm H

O, and a reduction in the percentage of patients demonstrating

uninhibited detrusor contractions (of at least 15 cm H

O) from 60% to 28%.

The pharmacokinetics of oxybutynin chloride extended-release tablets in these patients were consistent

with those reported for adults [see Clinical Pharmacology (12.3)] .

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.

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 tablets

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 tablets in patients with

renal impairment.

8.7 Hepatic Impairment

There were no studies conducted with oxybutynin chloride extended-release tablets 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 extended-release tablets are an antispasmodic, muscarinic antagonist. Each

oxybutynin chloride extended-release tablet contains 5 mg, 10 mg, or 15 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 phenylcyclohexylglycolate

hydrochloride. The empirical formula of oxybutynin chloride is C

·HCl. Its structural

formula is:

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.

Oxybutynin chloride extended-release tablets also contain the following inactive ingredients:

hydrogenated vegetable oil, hypromellose, lactose monohydrate, methyacrylic acid copolymer,

microcrystalline cellulose, talc and triethyl citrate. The 5 mg tablets contain FD&C Blue No. 2

Aluminum Lake and FD&C Red No. 40 Aluminum Lake. The 10 mg tablets contain FD&C Red No. 40

Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake.

System Components and Performance

Oxybutynin chloride extended-release tablets employ an enteric-coated hydrophilic hydrogel matrix to

deliver oxybutynin chloride at a controlled rate over approximately 24 hours. The system comprises a

core, which consists of the drug, rate-controlling hydrogel and other excipients. The core is

surrounded by a pH-dependent membrane. In an acidic environment such as the stomach, minimal drug

release will occur due to the resistance of the pH-dependent outer membrane. Upon reaching an

environment of pH 5.5 and above, the outer membrane dissolves exposing the inner core tablet, which

partially hydrates to form a gel layer. Drug release is via slow diffusion out of the gel layer and

subsequent gel erosion.

This product meets USP Drug Release Test #4.

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 tablets

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

(ng/mL)

(0.6)

(1.0)

12.7

(5.4)

11.8

(5.3)

13.2

(6.2)

12.4

(6.1)

(ng·h/mL)

18.4

(10.3)

34.2

(16.9)

(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 tabletst 10 mg and oxybutynin 5 mg administered every 8 hours (n=23

for each treatment).

(0-48)

Steady state oxybutynin plasma concentrations are achieved by Day 3 of repeated oxybutynin chloride

extended-release tablets dosing, with no observed drug accumulation or change in oxybutynin and

desethyloxybutynin pharmacokinetic parameters.

Oxybutynin chloride extended-release tablets 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 tablets total daily dose ranging

from 5 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 tablets, 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 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-Desethyl-

oxybutynin

S-Desethyl-

oxybutynin

(ng/mL)

0.7 ± 0.4

1.3 ± 0.8

7.8 ± 3.7

4.2 ± 2.3

AUC (ng·h/mL)

12.8 ± 7.0

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 tablets 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

and AUC) following

administration of 5 to 20 mg of oxybutynin chloride extended-release tablets are dose proportional.

Use in Specific Populations

Pediatric

The pharmacokinetics of oxybutynin chloride extended-release tablets 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 tablets 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 tablets.

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

tablets.

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 tablets were 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 (89.0%) 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 Urinary Incontinence Episodes Per Week

Study 1

n

Oxybutynin Chloride

Extended-Release Tablets

n

Placebo

Mean Baseline

15.9

20.9

Mean (SD) Change from Baseline

-15.8 (8.9)

-7.6 (8.6)

95% Confidence Interval for Difference

(-13.6, -2.8)

(Oxybutynin Chloride Extended-Release Tablets – Placebo)

Covariate adjusted mean with missing observations set to baseline values

The difference between oxybutynin chloride extended-release tablets and placebo was statistically significant.

Study 2

n

Oxybutynin Chloride

Extended-Release Tablets

n

Oxybutynin

Mean Baseline

27.6

23.0

Mean (SD) Change from Baseline

-17.6 (11.9)

-19.4 (11.9)

95% Confidence Interval for Difference

(-2.8, 6.5)

(Oxybutynin Chloride Extended-Release Tablets – Oxybutynin)

Study 3

n

Oxybutynin Chloride

Extended-Release Tablets

n

Oxybutynin

Mean Baseline

18.9

19.5

Mean (SD) Change from Baseline

-14.5 (8.7)

-13.8 (8.6)

95% Confidence Interval for Difference

(-3.0, 1.6)

(Oxybutynin Chloride Extended-Release Tablets – Oxybutynin)

Covariate adjusted mean with missing observations set to baseline values

Covariate adjusted mean with missing observations set to baseline values

The difference between oxybutynin chloride extended-release tablets and oxybutynin fulfilled the criteria for

comparable efficacy.

16 HOW SUPPLIED/STORAGE AND HANDLING

Oxybutynin chloride extended-release tablets, 10 mg – Each light pink, film-coated, round convex tablet

is debossed with "G 342" on one side and plain on the other side.

Bottles of

2400

NDC 0179-0187-88

16.1 Storage

Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Protect from moisture

and humidity.

Dispense in a tightly-closed, light-resistant container (USP).

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:

Urinary retention and constipation

Heat 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 1-888-838-2872.

Manufactured By:

IMPAX Laboratories, Inc.

Hayward, CA 94544 USA

Manufactured For:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rx only

675-04

Rev. 10/2013

Repackaged By:

KAISER FOUNDATION HOSPITALS

Livermore, CA 94551

PRINCIPAL DISPLAY PANEL - 10 mg Tablet Bottle Label

NDC 0179- 0187-88

OXYBUTYNIN CHLORIDE

Extended-Release Tablets

10 mg

Each film-coated, extended-release tablet

contains 10 mg of oxybutynin chloride USP.

Rx only

2400 TABLETS

KAISER FOUNDATION HOSPITALS

OXYBUTYNIN CHLORIDE

oxybutynin chloride tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:0 179 -0 18 7(NDC:0 0 9 3-520 7)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

KAISER FOUNDATION HOSPITALS

O XYBUTYNIN CHLO RIDE (UNII: L9 F3D9 RENQ) (OXYBUTYNIN - UNII:K9 P6 MC70 9 2)

OXYBUTYNIN CHLORIDE

10 mg

Inactive Ingredients

Ingredient Name

Stre ng th

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

METHACRYLIC ACID (UNII: 1CS0 2G8 6 56 )

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

TALC (UNII: 7SEV7J4R1U)

TRIETHYL CITRATE (UNII: 8 Z9 6 QXD6 UM)

FD&C RED NO . 4 0 (UNII: WZB9 127XOA)

FD&C YELLO W NO . 6 (UNII: H77VEI9 3A8 )

Product Characteristics

Color

pink (light pink)

S core

no sco re

S hap e

ROUND (film-co ated, ro und, co nvex)

S iz e

Flavor

Imprint Code

G342

Contains

Packag ing

#

Item Code

Package Description

Marketing Start

Date

Marketing End

Date

1

NDC:0 179 -0 18 7-

240 0 in 1 BOTTLE, PLASTIC; Type 0 : No t a Co mbinatio n

Pro duc t

10 /14/20 15

0 6 /30 /20 20

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 76 745

10 /14/20 15

0 6 /30 /20 20

Labeler -

KAISER FOUNDAT ION HOSPIT ALS (053052619)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

KAISER FOUNDATION HOSPITALS

0 530 526 19

re pa c k(0 179 -0 18 7)

Revised: 11/2018

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