OXYBUTYNIN CHLORIDEEXTENDED-RELEASETABLETS5 mg and 10 mg

oxybutynin chloride (Oxybutynin Chloridetablet, film coated, extended release 
[Mylan Pharmaceuticals Inc.]

5 mg and 10 mg

Rx only

DESCRIPTION

Oxybutynin chloride is an antispasmodic, anticholinergic agent. Each oxybutynin chloride extended-release tablet 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 phenylcyclohexylglycolate hydrochloride. The molecular formula of oxybutynin chloride is C22H31NO3 • HCl.

Its structural formula is:

Image from Drug Label Content

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 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 D&C Yellow No. 6 aluminum lake.

In addition, oxybutynin extended-release tablets may also contain imprinting ink consisting of either black pigment and natural resin or black iron oxide and propylene glycol.

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.

CLINICAL PHARMACOLOGY

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

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

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 1. The plasma concentration-time profiles for R- and S-oxybutynin are similar in shape; Figure 1 shows the profile for R-oxybutynin.

Table 1 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-OxybutyninS-Oxybutynin
Cmax (ng/mL)1.0(0.6)1.8(1.0)
Tmax (h)12.7(5.4)11.8(5.3)
t1/2 (h)13.2(6.2)12.4(6.1)
AUC(0–48) (ng∙h/mL)18.4(10.3)34.2(16.9)
AUCinf (ng∙h/mL)21.3(12.2)39.5(21.2)
Image from Drug Label Content

Figure 1. Mean R-oxybutynin plasma concentrations following a single dose of oxybutynin chloride ER 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.

Pharmacokinetic information for pediatric patients 5 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.

Food Effects

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

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. 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 (Cmax and AUC) following administration of 5 to 20 mg of oxybutynin chloride extended-release tablets are dose proportional.

Special Populations

Geriatric

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

Pediatric

Pharmacokinetic information for pediatric patients 5 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.

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.

Renal Insufficiency

There is no experience with the use of oxybutynin chloride extended-release in patients with renal insufficiency.

Hepatic Insufficiency

There is no experience with the use of oxybutynin chloride extended-release in patients with hepatic insufficiency.

Drug-Drug Interactions

See PRECAUTIONS: Drug Interactions.

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 studies and one open label study. 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 forced dose escalation design, whereas the other 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. Controlled 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

*
Covariate adjusted mean with missing observations set to baseline values
The difference between oxybutynin chloride ER and placebo was statistically significant.
Study 1NOxybutynin
Chloride ER
NPlacebo
Image from Drug Label Content
Mean Baseline3415.91620.9
Mean (SD) Change from Baseline*34-15.8 (8.9)16-7.6 (8.6)
95% Confidence Interval for Difference
(oxybutynin chloride ER - Placebo)
(-13.6, -2.8)
*
Covariate adjusted mean with missing observations set to baseline values
Study 2NOxybutynin
Chloride ER
Noxybutynin
Image from Drug Label Content
Mean Baseline5327.65223.0
Mean (SD) Change from Baseline*53-17.6 (11.9)52-19.4 (11.9)
95% Confidence Interval for Difference
(oxybutynin chloride ER - oxybutynin)
(-2.8, 6.5)
*
Covariate adjusted mean with missing observations set to baseline values
The difference between oxybutynin chloride ER and oxybutynin fulfilled the criteria for comparable efficacy.
Study 3NOxybutynin
Chloride ER
Noxybutynin
Image from Drug Label Content
Mean Baseline11118.911519.5
Mean (SD) Change from Baseline*111-14.5 (8.7)115-13.8 (8.6)
95% Confidence Interval for Difference
(oxybutynin chloride ER - oxybutynin)
(-3.0, 1.6)

INDICATIONS AND USAGE

Oxybutynin chloride extended-release tablets are once-daily controlled-release tablets indicated for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency.

Pediatric use information for the treatment of patients aged 6 years and older with symptoms of detrusor overactivity associated with a neurological condition (e.g., spina bifida) is approved for Alza Corporation's oxybutynin extended-release tablets. However, due to Alza Corporation's marketing exclusivity rights, this drug product is not labeled for pediatric use.

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

PRECAUTIONS

General

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

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.

Information for Patients

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 coadministered.

Concurrent ingestion of antacid (20 mL of antacid containing aluminum hydroxide, magnesium hydroxide, and simethicone) did not significantly affect the exposure of oxybutynin or desethyloxybutynin.

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

Pediatric Use

Clinical study information for pediatric patients 6 to 15 years of age with symptoms of detrusor overactivity in association 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: Gender).

ADVERSE REACTIONS

Adverse Events with Oxybutynin Chloride Extended-release Tablets

The safety and efficacy of oxybutynin chloride was evaluated in a total of 580 participants who received oxybutynin chloride extended-release tablets in four clinical trials (429 patients, 151 healthy volunteers). These participants were treated with 5 to 30 mg/day for up to 4.5 months. Three of these studies 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 events from two additional fixed dose, active controlled, 12 week treatment duration, post-marketing studies, in which 576 patients were treated with oxybutynin chloride extended-release tablets 10 mg/day, are also listed in Table 2 (second column). The adverse events are reported regardless of causality.

Table 2 Incidence (%) of Adverse Events Reported by ≥ 5% of Patients Using Oxybutynin Chloride Extended-release Tablets (5 to 30 mg/day) and % of Corresponding Adverse Events in Two Fixed Dose (10 mg/day) Studies
Body SystemAdverse EventOxybutynin Chloride
ER Tablets
5 to 30 mg/day
(n = 429)
Oxybutynin Chloride
ER Tablets
10 mg/day
(n = 576)
Generalheadache
asthenia
pain
10
7
7
6
3
4
Digestivedry mouth
constipation
diarrhea
nausea
dyspepsia
61
13
9
9
7
29
7
7
2
5
Nervoussomnolence
dizziness
12
6
2
4
Respiratoryrhinitis62
Special
  senses
blurred vision
dry eyes
8
6
1
3
Urogenitalurinary tract
infection
55

The most common adverse events reported by patients receiving 5 to 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 events was 6.8% in the 429 patients from the four studies of efficacy and safety who received 5 to 30 mg/day. The most frequent adverse event causing early discontinuation of study medication was nausea (1.9%), while discontinuation due to dry mouth was 1.2%.

In addition, the following adverse events were reported by 2 to < 5% of the 429 patients who received 5 to 30 mg/day of oxybutynin chloride extended-release tablets in the four efficacy and safety studies. General: abdominal pain, dry nasal and sinus mucous membranes, accidental injury, back pain, flu syndrome; Cardiovascular: hypertension, palpitation, vasodilatation; Digestive: flatulence, gastroesophageal reflux; Musculoskeletal: arthritis; Nervous: insomnia, nervousness, confusion; Respiratory: upper respiratory tract infection, cough, sinusitis, bronchitis, pharyngitis; Skin: dry skin, rash; Urogenital: impaired urination (hesitancy), increased post void residual volume, urinary retention, cystitis.

Additional rare adverse events reported from worldwide post-marketing experience with oxybutynin chloride extended-release tablets include: peripheral edema, cardiac arrhythmia, tachycardia, hallucinations, convulsions, and impotence.

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

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.

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.

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.

Pediatric Patients

Dosing information for pediatric patients aged 6 years and older 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.

HOW SUPPLIED

Oxybutynin chloride extended-release tablets 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

Store at 20° to 25°C (68° to 77°F). [See USP for 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.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505

REVISED NOVEMBER 2006
OXBN:R1


Oxybutynin Chloride (Oxybutynin Chloride)
PRODUCT INFO
Product Code0378-6605Dosage FormTABLET, FILM COATED, EXTENDED RELEASE
Route Of AdministrationORALDEA Schedule
INGREDIENTS
Name (Active Moiety)TypeStrength
Oxybutynin Chloride (Oxybutynin) Active5 MILLIGRAM  In 1 TABLET
colloidal silicon dioxideInactive 
D&C yellow #10 aluminum lakeInactive 
dibasic calcium phosphate (anhydrous)Inactive 
FD&C blue #1 aluminum lakeInactive 
FD&C red #40 aluminum lakeInactive 
hypromelloseInactive 
magnesium stearateInactive 
methacrylic acid copolymer dispersionInactive 
polydextroseInactive 
polyethylene glycolInactive 
polysorbate 80Inactive 
povidoneInactive 
sodium hydroxideInactive 
talcInactive 
titanium dioxideInactive 
triacetinInactive 
triethyl citrateInactive 
black pigmentInactive 
natural resinInactive 
black iron oxideInactive 
propylene glycolInactive 
IMPRINT INFORMATION
CharacteristicAppearanceCharacteristicAppearance
ColorGREEN (Light Green) Score1
ShapeROUNDSymbolfalse
Imprint Code M;O;5 Coatingtrue
Size8mm
PACKAGING
#NDCPackage DescriptionMultilevel Packaging
10378-6605-01100 TABLET In 1 BOTTLE, PLASTICNone
20378-6605-05500 TABLET In 1 BOTTLE, PLASTICNone

Oxybutynin Chloride (Oxybutynin Chloride)
PRODUCT INFO
Product Code0378-6610Dosage FormTABLET, FILM COATED, EXTENDED RELEASE
Route Of AdministrationORALDEA Schedule
INGREDIENTS
Name (Active Moiety)TypeStrength
Oxybutynin Chloride (Oxybutynin) Active10 MILLIGRAM  In 1 TABLET
colloidal silicon dioxideInactive 
dibasic calcium phosphate (anhydrous)Inactive 
D&C yellow #6 aluminum lakeInactive 
hypromelloseInactive 
magnesium stearateInactive 
methacrylic acid copolymer dispersionInactive 
polydextroseInactive 
polyethylene glycolInactive 
polysorbate 80Inactive 
povidoneInactive 
sodium hydroxideInactive 
talcInactive 
titanium dioxideInactive 
triacetinInactive 
triethyl citrateInactive 
black pigmentInactive 
natural resinInactive 
black iron oxideInactive 
propylene glycolInactive 
IMPRINT INFORMATION
CharacteristicAppearanceCharacteristicAppearance
ColorORANGE (Peach) Score1
ShapeROUNDSymbolfalse
Imprint Code M;O;10 Coatingtrue
Size8mm
PACKAGING
#NDCPackage DescriptionMultilevel Packaging
10378-6610-01100 TABLET In 1 BOTTLE, PLASTICNone
20378-6610-05500 TABLET In 1 BOTTLE, PLASTICNone

Revised: 08/2007Mylan Pharmaceuticals Inc.