Oxybutynin chloride 15 MG 24 HR Extended Release Oral Tablet
DRUG INTERACTIONS
7 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.
Anticholinergic agents may also antagonize the effects of prokinetic agents, such as metoclopramide.
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.
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 )
OVERDOSAGE
10 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.
DESCRIPTION
11 Oxybutynin chloride is 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 22 H 31 NO 3 ∙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.
Chemical Structure System Components and Performance Oxybutynin chloride extended-release tablets uses osmotic pressure to deliver oxybutynin chloride at a controlled rate over approximately 24 hours.
The system, which resembles a conventional tablet in appearance, comprises an osmotically active bilayer core surrounded by a semipermeable membrane.
The bilayer core is composed of a drug layer containing the drug and excipients, and a push layer containing osmotically active components.
There is a precision-laser drilled orifice in the semipermeable membrane on the drug-layer side of the tablet.
In an aqueous environment, such as the gastrointestinal tract, water permeates through the membrane into the tablet core, causing the drug to go into suspension and the push layer to expand.
This expansion pushes the suspended drug out through the orifice.
The semipermeable membrane controls the rate at which water permeates into the tablet core, which in turn controls the rate of drug delivery.
The controlled rate of drug delivery into the gastrointestinal lumen is thus independent of pH or gastrointestinal motility.
The function of oxybutynin chloride extended-release tablets depends on the existence of an osmotic gradient between the contents of the bilayer core and the fluid in the gastrointestinal tract.
Since the osmotic gradient remains constant, drug delivery remains essentially constant.
The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the feces as an insoluble shell.
CLINICAL STUDIES
14 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 34 15.9 16 20.9 Mean (SD) Change from Baseline Covariate adjusted mean with missing observations set to baseline values 34 -15.8 (8.9) 16 -7.6 (8.6) 95% Confidence Interval for Difference (-13.6, -2.8) The difference between oxybutynin chloride extended-release tablets and placebo was statistically significant.
(Oxybutynin Chloride Extended-Release Tablets – Placebo) Study 2 n Oxybutynin Chloride Extended-Release Tablets n Oxybutynin Mean Baseline 53 27.6 52 23.0 Mean (SD) Change from Baseline Covariate adjusted mean with missing observations set to baseline values 53 -17.6 (11.9) 52 -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 111 18.9 115 19.5 Mean (SD) Change from Baseline Covariate adjusted mean with missing observations set to baseline values 111 -14.5 (8.7) 115 -13.8 (8.6) 95% Confidence Interval for Difference (-3.0, 1.6) The difference between oxybutynin chloride extended-release tablets and oxybutynin fulfilled the criteria for comparable efficacy.
(Oxybutynin Chloride Extended-Release Tablets – Oxybutynin) Figure Figure Figure
HOW SUPPLIED
16 /STORAGE AND HANDLING Oxybutynin chloride extended-release tablets, 5 mg – Each light purple, film-coated, round convex tablet is debossed with “G 341” on one side and plain on the other side.
Bottles of 100 NDC 0093-5206-01 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 100 NDC 0093-5207-01 Oxybutynin chloride extended-release tablets, 15 mg – Each off-white, film-coated, round convex tablet is debossed with “G 343” on one side and plain on the other side.
Bottles of 100 NDC 0093-5208-01 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).
GERIATRIC USE
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).
DOSAGE FORMS AND STRENGTHS
3 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.
Extended release tablets 5 mg, 10 mg and 15 mg ( 3 )
MECHANISM OF ACTION
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.
INDICATIONS AND USAGE
1 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 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 )
PEDIATRIC USE
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 2 O to 33 cm H 2 O, and a reduction in the percentage of patients demonstrating uninhibited detrusor contractions (of at least 15 cm H 2 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.
PREGNANCY
8.1 Pregnancy Pregnancy Category B.
There are no adequate and well-controlled studies using oxybutynin chloride 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.
NUSRING MOTHERS
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.
WARNING AND CAUTIONS
5 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 ) Use with caution due to aggravation of symptoms: Pre-existing dementia in patients treated with cholinesterase inhibitors ( 5.2 ), Parkinson’s disease ( 5.2 ), Myasthenia gravis ( 5.3 ), and Decreased gastrointestinal motility in patients with autonomic neuropathy.
( 5.4 ).
Urinary Retention: Use with caution in patients with clinically significant bladder outflow obstruction because of the risk of urinary retention ( 5.5 ) 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.
( 5.6 ) 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.
Oxybutynin chloride extended-release tablets should be used with caution in patients with Parkinson’s disease 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 aggravation of symptoms.
5.4 Worsening of Symptoms of Decreased Gastrointestinal Motility in Patients with Autonomic Neuropathy Oxybutynin chloride extended-release tablets should be used with caution in patients with autonomic neuropathy due to the risk of aggravation of symptoms of decreased gastrointestinal motility.
5.5 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) ] .
5.6 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.
INFORMATION FOR PATIENTS
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.
The medication is contained within a nonabsorbable shell designed to release the drug at a controlled rate.
The tablet shell is eliminated from the body; patients should not be concerned if they occasionally notice in their stool something that looks like a tablet.
Oxybutynin chloride extended-release tablets should be taken at approximately the same time each day.
DOSAGE AND ADMINISTRATION
2 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.
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 ) 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).