FDA Label for Oxybutynin Chloride Extended Release

1 Indications And Usage

Oxybutynin chloride extended-release tablets 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 is 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: White, round, biconvex tablet with "270" printed on one side and "KU" printed on the other side with black ink.

10 mg: White, round, biconvex tablet with "271" printed on one side and "KU" printed on the other side with black ink.

15 mg: White, round, biconvex tablet with "272" printed on one side and "KU" printed on the other side with black ink.

4 Contraindications

Oxybutynin chloride extended-release tablets is contraindicated in patients with urinary retention, gastric retention and other severe decreased gastrointestinal motility conditions, uncontrolled narrow-angle glaucoma.

Oxybutynin chloride extended-release tablets 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.

5.1 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 affects 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 symptom aggravation.

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.

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 IR (5 to 20 mg/day in 199 subjects) was an active comparator. Adverse reactions reported by ≥ 1% of subjects are shown in Table 1.

The discontinuation rate due to adverse reactions was 4.4% with Oxybutynin chloride extended-release tablets compared to 0% with Oxybutynin chloride IR. 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.

To report SUSPECTED ADVERSE REACTIONS contact AvKARE, Inc. at 1-855-361-3993; email [email protected]; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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. 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 was 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.

8.3 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 is 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 6–15 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 ₂O to 33 cm H ₂O, and a reduction in the percentage of patients demonstrating uninhibited detrusor contractions (of at least 15 cm H ₂O) 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 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 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 is an antispasmodic, muscarinic antagonist. Each Oxybutynin chloride extended-release tablets 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 ₂₂H ₃₁NO ₃•HCl.

Its structural formula is:

Chemical Structure - oxybutynin 1

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 inert ingredients: lactose, mannitol, dextrose, tartaric acid, colloidal silicon dioxide, magnesium stearate, cellulose acetate, polyethylene glycol, titanium dioxide, triacetin, black iron oxide, propylene glycol, hypromellose.

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.

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 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 (89.0%) 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.

Figure 2 - oxybutynin 4

16 How Supplied/Storage And Handling

Oxybutynin chloride extended-release tablets 5 mg are round, biconvex, white coated tablets imprinted in black ink with "270" on one side and "KU" on the other side.

They are supplied as follows:

Bottles of 100 Tablets   NDC 42291-633-01
Bottles of 500 Tablets   NDC 42291-633-50

Oxybutynin chloride extended-release tablets 10 mg are round, biconvex, white coated tablets imprinted in black ink with "271" on one side and "KU" on the other side.

They are supplied as follows:

Bottles of 100 Tablets   NDC 42291-634-01
Bottles of 500 Tablets   NDC 42291-634-50

Oxybutynin chloride extended-release tablets 15 mg are round, biconvex, white coated tablets imprinted in black ink with "272" on one side and "KU" on the other side.

They are supplied as follows:

Bottles of 100 Tablets   NDC 42291-635-01

16.1 Storage

Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Protect from moisture and humidity.

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 such as:
  • 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.

  For more information call 1-855-361-3993 or visit avkare.com.

  
  

Package Label.Principal Display Panel

AvKARE

NDC 42291-633-50

Oxybutynin Chloride Extended-Release Tablets USP

5 mg

500 Tablets   Rx Only

Each tablet contains 5 mg oxybutynin chloride in an extended-release formulation.

Usual Dosage: Once daily.
See package insert for dosage information.

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].
Protect from moisture and humidity.

Keep out of the reach of children.

Manufactured for:
AvKARE, Inc.
Pulaski, TN 38478

Mfg. Rev. 3E          AV 03/16 (P)

^N₃   4229163350   ₆