Label: OXYBUTYNIN CHLORIDE tablet

Rx only

Each scored oxybutynin chloride tablet contains 5 mg of oxybutynin chloride. 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. The structural formula appears below:

Oxybutynin chloride is a white crystalline solid with a molecular weight of 393.95. It is readily soluble in water and acids, but relatively insoluble in alkalis.

Oxybutynin Chloride Tablets also contain: FD&C Blue #1 aluminum lake, magnesium stearate, microcrystalline cellulose, and pregelatinized starch.

Oxybutynin Chloride Tablets are for oral administration.

Therapeutic Category: Antispasmodic, anticholinergic.

The product meets USP Dissolution Test 2.

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

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

Pharmacokinetics

Absorption

Following oral administration of oxybutynin chloride, oxybutynin is rapidly absorbed achieving C maxwithin an hour, following which plasma concentration decreases with an effective half-life of approximately 2 to 3 hours. The absolute bioavailability of oxybutynin is reported to be about 6% (range 1.6 to 10.9%) for the tablets. Wide interindividual variation in pharmacokinetic parameters is evident following oral administration of 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 1shows the profile for R-oxybutynin.

Parameters (units)	R-Oxybutynin	S-Oxybutynin
C max(ng/mL)	3.6 (2.2)	7.8 (4.1)
T max(h)	0.89 (0.34)	0.65 (0.32)
AUC t(ng•h/mL)	22.6 (11.3)	35.0 (17.3)
AUC inf(ng•h/mL)	24.3 (12.3)	37.3 (18.7)

Figure 1.Mean R-oxybutynin plasma concentrations following three doses of oxybutynin chloride 5 mg administered every 8 hours for 1 day in 23 healthy adult volunteers

Oxybutynin chloride steady-state pharmacokinetics were also studied in 11 pediatric patients with detrusor overactivity associated with a neurological condition (e.g., spina bifida). These pediatric patients were on oxybutynin chloride tablets with total daily dose ranging from 7.5 mg to 15 mg (0.22 to 0.53 mg/kg). Overall, most patients (86.9%) were taking a total daily oxybutynin chloride dose between 10 mg and 15 mg. Sparse sampling technique was used to obtain serum samples. When all available data are normalized to an equivalent of 5 mg twice daily oxybutynin chloride, the mean pharmacokinetic parameters derived for R- and S-oxybutynin and R- and S-desethyloxybutynin are summarized in Table 2. The plasma-time concentration profiles for R- and S-oxybutynin are similar in shape; Figure 2shows the profile for R-oxybutynin when all available data are normalized to an equivalent of 5 mg twice daily.

Table 2    Mean ± SD R- and S-Oxybutynin and R- and S-Desethyloxybutynin Pharmacokinetic Parameters In Children Aged 5 to 15 Following Administration of 7.5 mg to 15 mg Total Daily Dose of Oxybutynin Chloride Tablets (N=11)

All Available Data Normalized to an Equivalent of Oxybutynin Chloride Tablets 5 mg BID or TID at Steady State

	R-Oxybutynin	S-Oxybutynin	R-Desethyloxybutynin	S-Desethyloxybutynin
C max*(ng/mL)	6.1 ± 3.2	10.1 ± 7.5	55.4 ± 17.9	28.2 ± 10.0
T max(hr)	1.0	1.0	2.0	2.0
AUC**(ng∙hr/mL)	19.8 ± 7.4	28.4 ± 12.7	238.8 ± 77.6	119.5 ± 50.7
*Reflects Cmax for pooled data **AUC 0-end of dosing interval

Figure 2.Mean steady-state (±SD) R-oxybutynin plasma concentrations following administration of total daily oxybutynin chloride tablet dose of 7.5 mg to 15 mg (0.22 mg/kg to 0.53 mg/kg) in children 5 to 15 years of age. – Plot represents all available data normalized to the equivalent of oxybutynin chloride 5 mg BID or TID at steady state

Food Effects

Data in the literature suggests that oxybutynin solution coadministered with food resulted in a slight delay in absorption and an increase in its bioavailability by 25% (n=18). 1

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 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.

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.

Oxybutynin chloride was well tolerated in patients administered the drug in controlled studies of 30 days' duration and in uncontrolled studies in which some of the patients received the drug for 2 years.

Oxybutynin chloride tablets are indicated for the relief of symptoms of bladder instability associated with voiding in patients with uninhibited neurogenic or reflex neurogenic bladder (i.e., urgency, frequency, urinary leakage, urge incontinence, dysuria).

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

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.

The safety and efficacy of oxybutynin chloride was evaluated in a total of 199 patients in three clinical trials. These participants were treated with oxybutynin chloride 5 to 20 mg/day for up to 6 weeks. Table 3shows the incidence of adverse events judged by investigators to be at least possibly related to treatment and reported by at least 5% of patients.

Table 3Incidence (%) of Adverse Events Reported by ≥ 5% of Patients Using Oxybutynin Chloride (5 to 20 mg/day)

The most common adverse events reported by patients receiving oxybutynin chloride 5 to 20 mg/day were the expected side effects of anticholinergic agents. The incidence of dry mouth was dose-related.

In addition, the following adverse events were reported by 1 to < 5% of patients using oxybutynin chloride (5 to 20 mg/day) in all studies. Infections and Infestations:nasopharyngitis, upper respiratory tract infection, bronchitis, cystitis, fungal infection; Metabolism and Nutrition Disorders:fluid retention; Psychiatric Disorders:confusional state; Nervous System Disorders:dysgeusia, sinus headache; Eye Disorders:keratoconjunctivitis sicca, eye irritation; Cardiac Disorders:palpitations, sinus arrhythmia; Vascular Disorders:flushing; Respiratory, Thoracic and Mediastinal Disorders:nasal dryness, cough, pharyngolaryngeal pain, dry throat, sinus congestion, hoarseness, asthma, nasal congestion; Gastrointestinal Disorders:diarrhea, abdominal pain, loose stools, flatulence, vomiting, abdominal pain upper, dysphagia, aptyalism, eructation, tongue coated; Skin and Subcutaneous Tissue Disorders:dry skin, pruritis; Musculoskeletal and Connective Tissue Disorders:back pain, arthralgia, pain in extremity, flank pain; Renal and Urinary Disorders:dysuria, pollakiuria; General Disorders and Administration Site Conditions:fatigue, edema peripheral, asthenia, pain, thirst, edema; Investigations:blood pressure increased, blood glucose increased, blood pressure decreased; Injury, Poisoning, and Procedural Complications:fall.

Postmarketing SurveillanceBecause postmarketing adverse events 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. The following additional adverse events have been reported from worldwide postmarketing experience with oxybutynin chloride: Psychiatric Disorders:psychotic disorder, agitation, hallucination, memory impairment; Nervous System Disorders:convulsions; Eye Disorders:cycloplegia, mydriasis, glaucoma; Cardiac Disorders:tachycardia, QT interval prolongation; chest discomfort ; Gastrointestinal Disorders:decreased gastrointestinal motility; frequent bowel movements; Skin and Subcutaneous Tissue Disorders:rash, decreased sweating; Renal and Urinary Disorders:impotence; Reproductive System and Breast Disorders:suppression of lactation; General Disorders and Administration Site Conditions:hypersensitivity reactions, including angioedema with airway obstruction, urticaria, and face edema; rare anaphylactic reactions requiring hospitalization for emergency treatment; Metabolism and Nutrition Disorders: anorexia; Respiratory, Thoracic and Mediastinal Disorders: dysphonia.

To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 or go to www.avkare.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 (e.g., restlessness, tremor, irritability, convulsions, delirium, hallucinations), flushing, fever, dehydration, cardiac arrhythmia, vomiting, and urinary retention. Other symptoms may include hypotension or hypertension, respiratory failure, paralysis, and coma.

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.

Oxybutynin Chloride Tablets USP, 5 mg, are round, light blue, scored tablets debossed "4853" and "V" on one side separated by a horizontal score and plain on the reverse side. The tablets are supplied as follows:

• Bottles of 500: NDC 42291-914-50

Pharmacist: Dispense in a tight, light-resistant container as defined in the USP/NF.

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

1 Yong C et al. Effect of Food on the Pharmacokinetics of Oxybutynin in normal subjects. Pharm Res. 1991; 8 (Suppl.): S-320.

2 Hughes KM et al. Measurement of oxybutynin and its N-desethyl metabolite in plasma, and its application to pharmacokinetic studies in young, elderly and frail elderly volunteers. Xenobiotica. 1992; 22 (7): 859–869.

3 Ouslander J et al. Pharmacokinetics and Clinical Effects of Oxybutynin in Geriatric Patients. J. Urol. 1988; 140: 47–50.

4 Yarker Y et al. Oxybutynin: A review of its Pharmacodynamic and Pharmacokinetic Properties, and its Therapeutic Use in Detrusor Instability. Drugs & Aging. 1995; 6 (3): 243–262.

Manufactured for:
AvKARE
Pulaski, TN 38478

Mfg. Rev. 11/21
AV 09/22 (W)

Please reference the HOW SUPPLIED section listed above for a description of individual drug products listed below. This drug product has been received by Aphena Pharma Solutions - Tennessee, LLC in a manufacturer or distributor packaged configuration and repackaged in full compliance with all applicable cGMP regulations. The package configurations available from Aphena are listed below:

5mg
NDC 71610-860-30, Bottles of 30 Tablets
NDC 71610-860-53, Bottles of 60 Tablets
NDC 71610-860-60, Bottles of 90 Tablets
NDC 71610-860-80, Bottles of 180 Tablets

Store between 20°-25°C (68°-77°F). See USP Controlled Room Temperature. Dispense in a tight light-resistant container as defined by USP. Keep this and all drugs out of the reach of children.

Repackaged by:

Cookeville, TN 38506

20201010AMH

NDC 71610-860 - Oxybutynin Chloride, USP 5mg Tablets - Rx Only