OXYBUTYNIN CHLORIDE

OXYBUTYNIN CHLORIDE- oxybutynin chloride tablet, extended release
Dispensing Solutions, Inc.

Rx only

DESCRIPTION

Oxybutynin chloride is an antispasmodic, anticholinergic agent. 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 C22 H31 NO3 •HCl.

Its structural formula is:

Chemical Structure
(click image for full-size original)

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 entericcoated 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.

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 tablets 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 to 48) (ng∙h/mL)18.4(10.3)34.2(16.9)
AUCinf (ng∙h/mL)21.3(12.2)39.5(21.2)

Figure 1
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Figure 1. Mean R-oxybutynin plasma concentrations following a single dose of oxybutynin chloride extended release tablets, 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 tablet 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

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 tablet 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 tablets were similar in all patients studied (up to 78 years of age).

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