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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.
Following the first dose of DITROPAN XL® (oxybutynin chloride), 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 DITROPAN XL® 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 DITROPAN XL® 10 mg (n=43)
|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)|
Figure 1: Mean R-oxybutynin plasma concentrations
following a single dose of DITROPAN XL® 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 DITROPAN XL® dosing, with no observed drug accumulation or change in oxybutynin and desethyloxybutynin pharmacokinetic parameters.
DITROPAN XL® steady state pharmacokinetics were studied in 19 children aged 5-15 years with detrusor overactivity associated with a neurological condition (e.g., spina bifida). The children were on DITROPAN XL® total daily dose ranging from 5 to 20 mg (0.10 to 0.77 mg/kg). Sparse sampling technique was used to obtain serum samples. When all available data are normalized to an equivalent of 5 mg per day DITROPAN XL®, 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 2 shows the profile for R-oxybutynin when all available data are normalized to an equivalent of 5 mg per day.
Table 2 : Mean ± SD R- and S-Oxybutynin and R- and
S-Desethyloxybutynin Pharmacokinetic Parameters in Children Aged 5-15 Following
Administration of 5 to 20 mg DITROPAN XL® Once Daily (n=19), All
Available Data Normalized to an Equivalent of DITROPAN XL® 5 mg Once
|R-Oxybutynin||S-Oxybutynin||R- Desethyloxybutynin||S- Desethyloxybutynin|
|Cmax (ng/mL)||0.7 ± 0.4||1.3 ± 0.8||7.8 ± 3.7||4.2 ± 2.3|
|AUC (ng•h/mL)||12.8 ± 7.0||23.7 ± 14.4||125.1 ± 66.7||73.6 ± 47.7|
Figure 2: Mean steady state (± SD) R-oxybutynin plasma
concentrations following administration of 5 to 20 mg DITROPAN XL® once
daily in children aged 5-15. Plot represents all available data normalized to
an equivalent of DITROPAN XL® 5 mg once daily.
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.
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 DITROPAN XL® administration, plasma concentrations of R- and S-desethyloxybutynin are 73% and 92%, respectively, of concentrations observed with oxybutynin.
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.
Pharmacokinetic parameters of oxybutynin and desethyloxybutynin (Cmax and AUC) following administration of 5-20 mg of DITROPAN XL® are dose proportional.
The pharmacokinetics of DITROPAN XL® were similar in all patients studied (up to 78 years of age).
The pharmacokinetics of DITROPAN XL® were evaluated in 19 children aged 5-15 years with detrusor overactivity associated with a neurological condition (e.g., spina bifida). The pharmacokinetics of DITROPAN XL® in these pediatric patients were consistent with those reported for adults (see Tables 1 and 2, and Figures 1 and 2 above).
There are no significant differences in the pharmacokinetics of oxybutynin in healthy male and female volunteers following administration of DITROPAN XL®.
Available data suggest that there are no significant differences in the pharmacokinetics of oxybutynin based on race in healthy volunteers following administration of DITROPAN XL®.
There is no experience with the use of DITROPAN XL® in patients with renal insufficiency.
There is no experience with the use of DITROPAN XL® in patients with hepatic insufficiency.
See PRECAUTIONS: DRUG INTERACTIONS.
DITROPAN XL® (oxybutynin chloride) 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 (89.0%) 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 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.
Last reviewed on RxList: 11/26/2012
This monograph has been modified to include the generic and brand name in many instances.
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