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 DITROPAN ® XL, 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.
Mean (SD) R- and S-Oxybutynin Pharmacokinetic
Parameters Following a Single Dose of DITROPAN ®
XL 10 mg (n=43)
Parameters (units)
|
R- Oxybutynin
|
S- 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-
48)(ng×h/ mL) |
18.4
|
(10.3)
|
34.2
|
(16.9)
|
| AUCinf
(ng×h/ mL) |
21.3
|
(12.2)
|
39.5
|
(21.2)
|
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.
Food Effects
The rate and extent of absorption and metabolism of oxybutynin
are similar under fed and fasted conditions.
Distribution
Plasma concentrations of oxybutynin decline biexponentially
following intravenous or oral administration. The volume
of distribution is 193 L after intravenous administration
of 5 mg oxybutynin chloride.
Metabolism
Oxybutynin is metabolized primarily by the cytochrome
P450 enzyme systems, particularly C.P.A. 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.
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 A.C. following administration of 5-20 mg of
DITROPAN ® XL are dose proportional.
Special Populations
Geriatric: The pharmacokinetics
of DITROPAN ®XL were similar in all patients studied
(up to 78 years of age).
Pediatric: The pharmacokinetics
of DITROPAN ®XL were not evaluated in individuals
younger than 18 years of age. See PRECAUTIONS: Pediatric
Use.
Gender: There are no significant
differences in the pharmacokinetics of oxybutynin in healthy
male and female volunteers following administration of
DITROPAN ®XL.
Race: 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.
Renal Insufficiency: There
is no experience with the use of DITROPAN ® XL in
patients with renal insufficiency.
Hepatic Insufficiency: There
is no experience with the use of DITROPAN ® XL in
patients with hepatic insufficiency.
Drug-Drug Interactions: See
DRUG INTERACTIONS.
Clinical Studies
DITROPAN ® XL 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 ³6
urge incontinence episodes per week and ³ 10 micturitions
per day. A study was a forced dose escalation design,
whereas 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.
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