Mechanism of Action
The symptoms associated with benign prostatic hyperplasia (BPH), such as urinary
frequency, nocturia, weak stream, hesitancy and incomplete emptying are related
to two components, anatomical (static) and function (dynamic). The static component
is related to an increase in prostate size caused, in part, by a proliferation of
smooth muscle cells in the prostatic stroma. However, the severity of BPH symptoms
and the degree of urethral obstruction do not correlate well with the size of the
prostate. The dynamic component of BPH is associated with an increase in smooth
muscle tone in the prostate and bladder neck. The degree of tone in this area is
mediated by the alpha1 adrenoceptor, which is present
in high density in the prostatic stroma, prostatic capsule and bladder neck. Blockade
of the alpha1 receptor decreases urethral resistance and
may relieve the BPH symptoms and improve urine flow. Doxazosin mesylate is a selective
inhibitor of the alpha1-subtype of alpha adrenergic receptors.
In human prostate, doxazosin mesylate antagonizes phenylephrine (alpha1
agonist)-induced contractions, in vitro, and binds with high affinity to
the alpha1A adrenoceptor.
Pharmacokinetics
The pharmacokinetics of CARDURA XL is different from that of doxazosin immediate-release
(IR). CARDURA XL provides a controlled release of doxazosin over a 24-hour period.
Absorption: Pharmacokinetic parameters describing absorption following 4
and 8 mg CARDURA XL daily doses are reported in Table 1 below. The relative bioavailability
of CARDURA XL compared with doxazosin IR was 54% at the 4 mg dose and 59% for the
8 mg dose.
Table 1: Mean (±SD) Plasma Concentration of Doxazosin at Steady State in Healthy
Volunteers: Pharmacokinetic Parameters
Effect of Food:
As illustrated in Figure 1, the maximum plasma concentration (Cmax)
and the area under the plasma concentration versus time curve (AUC) were approximately
32% and 18% higher, respectively, after CARDURA XL was administered in the fed state
compared with the fasted state. In order to provide the most consistent exposure,
CARDURA XL should be administered with breakfast. (See DOSAGE and ADMINISTRATION.)
Figure 1: Mean (±SD) Plasma Concentration of Doxazosin Following Single Oral Doses
of 8 mg CARDURA XL (Fed and Fasted)
Effect of GI Retention Time
Markedly reduced GI retention times (e.g. short bowel syndrome) may influence the
pharmacokinetics of CARDURA XL and possibly result in lower plasma concentrations.
Conversely, markedly prolonged GI retention times (e.g. chronic constipation) can
increase systemic exposure to doxazosin and potentially result in increased adverse
reactions. (See: PRECAUTIONS; General.)
Distribution
At the plasma concentrations achieved by therapeutic doses, approximately 98% of
the circulating drug is bound to plasma proteins.
Metabolism
Doxazosin is extensively metabolized in the liver. In vitro studies suggest
that the primary pathway for elimination is via CYP3A4; however, CYP2D6 and CYP2C19
metabolic pathways also exist to a lesser extent. No in vivo drug interaction
studies have been performed with CARDURA XL. Although several active metabolites
of doxazosin have been identified, the pharmacokinetics of these metabolites has
not been characterized. (See PRECAUTIONS; Drug Interactions.)
Excretion
In a study of two subjects administered radiolabeled doxazosin IR 2 mg orally and
1 mg intravenously on two separate occasions, approximately 63% of the dose was
eliminated in the feces and 9% of the dose was found in the urine. On average, only
4.8% of the dose was excreted as unchanged drug in the feces and only a trace of
the total radioactivity in the urine was attributed to unchanged drug. The apparent
elimination half-life of CARDURA XL is 15-19 hours.
Pharmacokinetics in Special Populations
Age: The effects of age on the pharmacokinetics of CARDURA XL were examined.
At steady state, increases of 27% in maximum plasma concentrations and 34% in the
area under the concentration-time curve were seen in the elderly (>65 years old)
compared to the young. (See PRECAUTIONS; Geriatric Use.)
Hepatic Impairment: Administration of a single 2 mg dose of doxazosin
IR to patients with mild hepatic impairment (Child-Pugh Class A) showed a 40% increase
in exposure to doxazosin compared to patients without hepatic impairment. No studies
have been performed to assess the effect of hepatic impairment on the pharmacokinetics
of CARDURA XL. CARDURA XL should be administered with caution to patients with evidence
of mild or moderately impaired hepatic function or to patients receiving drugs known
to influence hepatic metabolism. Use in patients with severe hepatic impairment
is not recommended.
Drug-Drug Interactions
No in vivo drug-drug interaction studies have been performed to assess the
effect of concomitant medications on the pharmacokinetics of CARDURA XL or to assess
the effect of CARDURA XL on the pharmacokinetics of other drugs. In one placebo-controlled
trial in normal volunteers, the administration of a single 1 mg dose of doxazosin
IR on day one of a four day regimen of cimetidine (400 mg twice daily) resulted
in a 10% increase in the mean AUC of doxazosin, 6% increase in mean Cmax
of doxazosin and no significant change in mean half-life of doxazosin. Based upon
the differences in dose and formulation, the applicability of these results to CARDURA
XL is unknown. Otherwise, the interaction potential with other inhibitors or substrates
of cytochrome P450 enzymes has not been determined. Pharmacodynamic interactions
between CARDURA XL and anti-hypertensive medications or other vasodilating agents
have also not been determined. Finally, drugs which reduce gastrointestinal motility
leading to markedly prolonged GI retention times (e.g. anticholinergic agents) may
increase systemic exposure to doxazosin.