Mechanism Of Action
Benign Prostatic Hyperplasia
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 functional (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 obstruction and BPH symptoms
and improve urine flow.
The mechanism of action of
CARDURA is selective blockade of the alpha1 (postjunctional) subtype of
adrenergic receptors. Studies in normal human subjects have shown that
doxazosin competitively antagonized the pressor effects of phenylephrine (an
alpha1 agonist) and the systolic pressor effect of norepinephrine. Doxazosin
and prazosin have similar abilities to antagonize phenylephrine. The
antihypertensive effect of CARDURA results from a decrease in systemic vascular
resistance. The parent compound doxazosin is primarily responsible for the
antihypertensive activity. The low plasma concentrations of known active and
inactive metabolites of doxazosin (2-piperazinyl, 6'-and 7'-hydroxy and 6-and
7-O-desmethyl compounds) compared to parent drug indicate that the contribution
of even the most potent compound (6'-hydroxy) to the antihypertensive effect of
doxazosin in man is probably small. The 6'-and 7'-hydroxy metabolites have
demonstrated antioxidant properties at concentrations of 5 μM, in vitro.
Benign Prostatic Hyperplasia
Administration of CARDURA to
patients with symptomatic BPH resulted in a statistically significant
improvement in maximum urinary flow rate [see Clinical Studies].
Effect On Normotensive Patients With Benign Prostatic
Although blockade of alpha1 adrenoceptors also lowers
blood pressure in hypertensive patients with increased peripheral vascular
resistance, CARDURA treatment of normotensive men with BPH did not result in a
clinically significant blood pressure lowering effect (Table 4). The proportion
of normotensive patients with a sitting systolic blood pressure less than 90
mmHg and/or diastolic blood pressure less than 60 mmHg at any time during
treatment with CARDURA 1–8 mg once daily was 6.7% with doxazosin and not
significantly different (statistically) from that with placebo (5%).
Administration of CARDURA results in a reduction in
systemic vascular resistance. In patients with hypertension, there is little
change in cardiac output. Maximum reductions in blood pressure usually occur
2–6 hours after dosing and are associated with a small increase in standing
heart rate. Like other alpha1-adrenergic blocking agents, doxazosin has a
greater effect on blood pressure and heart rate in the standing position.
After oral administration of therapeutic doses, peak
plasma levels of CARDURA occur at about 2–3 hours. Bioavailability is
approximately 65%, reflecting first-pass metabolism of doxazosin by the liver.
The effect of food on the pharmacokinetics of CARDURA was examined in a
crossover study with twelve hypertensive subjects. Reductions of 18% in mean
maximum plasma concentration (Cmax) and 12% in the area under the
concentration-time curve (AUC) occurred when CARDURA was administered with
food. Neither of these differences is clinically significant.
In a crossover study in 24 normotensive subjects, the
pharmacokinetics and safety of doxazosin were shown to be similar with morning
and evening dosing regimens. The AUC after morning dosing was, however, 11%
less than that after evening dosing and the time to peak concentration after
evening dosing occurred significantly later than that after morning dosing (5.6
vs. 3.5 hours).
At the plasma concentrations achieved by therapeutic
doses, approximately 98% of the circulating drug is bound to plasma proteins.
CARDURA is extensively metabolized in the liver, mainly
by O-demethylation of the quinazoline nucleus or hydroxylation of the
benzodioxan moiety. In vitro studies suggest that the primary pathway for
elimination is via CYP 3A4; however, CYP 2D6 and CYP 2C9 metabolic pathways are
also involved to a lesser extent. Although several active metabolites of
doxazosin have been identified, the pharmacokinetics of these metabolites have
not been characterized.
Plasma elimination of doxazosin is biphasic, with a
terminal elimination half-life of about 22 hours. Steady-state studies in
hypertensive patients given doxazosin doses of 2 to 16 mg once daily showed
linear kinetics and dose proportionality. In two studies, following the
administration of 2 mg orally once daily, the mean accumulation ratios
(steady-state AUC vs. first-dose AUC) were 1.2 and 1.7. Enterohepatic recycling
is suggested by secondary peaking of plasma doxazosin concentrations.
In a study of two subjects administered radiolabelled
doxazosin 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 pharmacokinetics of CARDURA in young ( < 65 years)
and elderly ( ≥ 65 years) subjects were similar for plasma half-life values
and oral clearance.
Pharmacokinetic studies in elderly patients and patients
with renal impairment have shown no significant alterations compared to younger
patients with normal renal function.
Administration of a single 2 mg dose to patients with
cirrhosis (Child-Pugh Class A) showed a 40% increase in exposure to doxazosin.
The impact of moderate (Child-Pugh Class B) or severe (Child-Pugh Class C)
hepatic impairment on the pharmacokinetics of doxazosin is not known [see
Use in Specific Populations].
There are only limited data on the effects of drugs known
to influence the hepatic metabolism of doxazosin (e.g., cimetidine).
Cimetidine: In healthy volunteers, the
administration of a single 1 mg dose of doxazosin on day 1 of a four-day
regimen of oral cimetidine (400 mg twice daily) resulted in a 10% increase in
mean AUC of doxazosin, and a slight but not significant increase in mean Cmax and
mean half-life of doxazosin.
In vitro data in human plasma indicate that CARDURA has
no effect on protein binding of digoxin, warfarin, phenytoin, or indomethacin.
Animal Toxicology And Pharmacology
An increased incidence of myocardial necrosis or fibrosis
was observed in long-term (6-12 months) studies in rats and mice (exposure 8
times human AUC exposure in rats and somewhat equivalent to human Cmax exposure
in mice). Findings were not seen at lower doses. In dogs no cardiotoxicity was
observed following 12 months of oral dosing at doses that resulted in maximum
plasma concentrations (Cmax) 14 times the Cmax exposure in humans receiving a
12 mg/day therapeutic dose or in Wistar rats at Cmax exposures 15 times human Cmax
exposure. There is no evidence that similar lesions occur in humans.
Benign Prostatic Hyperplasia (BPH)
The efficacy of CARDURA was evaluated extensively in over
900 patients with BPH in double-blind, placebo-controlled trials. CARDURA
treatment was superior to placebo in improving patient symptoms and urinary
flow rate. Significant relief with CARDURA was seen as early as one week into
the treatment regimen, with CARDURA-treated patients (N=173) showing a
significant (p < 0.01) increase in maximum flow rate of 0.8 mL/sec compared to
a decrease of 0.5 mL/sec in the placebo group (N=41). In long-term studies,
improvement was maintained for up to 2 years of treatment. In 66–71% of
patients, improvements above baseline were seen in both symptoms and maximum
urinary flow rate.
In three placebo-controlled studies of 14–16 weeks' duration,
obstructive symptoms (hesitation, intermittency, dribbling, weak urinary
stream, incomplete emptying of the bladder) and irritative symptoms (nocturia,
daytime frequency, urgency, burning) of BPH were evaluated at each visit by
patient-assessed symptom questionnaires. The bothersomeness of symptoms was
measured with a modified Boyarsky questionnaire. Symptom severity/frequency was
assessed using a modified Boyarsky questionnaire or an AUA-based questionnaire.
Uroflowmetric evaluations were performed at times of peak (2–6 hours post-dose)
and/or trough (24 hours post-dose) plasma concentrations of CARDURA.
The results from the three placebo-controlled studies
(N=609) showing significant efficacy with 4 mg and 8 mg doxazosin are
summarized in Table 3. In all three studies, CARDURA resulted in statistically
significant relief of obstructive and irritative symptoms compared to placebo.
Statistically significant improvements of 2.3–3.3 mL/sec in maximum flow rate
were seen with CARDURA in Studies 1 and 2, compared to 0.1–0.7 mL/sec with
In one fixed-dose study (Study
2), CARDURA therapy (4 to 8 mg, once daily) resulted in a significant and
sustained improvement in maximum urinary flow rate of 2.3–3.3 mL/sec (Table 3)
compared to placebo (0.1 mL/sec). In this study, the only study in which weekly
evaluations were made, significant improvement with CARDURA vs. placebo was
seen after one week. The proportion of patients who responded with a maximum flow
rate improvement of ≥ 3 mL/sec was significantly larger with CARDURA
(34–42%) than placebo (13–17%). A significantly greater improvement was also
seen in average flow rate with CARDURA (1.6 mL/sec) than with placebo (0.2
mL/sec). The onset and time course of symptom relief and increased urinary flow
from Study 1 are illustrated in Figure 1.
Figure 1 : Study 1
In a pooled analysis of
placebo-controlled hypertension studies with about 300 hypertensive patients
per treatment group, doxazosin, at doses of 1 to 16 mg given once daily,
lowered blood pressure at 24 hours by about 10/8 mmHg compared to placebo in
the standing position and about 9/5 mmHg in the supine position. Peak blood
pressure effects (1–6 hours) were larger by about 50–75% (i.e., trough values
were about 55–70% of peak effect), with the larger peak-trough differences seen
in systolic pressures. There was no apparent difference in the blood pressure
response of Caucasians and blacks or of patients above and below age 65. In the
same patient population, patients receiving CARDURA gained a mean of 0.6 kg
compared to a mean loss of 0.1 kg for placebo patients.
TABLE 4 : Mean Changes in Blood Pressure from Baseline to the Mean of
the Final Efficacy Phase in Normotensives (Diastolic BP < 90 mmHg) in Two
Double-blind, Placebo-controlled U.S. Studies with CARDURA 1 to 8 mg once
|Sitting BP (mmHg)
|Standing BP (mmHg)
|*p ≤ 0.05 compared to placebo