Cardura
Generic Name: doxazosin
mesylate
Dosage Form: tablet
Indications and Usage for Cardura
Benign Prostatic Hyperplasia (BPH)
Cardura is indicated for the treatment of the signs
and symptoms of BPH.
Hypertension
Cardura is indicated for the treatment of
hypertension, to lower blood pressure. Lowering blood pressure reduces the risk
of fatal and nonfatal cardiovascular events, primarily strokes and myocardial
infarctions. These benefits have been seen in controlled trials of
antihypertensive drugs from a wide variety of pharmacologic classes, including
this drug.
Control of high blood pressure should be part of
comprehensive cardiovascular risk management, including, as appropriate, lipid
control, diabetes management, antithrombotic therapy, smoking cessation,
exercise, and limited sodium intake. Many patients will require more than one
drug to achieve blood pressure goals. For specific advice on goals and
management, see published guidelines, such as those of the National High Blood
Pressure Education Program's Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure (JNC).
Numerous antihypertensive drugs, from a variety of
pharmacologic classes and with different mechanisms of action, have been shown
in randomized controlled trials to reduce cardiovascular morbidity and
mortality, and it can be concluded that it is blood pressure reduction, and not
some other pharmacologic property of the drugs, that is largely responsible for
those benefits. The largest and most consistent cardiovascular outcome benefit
has been a reduction in the risk of stroke, but reductions in myocardial
infarction and cardiovascular mortality also have been seen regularly.
Elevated systolic or diastolic pressure causes
increased cardiovascular risk, and the absolute risk increase per mmHg is
greater at higher blood pressures, so that even modest reductions of severe
hypertension can provide substantial benefit. Relative risk reduction from
blood pressure reduction is similar across populations with varying absolute
risk, so the absolute benefit is greater in patients who are at higher risk
independent of their hypertension (for example, patients with diabetes or
hyperlipidemia), and such patients would be expected to benefit from more
aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood
pressure effects (as monotherapy) in black patients, and many antihypertensive
drugs have additional approved indications and effects (e.g., on angina, heart
failure, or diabetic kidney disease). These considerations may guide selection
of therapy.
Cardura may be used alone or in combination with
other antihypertensives.
Cardura Dosage and Administration
Dosing Information
Following the initial dose and with each dose
increase of Cardura, monitor blood pressure for at least 6 hours following
administration. If Cardura administration is discontinued for several days,
therapy should be restarted using the initial dosing regimen.
Benign Prostatic Hyperplasia
The recommended initial dosage of Cardura is 1 mg
given once daily either in the morning or evening.
Depending on the individual patient's urodynamics
and BPH symptomatology, the dose may be titrated at 1 to 2 week intervals to 2
mg, and thereafter to 4 mg and 8 mg once daily. The maximum recommended dose
for BPH is 8 mg once daily.
Routinely monitor blood pressure in these patients.
Hypertension
The initial dosage of Cardura is 1 mg given once
daily. Daily dosage may be doubled up 16 mg once daily, as needed, to achieve
the desired reduction in blood pressure.
Dosage Forms and Strengths
Tablets (scored): 1 mg (white), 2 mg (yellow), 4 mg
(orange) or 8 mg (green).
Contraindications
The use of Cardura is contraindicated in patients
with a hypersensitivity to doxazosin, other quinazolines (e.g., prazosin,
terazosin), or any of its components.
Warnings and Precautions
Postural Hypotension
Postural hypotension with or without symptoms
(e.g., dizziness) may develop within a few hours following administration of
Cardura. However, infrequently, symptomatic postural hypotension has also been
reported later than a few hours after dosing. As with other alpha-blockers,
there is a potential for syncope, especially after the initial dose or after an
increase in dosage strength. Advise patient how to avoid symptoms resulting
from postural hypotension and what measures to take should they develop.
Concomitant administration of Cardura with a PDE-5
inhibitor can result in additive blood pressure lowering effects and
symptomatic hypotension.
Cataract Surgery
Intraoperative Floppy Iris Syndrome (IFIS) has been
observed during cataract surgery in some patients on or previously treated with
alpha1 blockers. This variant of small pupil
syndrome is characterized by the combination of a flaccid iris that billows in
response to intraoperative irrigation currents, progressive intraoperative
miosis despite preoperative dilation with standard mydriatic drugs, and
potential prolapse of the iris toward the phacoemulsification incisions. The
patient's surgeon should be prepared for possible modifications to their
surgical technique, such as the utilization of iris hooks, iris dilator rings,
or viscoelastic substances. There does not appear to be a benefit of stopping
alpha1blocker therapy prior to cataract surgery.
Prostate Cancer
Carcinoma of the prostate causes many of the
symptoms associated with BPH and the two disorders frequently co-exist.
Carcinoma of the prostate should therefore be ruled out prior to commencing
therapy with Cardura for the treatment of BPH.
Priapism
Alpha1 antagonists, including doxazosin, have been
associated with priapism (painful penile erection, sustained for hours and
unrelieved by sexual intercourse or masturbation). This condition can lead to
permanent impotence if not promptly treated.
Adverse Reactions
Clinical Trials Experience
Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in practice.
Benign Prostatic Hyperplasia (BPH)
The incidence of adverse events has been
ascertained from worldwide clinical trials in 965 BPH patients. The incidence
rates presented below (Table 2) are based on combined data from seven
placebo-controlled trials involving once-daily administration of Cardura in
doses of 1 to 16 mg in hypertensives and 0.5 to 8 mg in normotensives. Adverse
reactions occurring more than 1% more frequently in BPH patients treated with
Cardura vs placebo are summarized in Table 1.
Table 1. Adverse Reactions Occurring more than 1% More Frequently in
BPH Patients Treated with Cardura Versus Placebo
|
|
BODY SYSTEM
|
Cardura
N=665
|
Placebo
N=300
|
|
*
Includes vertigo
|
|
NERVOUS SYSTEM DISORDERS
|
|
Dizziness*
|
15.6%
|
9.0%
|
|
Somnolence
|
3.0%
|
1.0%
|
|
CARDIAC DISORDERS
|
|
Hypotension
|
1.7%
|
0%
|
|
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
|
|
Dyspnoea
|
2.6%
|
0.3%
|
|
GASTROINTESTINAL DISORDERS
|
|
Dry
Mouth
|
1.4%
|
0.3%
|
|
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
|
|
Fatigue
|
8.0%
|
1.7%
|
|
Oedema
|
2.7%
|
0.7%
|
Other adverse reactions occurring less than 1% more
frequently in BPH patients treated with Cardura vs placebo but plausibly
related to Cardura include: palpitations.
Hypertension
Cardura has been administered to approximately 4000
hypertensive patients in clinical trials, of whom 1679 were included in the
hypertension clinical development program. In placebo-controlled studies,
adverse events occurred in 49% and 40% of patients in the doxazosin and placebo
groups, respectively, and led to discontinuation in 2% of patients in each
group.
Adverse reactions occurring more than 1% more
frequently in hypertensive patients treated with Cardura vs placebo are
summarized in Table 1. . Postural effects and edema appeared to be
dose-related. The prevalence rates presented below are based on combined data
from placebo-controlled studies involving once-daily administration of
doxazosin at doses ranging from 1 to 16 mg.
Table 2. Adverse Reactions Occurring more than 1% More Frequently in
Hypertensive Patients Treated with Cardura versus Placebo
|
|
BODY SYSTEM
|
Cardura
N=339
|
Placebo
N=336
|
|
NERVOUS SYSTEM DISORDERS
|
|
Dizziness
|
19%
|
9%
|
|
Somnolence
|
5%
|
1%
|
|
RESPIRATORY, THORACIC AND MEDIASTINAL
DISORDERS
|
|
Rhinitis
|
3%
|
1%
|
|
RENAL AND URINARY DISORDERS
|
|
Polyuria
|
2%
|
0%
|
|
REPRODUCTIVE SYSTEM AND BREAST DISORDERS
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
|
|
Fatigue
/ Malaise
|
12%
|
6%
|
Other adverse reactions occurring less than 1% more
frequently in hypertensive patients treated with Cardura vs placebo but
plausibly related to Cardura use include vertigo, hypotension, hot flushes,
epistaxis and oedema.
Cardura has been associated with decreases in white
blood cell counts
Laboratory changes observed in
clinical studies
Leukopenia/Neutropenia: Decreases in mean
white blood cell (WBC) and mean neutrophil count were observed in controlled
clinical trials of hypertensive patients receiving Cardura. In cases where
follow-up was available, WBC and neutrophil counts returned to normal after
discontinuation of Cardura. No patients became symptomatic as a result of the
low WBC or neutrophil counts.
Postmarketing Experience
The following adverse reactions have been
identified during post-approval use of Cardura. Because these reactions are
reported voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.
In post-marketing experience, the following
additional adverse reactions have been reported:
Blood and Lymphatic System Disorders: leukopenia,
thrombocytopenia;
Immune System Disorders: allergic reaction;
Nervous System Disorders: hypoesthesia;
Eye Disorders: Intraoperative Floppy Iris
Syndrome [see Warnings and precautions
(5.4)];
Cardiac Disorders: bradycardia;
Respiratory, Thoracic and Mediastinal Disorders: bronchospasm
aggravated;
Gastrointestinal Disorders: vomiting;
Hepatobiliary Disorders: cholestasis,
hepatitis cholestatic;
Skin and Subcutaneous Tissue Disorders: urticaria;
Musculoskeletal and Connective Tissue Disorders: muscle cramps,
muscle weakness;
Renal and Urinary Disorders: hematuria,
micturition disorder, micturition frequency, nocturia;
Reproductive System and Breast Disorders: gynecomastia,
priapism.
Drug Interactions
. CYP 3A Inhibitors
In vitro studies suggest that doxazosin
is a substrate of CYP 3A4. Strong CYP3A inhibitors may increase exposure to
doxazosin. Monitor blood pressure and for symptoms of hypotension when Cardura
is used concomitantly with strong CYP3A inhibitors [see Clinical
Pharmacology (12.3)].
Phosphodiesterase-5 (PDE-5)
inhibitors
Concomitant administration of Cardura with a
phosphodiesterase-5 (PDE-5) inhibitor can result in additive blood pressure
lowering effects and symptomatic hypotension. Monitor blood pressure and for
symptoms of hypotension [see Warnings and Precautions
(5.1)].
USE IN SPECIFIC POPULATIONS
Pregnancy
Risk Summary
The limited available data with Cardura in pregnant
women are not sufficient to inform a drug-associated risk for major birth
defects and miscarriage. However, untreated hypertension during pregnancy can
result in increased maternal risks [see Clinical
Considerations]. In animal reproduction studies, no
adverse developmental effects were observed when doxazosin was orally
administered to pregnant rabbits and rats during the period of organogenesis at
doses of up to 41 and 20 mg/kg, respectively (exposures in rabbits and rats
were 10 and 4 times, respectively, the human AUC exposures with a 12 mg/day
therapeutic dose). A dosage regimen of 82 mg/kg/day in the rabbit was
associated with reduced fetal survival [see Data].
The estimated background risk of major birth
defects and miscarriage for the indicated population is unknown. In theU.S.general
population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2–4% and 15–20%,
respectively.
Clinical Considerations
Disease-associated maternal and/or
embryo/fetal risk
Hypertension in pregnancy increases the maternal
risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery
complications (e.g., need for cesarean section, and post-partum hemorrhage).
Hypertension increases the fetal risk for intrauterine growth restriction and
intrauterine death.
Data
Animal Data
Radioactivity was found to cross the placenta
following oral administration of labelled doxazosin to pregnant rats. Studies
in pregnant rabbits and rats at daily oral doses of up to 41 and 20 mg/kg,
respectively (plasma drug concentrations of 10 and 4 times, respectively, the
human AUC exposures with a 12 mg/day therapeutic dose), have revealed no
evidence of adverse developmental effects. A dosage regimen of 82 mg/kg/day in
the rabbit was associated with reduced fetal survival. In peri- and postnatal
studies in rats, postnatal development at maternal doses of 40 or 50 mg/kg/day
of doxazosin (about 8 times human AUC exposure with a 12 mg/day therapeutic
dose) was delayed, as evidenced by slower body weight gain and slightly later
appearance of anatomical features and reflexes.
Lactation
Risk Summary
There is limited information on the presence of
Cardura in human milk [see Data]. There is no
information on the effects of Cardura on the breastfeed infant or the effects
on milk production.
Data
A single case study reports that Cardura is present
in human milk, which resulted in an infant dose of less than 1% of the maternal
weight-adjusted dosage and a milk/plasma ratio of 0.1. However, these data are
insufficient to confirm the presence of Cardura in human milk.
Pediatric Use
The safety and effectiveness of Cardura have not
been established in children.
Geriatric Use
Benign Prostatic Hyperplasia (BPH)
The safety and effectiveness profile of Cardura was
similar in the elderly (age ≥ 65 years) and younger (age < 65 years)
patients.
Hypertension
Clinical studies of Cardura did not include
sufficient numbers of subjects aged 65 and over to determine whether they
respond differently from younger subjects. Other reported clinical experience
has not identified differences in responses between the elderly and younger
patients.
In general, dose selection for an elderly patient should
be cautious, usually starting at the low end of the dosing range, reflecting
the greater frequency of decreased hepatic, renal or cardiac function, and of
concomitant disease or other drug therapy.
Hepatic Impairment
Cardura is extensively metabolized in the liver.
Hepatic impairment is expected to increase exposure to doxazosin. Use of
Cardura in patients with severe hepatic impairment (Child-Pugh Class C) is not
recommended. Monitor blood pressure and for symptoms of hypotension in patients
with lesser degrees of hepatic impairment (Child-Pugh Class A and B) [see Clinical
Pharmacology (12.3)].
Overdosage
Experience with Cardura overdosage is limited. Two
adolescents, who each intentionally ingested 40 mg Cardura with diclofenac or
acetaminophen, were treated with gastric lavage with activated charcoal and
made full recoveries. A two-year-old child who accidently ingested 4 mg Cardura
was treated with gastric lavage and remained normotensive during the five-hour
emergency room observation period. A six-month-old child accidentally received
a crushed 1 mg tablet of Cardura and was reported to have been drowsy. A
32-year-old female with chronic renal failure, epilepsy, and depression
intentionally ingested 60 mg Cardura (blood level = 0.9 mcg/mL; normal values
in hypertensives = 0.02 mcg/mL); death was attributed to a grand mal seizure
resulting from hypotension. A 39-year-old female who ingested 70 mg Cardura,
alcohol, and Dalmane® (flurazepam) developed hypotension which
responded to fluid therapy.
The oral LD50 of doxazosin is
greater than 1000 mg/kg in mice and rats. The most likely manifestation of
overdosage would be hypotension, for which the usual treatment would be
intravenous infusion of fluid. As doxazosin is highly protein bound, dialysis
would not be indicated.
Cardura Description
Cardura® (doxazosin mesylate) is a
quinazoline compound that is a selective inhibitor of the alpha1subtype of
alpha-adrenergic receptors. The chemical name of doxazosin mesylate is
1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(1,4-benzodioxan-2-ylcarbonyl)
piperazine methanesulfonate. The empirical formula for doxazosin mesylate is C23H25N5O5 ∙ CH4O3S and the molecular weight
is 547.6. It has the following structure:
Cardura (doxazosin mesylate) is freely soluble in
dimethylsulfoxide, soluble in dimethylformamide, slightly soluble in methanol,
ethanol, and water (0.8% at 25°C), and very slightly soluble in acetone and
methylene chloride. Cardura is available as colored tablets for oral use and
contains 1 mg (white), 2 mg (yellow), 4 mg (orange) and 8 mg (green) of
doxazosin as the free base.
The inactive ingredients for all tablets are:
microcrystalline cellulose, lactose, sodium starch glycolate, magnesium
stearate and sodium lauryl sulfate. The 2 mg tablet contains D & C yellow
10 and FD & C yellow 6; the 4 mg tablet contains FD & C yellow 6; the 8
mg tablet contains FD & C blue 2 and D & C yellow 10.
Cardura - Clinical Pharmacology
Mechanism of Action
Benign Prostatic Hyperplasia (BPH)
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.
Hypertension
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.
Pharmacodynamics
Benign Prostatic Hyperplasia (BPH)
Administration of Cardura to patients with
symptomatic BPH resulted in a statistically significant improvement in maximum
urinary flow rate [see Clinical Studies (14.1)].
Effect on Normotensive Patients with
Benign Prostatic Hyperplasia (BPH)
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%).
Hypertension
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.
Pharmacokinetics
Absorption
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).
Distribution
At the plasma concentrations achieved by
therapeutic doses, approximately 98% of the circulating drug is bound to plasma
proteins.
Metabolism
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.
Excretion
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.
Specific Populations
Geriatric
The pharmacokinetics of Cardura in young (<65
years) and elderly (≥65 years) subjects were similar for plasma half-life
values and oral clearance.
Renal Impairment
Pharmacokinetic studies in elderly patients and
patients with renal impairment have shown no significant alterations compared
to younger patients with normal renal function.
Hepatic Impairment
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 (8.6)].
Drug Interactions
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.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis,
Impairment of Fertility
Carcinogenesis and Mutagenesis: Chronic dietary
administration (up to 24 months) of doxazosin mesylate at maximally tolerated
doses of 40 mg/kg/day in rats and 120 mg/kg/day in mice revealed no evidence of
carcinogenic potential. The highest doses evaluated in the rat and mouse
studies are associated with AUCs (a measure of systemic exposure) that are 8
times and 4 times, respectively, the human AUC at a dose of 16 mg/day.
Mutagenicity studies revealed no drug- or
metabolite-related effects at either chromosomal or subchromosomal levels.
Fertility in Males: Studies in rats showed
reduced fertility in males treated with doxazosin at oral doses of 20 (but not
5 or 10) mg/kg/day, about 4 times the AUC exposures obtained with a 12 mg/day
human dose. This effect was reversible within two weeks of drug withdrawal.
There have been no reports of any effects of doxazosin on male fertility in humans.
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.
Clinical Studies
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
placebo.
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.
Hypertension
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-controlledU.S.Studies with Cardura 1 to 8
mg once daily.
|
|
|
PLACEBO (N=85)
|
Cardura (N=183)
|
|
*
p ≤0.05
compared to placebo
|
|
Sitting
BP (mmHg)
|
Baseline
|
Change
|
Baseline
|
Change
|
|
Systolic
|
128.4
|
–1.4
|
128.8
|
–4.9*
|
|
Diastolic
|
79.2
|
–1.2
|
79.6
|
–2.4*
|
|
Standing
BP (mmHg)
|
Baseline
|
Change
|
Baseline
|
Change
|
|
Systolic
|
128.5
|
–0.6
|
128.5
|
–5.3*
|
|
Diastolic
|
80.5
|
–0.7
|
80.4
|
–2.6*
|
How Supplied/Storage and Handling
Cardura (doxazosin mesylate) is available as scored
tablets for oral administration. Each tablet contains doxazosin mesylate
equivalent to 1 mg (white), 2 mg (yellow), 4 mg (orange) or 8 mg (green) of the
active constituent, doxazosin.
|
Bottle
of 100:
|
1
mg
|
NDC
0049-2750-66
|
|
|
2
mg
|
NDC
0049-2760-66
|
|
|
4
mg
|
NDC
0049-2770-66
|
|
|
8
mg
|
NDC
0049-2780-66
|
|
|
|
|
|
Unit
Dose Package of 100:
|
1
mg
|
NDC
0049-2750-41
|
|
|
2
mg
|
NDC
0049-2760-41
|
|
|
4
mg
|
NDC
0049-2770-41
|
|
|
8
mg
|
NDC
0049-2780-41
|
Recommended Storage: Store at 25°C (77°F);
excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room
Temperature].
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (Patient Information).
Postural Hypotension
Advise patients of the possibility of syncopal and
orthostatic symptoms, especially at the initiation of therapy, and urged to
avoid driving or hazardous tasks for 24 hours after the first dose, after a
dosage increase, and after interruption of therapy when treatment is resumed.
Advise patients to report symptoms to their healthcare provider.
Priapism
Advise patients of the possibility of priapism and
to seek immediate medical attention if symptoms occur.
This product's label may have been updated. For full
prescribing information, please visit www.pfizer.com.
LAB-0071-7.0
|
This
Patient Information has been approved by the U.S. Food and Drug
Administration
|
6/2016
|
|
PATIENT INFORMATION
Cardura®(kar-DUR-a)
(doxazosin mesylate tablets)
|
|
What is Cardura?
|
|
Cardura
is a prescription medicine that contains doxazosin mesylate and is called an
"alpha-blocker". Cardura is used to treat:
· the
symptoms of benign prostatic hyperplasia (BPH)
· high blood
pressure (hypertension)
|
|
It
is not known if Cardura is safe and effective in children.
|
|
Who should not take Cardura?
|
|
Do not take Cardura if you:
· are allergic to doxazosin, other quinazolines, or
any of the ingredients in Cardura. See the end of this Patient Information
leaflet for a complete list of ingredients in Cardura.
|
|
What should I tell my healthcare provider before taking Cardura?
|
|
Before taking Cardura, tell your healthcare provider about all of your
medical conditions, including if you:
· have had low blood pressure, especially after
taking other medicine. Signs of low blood pressure include fainting,
dizziness, and lightheadedness.
· have any planned eye surgery
· have prostate cancer or a history of prostate
cancer. Your healthcare provider may have you checked for prostate cancer
before you start taking and while you take Cardura.
· have liver problems
· are pregnant or plan to become pregnant. It is
not known if Cardura will harm your unborn baby.
· are breastfeeding or plan to breastfeed. It is
not known if Cardura passes into your breastmilk. Talk to your healthcare
provider about the best way to feed your baby if you take Cardura.
|
|
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and
herbal supplements. Cardura may affect the way other medicines work, and
other medicines may affect the way Cardura works causing side effects.
|
|
Especially tell your healthcare provider if you take:
· other medicine for high blood pressuremedicine to
treat erectile dysfunction (ED) called a phosphodiesterase type 5 (PDE-5)
inhibitor. The use of Cardura with PDE-5 inhibitors can lead to a drop in
blood pressure or to fainting.
|
|
Know
the medicines you take. Keep a list of them to show your healthcare provider
and pharmacist when you get a new medicine.
|
|
How should I take Cardura?
· Take Cardura exactly as your healthcare provider
tells you to take it.
· Your healthcare provider will tell you how much
Cardura to take and when to take it.
· Your healthcare provider may need to change your
dose of Cardura until it is the right dose for you.
|
|
What should I avoid while taking Cardura?
|
|
Do
not drive or perform any hazardous task until at least 24 hours after you
have taken Cardura if you are taking:
· your first
dose of Cardura
· Cardura
for the first time after your healthcare provider has increased
your dose of Cardura
· Cardura
for the first time after any breaks (interruptions) in your
treatment with Cardura
|
|
What are the possible side effects of Cardura?
|
|
Cardura may cause serious side effects, including:
· A sudden drop in blood pressure, especially when
you first start treatment or when there is an increase in your dose of
Cardura, is common but can also be serious. This may cause you to faint, or
to feel dizzy or lightheaded. Your risk of having this problem may be
increased if you take Cardura with certain other medicines that lower blood
pressure including PDE-5 inhibitors. Your healthcare provider may monitor
your blood pressure while you take Cardura. See "What should I avoid while taking
Cardura?"
· Eye problems during cataract surgery. A condition
called Intraoperative Floppy Iris Syndrome (IFIS) can happen during cataract
surgery if you take or have taken alpha-blockers such as Cardura. If you need
to have cataract surgery, be sure to tell your healthcare provider if you
take or have taken Cardura.
· A painful erection that will not go away. Cardura
can cause a painful erection (priapism), which cannot be relieved by having sex.
If this happens, get medical help right away. If priapism is not treated, you
may not be able to get an erection in the future.
|
|
The
most common side effects of Cardura are:
|
|
|
· weakness
or lack of energy (asthenia)
|
· dizziness
|
|
|
Tell
your healthcare provider if you have any side effect that bothers you or that
does not go away. These are not all the possible side effects of Cardura. For
more information, ask your healthcare provider or pharmacist.
|
|
Call
your doctor for medical advice about side effects. You may report side
effects to FDA at 1-800-FDA-1088.
|
|
General information about the safe and effective use of Cardura.
|
|
Medicines
are sometimes prescribed for purposes other than those listed in a Patient
Information leaflet. Do not use Cardura for a condition for which it was not
prescribed. Do not give Cardura to other people, even if they have the same
symptoms you have. It may harm them.
|
|
This
Patient Information leaflet summarizes the most important information about
Cardura. For more information, ask your healthcare provider. You can ask your
healthcare provider or pharmacist for information that is written for
healthcare professionals.
|
|
What are the ingredients in Cardura?
|
|
Active ingredient: doxazosin mesylate
|
|
Inactive ingredients: microcrystalline
cellulose, lactose, sodium starch glycolate, magnesium stearate and sodium
lauryl sulfate.
|
|
|
LAB-0070-4.0
|
|
Any
trademark information should appear here
|
|
For
more information, go to www.Pfizer.com or call 1-800-438-1985.
|
|
|
|
|
|
PRINCIPAL DISPLAY PANEL - 1 mg Tablet
Bottle Label
Pfizer
NDC 0049-2750-66
Cardura®
(doxazosin mesylate)
tablets
1 mg*
100 Tablets
Rx only
PRINCIPAL DISPLAY PANEL - 2 mg Tablet
Bottle Label
Pfizer
NDC 0049-2760-66
Cardura®
(doxazosin mesylate)
tablets
2 mg*
100 Tablets
Rx only
PRINCIPAL DISPLAY PANEL - 4 mg Tablet
Bottle Label
Pfizer
NDC 0049-2770-66
Cardura®
(doxazosin mesylate)
tablets
4 mg*
100 Tablets
Rx only
PRINCIPAL DISPLAY PANEL - 8 mg Tablet
Bottle Label
Pfizer
NDC 0049-2780-66
Cardura®
(doxazosin mesylate)
tablets
8 mg*
100 Tablets
Rx only
|
Cardura doxazosin
mesylate tablet
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:0049-2750
|
|
Route of Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
DOXAZOSIN MESYLATE (DOXAZOSIN)
|
DOXAZOSIN
|
1 mg
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
MICROCRYSTALLINE CELLULOSE
|
|
|
LACTOSE, UNSPECIFIED FORM
|
|
|
SODIUM STARCH GLYCOLATE TYPE A POTATO
|
|
|
MAGNESIUM STEARATE
|
|
|
SODIUM LAURYL SULFATE
|
|
|
|
Product Characteristics
|
|
Color
|
WHITE
|
Score
|
2 pieces
|
|
Shape
|
OVAL
|
Size
|
9mm
|
|
Flavor
|
|
Imprint Code
|
Cardura;1;mg
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:0049-2750-66
|
100 TABLET in 1 BOTTLE
|
|
|
2
|
NDC:0049-2750-41
|
100 BLISTER PACK in 1 CARTON
|
|
|
2
|
|
1 TABLET in 1 BLISTER PACK
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA019668
|
11/02/1990
|
|
|
|
Cardura doxazosin
mesylate tablet
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:0049-2760
|
|
Route of Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
DOXAZOSIN MESYLATE (DOXAZOSIN)
|
DOXAZOSIN
|
2 mg
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
MICROCRYSTALLINE CELLULOSE
|
|
|
LACTOSE, UNSPECIFIED FORM
|
|
|
SODIUM STARCH GLYCOLATE TYPE A POTATO
|
|
|
MAGNESIUM STEARATE
|
|
|
SODIUM LAURYL SULFATE
|
|
|
D&C YELLOW NO. 10
|
|
|
FD&C YELLOW NO. 6
|
|
|
|
Product Characteristics
|
|
Color
|
YELLOW
|
Score
|
2 pieces
|
|
Shape
|
OVAL
|
Size
|
9mm
|
|
Flavor
|
|
Imprint Code
|
Cardura;2;mg
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:0049-2760-66
|
100 TABLET in 1 BOTTLE
|
|
|
2
|
NDC:0049-2760-41
|
100 BLISTER PACK in 1 CARTON
|
|
|
2
|
|
1 TABLET in 1 BLISTER PACK
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA019668
|
11/02/1990
|
|
|
|
Cardura doxazosin
mesylate tablet
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:0049-2770
|
|
Route of Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
DOXAZOSIN MESYLATE (DOXAZOSIN)
|
DOXAZOSIN
|
4 mg
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
MICROCRYSTALLINE CELLULOSE
|
|
|
LACTOSE, UNSPECIFIED FORM
|
|
|
SODIUM STARCH GLYCOLATE TYPE A POTATO
|
|
|
MAGNESIUM STEARATE
|
|
|
SODIUM LAURYL SULFATE
|
|
|
FD&C YELLOW NO. 6
|
|
|
|
Product Characteristics
|
|
Color
|
ORANGE
|
Score
|
2 pieces
|
|
Shape
|
OVAL
|
Size
|
12mm
|
|
Flavor
|
|
Imprint Code
|
Cardura;4;mg
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:0049-2770-66
|
100 TABLET in 1 BOTTLE
|
|
|
2
|
NDC:0049-2770-41
|
100 BLISTER PACK in 1 CARTON
|
|
|
2
|
|
1 TABLET in 1 BLISTER PACK
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA019668
|
11/02/1990
|
|
|
|
Cardura doxazosin
mesylate tablet
|
|
Product Information
|
|
Product Type
|
HUMAN PRESCRIPTION DRUG LABEL
|
Item Code (Source)
|
NDC:0049-2780
|
|
Route of Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active Ingredient/Active Moiety
|
|
Ingredient Name
|
Basis of Strength
|
Strength
|
|
DOXAZOSIN MESYLATE (DOXAZOSIN)
|
DOXAZOSIN
|
8 mg
|
|
|
Inactive Ingredients
|
|
Ingredient Name
|
Strength
|
|
MICROCRYSTALLINE CELLULOSE
|
|
|
LACTOSE, UNSPECIFIED FORM
|
|
|
SODIUM STARCH GLYCOLATE TYPE A POTATO
|
|
|
MAGNESIUM STEARATE
|
|
|
SODIUM LAURYL SULFATE
|
|
|
D&C YELLOW NO. 10
|
|
|
|
Product Characteristics
|
|
Color
|
GREEN
|
Score
|
2 pieces
|
|
Shape
|
OVAL
|
Size
|
12mm
|
|
Flavor
|
|
Imprint Code
|
Cardura;8;mg
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package Description
|
|
|
1
|
NDC:0049-2780-66
|
100 TABLET in 1 BOTTLE
|
|
|
2
|
NDC:0049-2780-41
|
100 BLISTER PACK in 1 CARTON
|
|
|
2
|
|
1 TABLET in 1 BLISTER PACK
|
|
|
|
|
|
Marketing Information
|
|
Marketing Category
|
Application Number or Monograph Citation
|
Marketing Start Date
|
Marketing End Date
|
|
NDA
|
NDA019668
|
11/02/1990
|
|
|
|
Labeler - Roerig
(829076996)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Pfizer
Pharmaceuticals LLC
|
|
829084545
|
ANALYSIS(0049-2750,
0049-2760, 0049-2770, 0049-2780), API MANUFACTURE(0049-2750, 0049-2760,
0049-2770, 0049-2780), MANUFACTURE(0049-2750, 0049-2760, 0049-2770,
0049-2780)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Pfizer
Pharmaceuticals LLC
|
|
829084552
|
PACK(0049-2750,
0049-2760, 0049-2770, 0049-2780)
|
Revised:
06/2016
Roerig
