DOXAZOSIN tablet

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Active ingredient:
DOXAZOSIN MESYLATE (UNII: 86P6PQK0MU) (DOXAZOSIN - UNII:NW1291F1W8)
Available from:
direct rx
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
1.1 Benign Prostatic Hyperplasia (BPH) Doxazosin tablets, USP are indicated for the treatment of the signs and symptoms of BPH. 1.2 Hypertension Doxazosin tablets, USP are 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, Detectio
Product summary:
Doxazosin tablets, USP are available as functionally scored tablets for oral administration. Each tablet contains doxazosin mesylate equivalent to 1 mg (white to off white), 2 mg (cream to yellow), 4 mg (cream to yellow) or 8 mg (white to off white) of the active constituent, doxazosin. 1 mg: White to off white, round, biconvex uncoated tablets, debossed with “C3” on one side and breakline on other side and supplied as follows: 2 mg: Cream to yellow colored, round, biconvex uncoated tablets, debossed with “C7” on one side and breakline on other side, may have mottled appearance and supplied as follows: 4 mg: Cream to yellow colored, round, biconvex uncoated tablets, debossed with “C4” on one side and breakline on other side, may have mottled appearance and supplied as follows: 8 mg: White to off white, round, biconvex uncoated tablets, debossed with “C5” on one side and breakline on other side and supplied as follows: Recommended Storage: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Authorization status:
Abbreviated New Drug Application
Authorization number:
72189-117-60

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DOXAZOSIN- doxazosin tablet

direct rx

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DOXAZOSIN

1.1 Benign Prostatic Hyperplasia (BPH)

Doxazosin tablets, USP are indicated for the treatment of the signs and symptoms of BPH.

1.2 Hypertension

Doxazosin tablets, USP are 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.

Doxazosin tablets, USP may be used alone or in combination with other antihypertensives.

2.1 Dosing Information

Following the initial dose and with each dose increase of doxazosin tablets, monitor blood pressure for

at least 6 hours following administration. If doxazosin tablets administration is discontinued for several

days, therapy should be restarted using the initial dosing regimen.

2.2 Benign Prostatic Hyperplasia

The recommended initial dosage of doxazosin tablets 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.

2.3 Hypertension

The initial dosage of doxazosin tablets 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.

Doxazosin tablets, USP are available as functionally scored tablets in following strengths:

1 mg: White to off white, round, biconvex uncoated tablets, debossed with “C3” on one side and

breakline on other side.

2 mg: Cream to yellow colored, round, biconvex uncoated tablets, debossed with “C7” on one side and

breakline on other side; may have mottled appearance.

4 mg: Cream to yellow colored, round, biconvex uncoated tablets, debossed with “C4” on one side and

breakline on other side; may have mottled appearance.

8 mg: White to off white, round, biconvex, uncoated tablets, debossed with “C5” on one side and

breakline on other side.

The use of doxazosin tablets is contraindicated in patients with a hypersensitivity to doxazosin, other

quinazolines (e.g., prazosin, terazosin), or any of its components.

5.1 Postural Hypotension

Postural hypotension with or without symptoms (e.g., dizziness) may develop within a few hours

following administration of doxazosin. 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 doxazosin with a PDE-5 inhibitor can result in additive blood pressure

lowering effects and symptomatic hypotension.

5.2 Cataract Surgery

Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients

on or previously treated with alpha 1 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 alpha 1

blocker therapy prior to cataract surgery.

5.3 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 doxazosin for the treatment of BPH.

5.4 Priapism

Alpha 1 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.

6.1 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 doxazosin in doses of 1 mg to 16 mg in

hypertensives and 0.5 mg to 8 mg in normotensives. Adverse reactions occurring more than 1% more

frequently in BPH patients treated with doxazosin vs placebo are summarized in Table 1.

Table 1. Adverse Reactions Occurring more than 1% More Frequently in BPH Patients Treated with

Doxazosin Versus Placebo

Doxazosin

Placebo

BODY SYSTEM

N=665

N=300

NERVOUS SYSTEM DISORDERS

Dizziness †

15.6%

9.0%

Somnolence

3.0%

1.0%

CARDIAC DISORDERS

Hypotension

1.7%

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%

†Includes vertigo

Other adverse reactions occurring less than 1% more frequently in BPH patients treated with doxazosin

vs placebo but plausibly related to doxazosin include: palpitations.

Hypertension

Doxazosin 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

doxazosin vs placebo are summarized in Table 2. 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 mg to 16 mg.

Table 2. Adverse Reactions Occurring more than 1% More Frequently in Hypertensive Patients Treated

with Doxazosin versus Placebo

Doxazosin

Placebo

BODY SYSTEM

N=339

N=336

NERVOUS SYSTEM DISORDERS

Dizziness

Somnolence

RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS

Rhinitis

RENAL AND URINARY DISORDERS

Polyuria

REPRODUCTIVE SYSTEM AND BREAST DISORDERS

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS

Fatigue / Malaise

Other adverse reactions occurring less than 1% more frequently in hypertensive patients treated with

doxazosin vs placebo but plausibly related to doxazosin use include vertigo, hypotension, hot flushes,

epistaxis and oedema.

Doxazosin 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 doxazosin. In cases where

follow-up was available, WBC and neutrophils counts returned to normal after discontinuation of

doxazosin. No patients became symptomatic as a result of the low WBC or neutrophil counts.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of doxazosin. 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 (5.2)].

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.

7.1 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

doxazosin is used concomitantly with strong CYP3A inhibitors [see CLINICAL PHARMACOLOGY

(12.3)] .

7.2 Phosphodiesterase-5 (PDE-5) inhibitors

Concomitant administration of doxazosin 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)] .

8.1 Pregnancy

Risk Summary

The limited available data with doxazosin 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 mg 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 the U.S. general population, the estimated background risk of major birth defects and

miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 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 mg 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 mg 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.

8.2 Lactation

Risk Summary

There is limited information on the presence of doxazosin in human milk [see DATA] . There is no

information on the effects of doxazosin on the breastfeed infant or the effects on milk production.

Data

A single case study reports that doxazosin 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 doxazosin in human milk.

8.4 Pediatric Use

The safety and effectiveness of doxazosin have not been established in children.

8.5 Geriatric Use

Benign Prostatic Hyperplasia (BPH)

The safety and effectiveness profile of doxazosin was similar in the elderly (age ≥ 65 years) and

younger (age < 65 years) patients.

Hypertension

Clinical studies of doxazosin 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.

8.6 Hepatic Impairment

Doxazosin is extensively metabolized in the liver. Hepatic impairment is expected to increase exposure

to doxazosin. Use of doxazosin 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)] .

Experience with doxazosin overdosage is limited. Two adolescents, who each intentionally ingested 40

mg doxazosin 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 doxazosin 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 doxazosin and

was reported to have been drowsy. A 32-year-old female with chronic renal failure, epilepsy, and

depression intentionally ingested 60 mg doxazosin (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 doxazosin, alcohol, and Dalmane ® (flurazepam) developed

hypotension which responded to fluid therapy.

The oral LD 50 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.

Doxazosin mesylate is a quinazoline compound that is a selective inhibitor of the alpha 1 subtype 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 C 23H 25N 5O 5 CH 4O 3S and the molecular weight is 547.6. It has the

following structure:

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. Doxazosin tablets, USP are available as colored tablets for oral use and contain 1

mg (white to off white), 2 mg (cream to yellow), 4 mg (cream to yellow) and 8 mg (white to off white)

of doxazosin as the free base.

The inactive ingredients for all tablets are: lactose monohydrate, microcrystalline cellulose, sodium

lauryl sulfate, magnesium stearate and sodium starch glycolate. The 2 mg & 4 mg tablet contains ferric

oxide yellow.

[Chemical Structure]

12.1 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 alpha 1 adrenoceptor, which is present in high

density in the prostatic stroma, prostatic capsule and bladder neck. Blockade of the alpha 1 receptor

decreases urethral resistance and may relieve the obstruction and BPH symptoms and improve urine

flow.

Hypertension

The mechanism of action of doxazosin is selective blockade of the alpha 1 (postjunctional) subtype of

adrenergic receptors. Studies in normal human subjects have shown that doxazosin competitively

antagonized the pressor effects of phenylephrine (an alpha 1 agonist) and the systolic pressor effect of

norepinephrine. Doxazosin and prazosin have similar abilities to antagonize phenylephrine. The

antihypertensive effect of doxazosin 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.

12.2 Pharmacodynamics

Benign Prostatic Hyperplasia (BPH)

Administration of doxazosin 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 alpha 1 adrenoceptors also lowers blood pressure in hypertensive patients with

increased peripheral vascular resistance, doxazosin 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 doxazosin 1 mg to 8 mg once daily was

6.7% with doxazosin and not significantly different (statistically) from that with placebo (5%).

Hypertension

Administration of doxazosin 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 to 6 hours after dosing and are associated with a small increase in standing heart rate. Like

other alpha 1-adrenergic blocking agents, doxazosin has a greater effect on blood pressure and heart

rate in the standing position.

12.3 Pharmacokinetics

Absorption

After oral administration of therapeutic doses, peak plasma levels of doxazosin occur at about 2 to 3

hours. Bioavailability is approximately 65%, reflecting first-pass metabolism of doxazosin by the liver.

The effect of food on the pharmacokinetics of doxazosin was examined in a crossover study with

twelve hypertensive subjects. Reductions of 18% in mean maximum plasma concentration (C max) and

12% in the area under the concentration-time curve (AUC) occurred when doxazosin 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

Doxazosin 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 mg 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 doxazosin 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 C max and mean half-life of doxazosin.

In vitro data in human plasma indicate that doxazosin has no effect on protein binding of digoxin,

warfarin, phenytoin, or indomethacin.

13.1 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.

13.2 Animal Toxicology and Pharmacology

An increased incidence of myocardial necrosis or fibrosis was observed in long-term (6 to 12 months)

studies in rats and mice (exposure 8 times human AUC exposure in rats and somewhat equivalent to

human C max 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

(C max) 14 times the C max exposure in humans receiving a 12 mg/day therapeutic dose or in Wistar rats

at C max exposures 15 times human C max exposure. There is no evidence that similar lesions occur in

humans.

14.1 Benign Prostatic Hyperplasia (BPH)

The efficacy of doxazosin was evaluated extensively in over 900 patients with BPH in double-blind,

placebo-controlled trials. Doxazosin treatment was superior to placebo in improving patient symptoms

and urinary flow rate. Significant relief with doxazosin was seen as early as one week into the treatment

regimen, with doxazosin-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 to 71% of patients,

improvements above baseline were seen in both symptoms and maximum urinary flow rate.

In three placebo-controlled studies of 14 to 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 to 6 hours post-dose) and/or trough (24 hours post-dose) plasma concentrations of

doxazosin.

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, doxazosin resulted in statistically

significant relief of obstructive and irritative symptoms compared to placebo. Statistically significant

improvements of 2.3 to 3.3 mL/sec in maximum flow rate were seen with doxazosin in Studies 1 and 2,

compared to 0.1 to 0.7 mL/sec with placebo.

[Table 1]

In one fixed-dose study (Study 2), doxazosin therapy (4 mg to 8 mg, once daily) resulted in a significant

and sustained improvement in maximum urinary flow rate of 2.3 to 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 doxazosin 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 doxazosin

(34 to 42%) than placebo (13 to 17%). A significantly greater improvement was also seen in average

flow rate with doxazosin (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

[Figure 1 – Study 1]

14.2 Hypertension

In a pooled analysis of placebo-controlled hypertension studies with about 300 hypertensive patients

per treatment group, doxazosin, at doses of 1 mg 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 to 6 hours) were larger by about 50 to 75% (i.e., trough

values were about 55 to 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 doxazosin

gained a mean of 0.6 kg compared to a mean loss of 0.1 kg for placebo patients.

TABLE 4

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