DOXAZOSIN- doxazosin mesylate tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
Doxazosin Mesylate (UNII: 86P6PQK0MU) (Doxazosin - UNII:NW1291F1W8)
Available from:
Aphena Pharma Solutions - Tennessee, LLC
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Doxazosin tablets are indicated for the treatment of the signs and symptoms of BPH. Doxazosin tablets 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). Numerou
Product summary:
Doxazosin Tablets, USP are available as tablets for oral administration. Each tablet contains doxazosin mesylate, USP equivalent to 1 mg, 2 mg, 4 mg or 8 mg of doxazosin. The 1 mg tablets are available as white to off-white caplet-shaped tablets, debossed with "AC 356" on one side and scored on the other side. They are supplied as follows: The 2 mg tablets are available as white to off-white round tablets, debossed with "AC" and "357" on the scored side and plain on the other side. They are supplied as follows: The 4 mg tablets are available as white to off-white round tablets, debossed with "AC 358' on the scored side and plain on the other side. They are supplied as follows: The 8 mg tablets are available as white to off-white caplet-shaped tablets, debossed with "AC 359" on one side and scored on other side. They are supplied as follows: Recommended Storage: Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature.]
Authorization status:
Abbreviated New Drug Application
Authorization number:
71610-482-60

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DOXAZOSIN- doxazosin mesylate tablet

Aphena Pharma Solutions - Tennessee, LLC

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use DOXAZOSIN TABLETS safely and

effectively. See full prescribing information for DOXAZOSIN TABLETS.

DOXAZOSIN tablets, for oral use

Initial U.S. Approval: 1990

INDICATIONS AND USAGE

Doxazosin tablets are an alpha adrenergic antagonist indicated for: (1)

Signs and symptoms of Benign Prostatic Hyperplasia (BPH)

Treatment of Hypertension

DOSAGE AND ADMINISTRATION

For the treatment of BPH: Initiate therapy at 1 mg once daily. Dose may be titrated at 1 to 2 week intervals, up to 8 mg

once daily. (2.2)

For the treatment of hypertension: Initiate therapy at 1 mg once daily. Dose may be titrated as needed, up to 16 mg

once daily. (2.3)

DOSAGE FORMS AND STRENGTHS

Tablets: 1 mg, 2 mg, 4 mg, 8 mg.

CONTRAINDICATIONS

Hypersensitivity to doxazosin, other quinazolines, or any other ingredient in doxazosin tableta. (4)

WARNINGS AND PRECAUTIONS

Postural hypotension with or without syncope may occur. (5.1)

Risk of Intraoperative Floppy Iris Syndrome during cataract surgery. (5.2)

Screen for the presence of prostate cancer prior to treatment for BPH and at regular intervals afterwards. (5.3)

ADVERSE REACTIONS

The most commonly reported adverse reactions from clinical trials are fatigue, malaise, hypotension, and dizziness. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Upsher-Smith Laboratories, LLC at 1-855-899-9180 or

FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Strong cytochrome P450 (CYP) 3A inhibitors may increase exposure to doxazosin and increased risk of hypotension.

(7.1)

Concomitant administration of doxazosin tablets with a phosphodies terase-5 (PDE-5) inhibitor can result in additive

blood pressure lowering effects and symptomatic hypotension. (7.2)

USE IN SPECIFIC POPULATIONS

Hepatic Impairment: Monitor for hypotension. (8.6, 12.3)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 5/2018

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.1 Benign Prostatic Hyperplasia (BPH)

1.2 Hypertension

2 DOSAGE AND ADMINISTRATION

2.1 Dosing Information

2.2 Benign Prostatic Hyperplasia

2.3 Hypertension

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Postural Hypotension

5.2 Cataract Surgery

5.3 Prostate Cancer

5.4 Priapism

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 CYP3A Inhibitors

7.2 Phosphodiesterase-5 (PDE-5) Inhibitors

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and Pharmacology

14 CLINICAL STUDIES

14.1 Benign Prostatic Hyperplasia (BPH)

14.2 Hypertension

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Benign Prostatic Hyperplasia (BPH)

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

1.2 Hypertension

Doxazosin tablets 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

Sections or subsections omitted from the full prescribing information are not listed.

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 may be used alone or in combination with other antihypertensives.

2 DOSAGE AND ADMINISTRATION

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.

3 DOSAGE FORMS AND STRENGTHS

Doxazosin tablets, USP are available containing doxazosin mesylate, USP equivalent to 1 mg, 2 mg, 4

mg or 8 mg of doxazosin.

The 1 mg tablets are available as white to off-white caplet-shaped tablets, debossed with 'AC 356"

on one side and scored on the other side.

The 2 mg tablets are available as white to off-white round tablets, debossed with 'AC 357" on the

scored and plain on the other side.

The 4 mg tablets are available as white to off-white round tablets, debossed with 'AC 358" on the

scored and plain on the other side.

The 8 mg tablets are available as white to off-white caplet-shaped tablets, debossed with 'AC 359"

on one side and scored on the other side.

4 CONTRAINDICATIONS

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

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

5 WARNINGS AND PRECAUTIONS

5.1 Postural Hypotension

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

following administration of doxazosin tablets. 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 tablets 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 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

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 tablets for the treatment of BPH.

5.4 Priapism

Alpha 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 ADVERSE REACTIONS

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 tablets 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 tablets vs placebo are summarized in Table

Table 1. Adverse Reactions Occurring more than 1% More Frequently

in BPH Patients Treated with Doxazosin Tablets Versus Placebo

BODY SYSTEM

Doxazosin tablets

N=665

Placebo

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%

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

tablets vs placebo but plausibly related to doxazosin tablets include: palpitations.

Hypertension

Doxazosin tablets have 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 tablets 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 mg to 16

Table 2. Adverse Reactions Occurring more than 1% More Frequently

in Hypertensive Patients Treated with Doxazosin Tablets versus Placebo

Includes vertigo

BODY SYSTEM

Doxazosin tablets

N=339

Placebo

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

hot flushes, epistaxis and oedema.

Doxazosin tablets have 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 tablets. In cases where follow-up was

available, WBC and neutrophil counts returned to normal after discontinuation of doxazosin tablets. 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 tablets.

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 postmarketing 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 DRUG INTERACTIONS

7.1 CYP3A Inhibitors

In vitro studies suggest that doxazosin is a substrate of CYP3A4. Strong CYP3A inhibitors may increase

exposure to doxazosin. Monitor blood pressure and for symptoms of hypotension when doxazosin

tablets are used concomitantly with strong CYP3A inhibitors [see Clinical Pharmacology (12.3)].

7.2 Phosphodiesterase-5 (PDE-5) Inhibitors

Concomitant administration of doxazosin tablets 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 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

The limited available data with doxazosin tablets 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/kg 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/kg 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/kg/day 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 breastfed 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 tablets have not been established in children.

8.5 Geriatric Use

Benign Prostatic Hyperplasia (BPH)

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

younger (age < 65 years) patients.

Hypertension

Clinical studies of doxazosin tablets 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 tablets are extensively metabolized in the liver. Hepatic impairment is expected to increase

exposure to doxazosin. Use of doxazosin tablets 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)].

10 OVERDOSAGE

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

ingested 40 mg doxazosin tablets 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 tablets 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 tablets and was reported to have been drowsy. A 32-year-old female with chronic renal

failure, epilepsy, and depression intentionally ingested 60 mg doxazosin tablets (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 tablets, alcohol, and

Dalmane

(flurazepam) developed hypotension which responded to fluid therapy.

The oral LD 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.

11 DESCRIPTION

Doxazosin tablets, USP is a quinazoline compound that is a selective inhibitor of the alpha subtype of

alpha-adrenergic receptors. The chemical name of doxazosin mesylate, USP is 1-(4-Amino-6,7-

dimethoxy-2-quinazolinyl)-4-(1,4 benzodioxan-2-ylcarbonyl) piperazine methanesulfonate. The

molecular formula for doxazosin mesylate is C

H N O · CH O S and the molecular weight is

547.6. It has the following structure:

Doxazosin mesylate, USP 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 tablets for oral use and contains 1 mg, 2

mg, 4 mg and 8 mg of doxazosin as the free base.

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

glycolate, magnesium stearate and sodium lauryl sulfate.

12 CLINICAL PHARMACOLOGY

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 adrenoceptor, which is present in high

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

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

flow.

Hypertension

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

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

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

pressor effect of norepinephrine. Doxazosin and prazosin have similar abilities to antagonize

phenylephrine. The antihypertensive effect of doxazosin tablets 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 tablets 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 adrenoceptors also lowers blood pressure in hypertensive patients with

increased peripheral vascular resistance, doxazosin tablets 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 tablets 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 tablets 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 -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 tablets 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 tablets was examined in a crossover

study with twelve hypertensive subjects. Reductions of 18% in mean maximum plasma concentration

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

were 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 versus 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 tablets are 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 CYP3A4; however, CYP2D6 and CYP2C9 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 versus first-dose AUC) were 1.2 and 1.7.

Enterohepatic recycling is suggested by secondary peaking of plasma doxazosin concentrations.

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