AHFS Class:

• alpha-Adrenergic Blocking Agents 24:16

Generic Name(s):

• Doxazosin Mesylate

Doxazosin mesylate is a quinazoline-derivative postsynaptic α₁-adrenergic blocking agent.1,2,3,4,5,6

Hypertension

Doxazosin mesylate is used alone or in combination with other classes of antihypertensive agents for the management of hypertension.1,2,3,4,6,1200 However, because of established clinical benefits (e.g., reductions in overall mortality and in adverse cardiovascular, cerebrovascular, and renal outcomes), current evidence-based practice guidelines for the management of hypertension in adults generally recommend the use of drugs from 4 classes of antihypertensive agents (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics).501,502,503,504,1200,1213

In a randomized, double-blind clinical study (the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT]),57,63,64 doxazosin, an α₁-blocker, was less effective in lowering mean systolic blood pressure (by about 2-3 mm Hg) than chlorthalidone, a thiazide-like diuretic.57 In order to achieve target blood pressure in hypertensive patients, use of doxazosin required additional hypotensive therapy more frequently than chlorthalidone.57 In addition, interim analysis (median follow-up: 3.3 years) of this study indicated that use of doxazosin in high-risk (at least 2 risk factors for coronary heart disease) hypertensive patients 55 years of age and older was associated with a higher risk of stroke and a higher incidence of combined cardiovascular disease events (including twice the risk of congestive heart failure) than use of chlorthalidone.57,58 Study investigators concluded that such increased risk of congestive heart failure could not have been caused by the relatively small difference in the mean target systolic blood pressure observed in patients receiving doxazosin compared with those receiving chlorthalidone.57,58 Therefore, based on these findings, the trial's Data Safety and Monitoring Board recommended that the doxazosin treatment arm be terminated prematurely.57,58,64 The remaining antihypertensive arms (e.g., calcium-channel blockers, ACE enzyme inhibitors, diuretics) and lipid-lowering (pravastatin vs usual care) components of the study subsequently were completed and reported.63,64,65

Current antihypertensive and urology guidelines no longer recommend α₁-blockers as preferred first-line therapy for any patients with hypertension, principally because of negative findings observed in ALLHAT.230,502,1200 However, α₁-blockers are effective antihypertensive drugs and many experts still consider their use appropriate for the management of resistant hypertension as a component of combination therapy.502,504,1200 Therapy with an α₁-blocker is most effective when used in combination with a diuretic.504 Some experts state that an α₁-blocker may be a second-line agent in antihypertensive treatment regimens in men with coexisting benign prostatic hyperplasia (BPH);504,1200 the American Urology Association (AUA) states that monotherapy with these drugs is not optimal in hypertensive patients with lower urinary tract symptoms (LUTS) or BPH and that such conditions should be managed separately.230

The beneficial effects of α₁-blockers on blood glucose and lipid concentrations may mitigate some of the adverse metabolic effects of diuretics,504 and α₁-blockers may offer some advantage in patients with underlying lipoprotein disorders (e.g., hypercholesterolemia) or in those with lipoprotein abnormalities induced by other antihypertensive agents (e.g., thiazide diuretics).1,53 The possibility that geriatric patients may be more susceptible than younger patients to the postural hypotensive effects of α₁-blockers should be considered in the selection of therapy.7,1200 Blood pressure response to α₁-blockers appears to be comparable in white and black patients.7

For further information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension in Adults and also see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Benign Prostatic Hyperplasia

Doxazosin is used to reduce urinary obstruction and relieve associated manifestations in hypertensive or normotensive patients with symptomatic benign prostatic hyperplasia (BPH, benign prostatic hypertrophy).1,21,33,35,37,40,41,42,43,44,46 For patients who can tolerate the potential cardiovascular and other effects of α₁-adrenergic blockade, doxazosin can effectively relieve mild to moderate obstructive manifestations (e.g., hesitancy, terminal dribbling of urine, interrupted or weak stream, impaired size and force of stream, sensation of incomplete bladder emptying or straining) and improve urinary flow rates in a substantial proportion of patients1,37,40,41,42,43,46 and may be a useful alternative to surgery, particularly in those who are awaiting or are unwilling to undergo surgical correction of the hyperplasia (e.g., via transurethral resection of the prostate [TURP]) or who are not candidates for such surgery.1,21,22,34,35,39,45

Therapy with α₁-blockers appears to be less effective in relieving irritative (e.g., nocturia, daytime frequency, urgency, dysuria) than obstructive symptomatology.23,24,25 In addition, therapy with the drugs generally can be expected to produce less subjective and objective improvement than prostatectomy,21,26 and periodic monitoring (e.g., performance of digital rectal examinations, serum creatinine determinations, serum prostate specific antigen [PSA] assays) is indicated in these patients to detect and manage other potential complications of or conditions associated with BPH (e.g., obstructive uropathy, prostatic carcinoma).21,24,28,29,30,31,35 While symptomatic improvement has been maintained for at least up to 2 years of doxazosin therapy in some patients,1 the long-term effects of α-blockers on the need for surgery and on the frequency of developing BPH-associated complications such as acute urinary obstruction remain to be established.22,28,35

Although the etiology of benign prostatic hyperplasia currently is unclear, age-associated changes in circulating hormones (e.g., androgens, estrogens) appear to be involved;29,38,93 approximately 40% of men have been reported to have clinical evidence of BPH by age 70.33 Hyperplasia of the prostatic tissue encircling the urethra produces narrowing of the bladder neck and prostatic urethra, leading to both obstructive (e.g., urinary hesitancy, slow/weak stream, straining, incomplete voiding) and irritative (e.g., urinary frequency, urgency, nocturia) manifestations; progressive obstruction of urinary flow eventually may lead to urinary retention and subsequent complications (e.g., urinary tract infection, bladder calculi, hydronephrosis).38

In addition to the mechanical component of urethral obstruction caused by the enlarged gland, a dynamic component of obstruction may be prominent in some patients; current evidence suggests that approximately 50% of prostate outflow obstruction is caused by reversible α-adrenergic (principally α₁) receptor-mediated contractions of smooth muscle in the prostatic capsule, prostatic adenoma, and bladder neck.22,26,28,30,38,87,89,90,91,92,93,94,95,96,97,105 While nonselective α-adrenergic blockers such as phenoxybenzamine have been used successfully to treat BPH,28,90,95,96,98,99,100,101,102,103,104 such nonselective blockade has been associated with adverse effects such as postural hypotension, dizziness, and tachycardia because blockade of α₂-adrenergic receptors interferes with the negative feedback mechanism controlling norepinephrine release from presynaptic nerve terminals.26,28,87,88,90,94,95,99 As a result, nonselective α-blocker therapy currently is not recommended for BPH;66 instead, therapy with selective α₁-blockers, which can relieve α₁-adrenergic-mediated bladder outflow obstruction, is recommended.66

Patients with mildly symptomatic BPH and those with moderate to severe symptoms that are not bothersome (i.e., that do not interfere with daily activities of living) generally should simply be followed rather than actively treated.66 Active therapy (e.g., drug therapy; minimally invasive therapies such as transurethral microwave heat; surgery such as TURP) should be considered for patients with moderate to severe BPH that is bothersome; the potential benefits and possible risks of various therapeutic options, including watchful waiting, should be discussed with the patient.66 Although drug therapy usually is not as effective as surgical therapy, it may provide adequate symptomatic relief with fewer and less serious adverse effects compared with surgery.66 Most experts currently consider therapy with an α₁-adrenergic blocker such as doxazosin to be an appropriate option for symptomatic treatment of bothersome lower urinary tract symptoms in patients with BPH.66 With the exception of prazosin (for which there are insufficient data to compare), currently available α₁-adrenergic blockers are considered comparably effective.66 Therapy with an α₁-adrenergic blocker generally is more effective in relieving lower urinary tract symptoms than that with a 5α-reductase inhibitor (e.g., finasteride), and 5α-reductase inhibitors are ineffective in patients without prostatic enlargement.66

Combination Therapy

Although studies of up to 1 year in duration generally have found combination therapy with an α₁-blocker and 5α-reductase inhibitor (e.g., finasteride) to be no more effective than α₁-adrenergic blocker monotherapy in providing symptomatic relief of BPH, a long-term (mean follow-up: 4.5 years), double-blind study (Medical Therapy of Prostatic Symptoms [MTOPS]) found that combined therapy with doxazosin (4-8 mg daily) and finasteride (5 mg daily) was more effective than therapy with either drug alone in preventing symptom progression (defined as an increase from baseline of at least 4 points in the American Urological Association [AUA] symptom score, acute urinary retention, urinary incontinence, renal insufficiency, or recurrent urinary tract infection).32,66,84 The percent reduction in the risk of symptom progression (generally manifested as an increase in AUA symptom score) relative to placebo was 34% with finasteride, 39% with doxazosin, and 67% with combination therapy.32,66,84 The risks of long-term acute urinary retention and the need for invasive therapy were reduced by combination therapy and by finasteride monotherapy but not by doxazosin monotherapy.66,84 Combination therapy or doxazosin or finasteride monotherapy each were effective in providing improvement in symptom scores, with combination therapy providing greater improvement than either drug alone.32,66,84

Most experts state that combined therapy with an α₁-adrenergic blocker and 5α-reductase inhibitor can be considered for men with bothersome moderate to severe BPH and demonstrable prostatic enlargement, weighing the benefit of preventing progression of BPH with the risks and cost of the combination.66,84,85 Men at risk for BPH progression are most likely to benefit from combination therapy.66,84 Although the benefit of combination therapy was not as substantial in men with low baseline prostate-specific antigen (PSA) levels compared with those with high baseline values in the MTOPS study,84 the potential benefit appears to be greatest in those in whom baseline risk of progression generally is high rather than specifically in those with larger prostates or higher PSA levels at baseline.66

Adverse effects associated with combined α₁-adrenergic blocker and 5α-reductase inhibitor therapy generally reflect the combined toxicity profile of each drug alone,66,84 although certain adverse effects (e.g., effects on sexual function and libido, postural hypotension, peripheral edema, dizziness, asthenia, rhinitis) may be more common with combined therapy.32 For further information on adverse effects associated with combined doxazosin and finasteride therapy, see Cautions in Finasteride 92:08.

Administration

Doxazosin mesylate is administered orally.1,1

The pharmacokinetics and safety were similar with morning or evening dosing of doxazosin conventional (immediate-release) tablets in a limited number of normotensive patients in one study; however, the area under the plasma concentration-time curve (AUC) was 11% less with morning dosing, and the time to peak concentration occurred later with evening dosing (5.6 versus 3.5 hours).1

Peak plasma concentrations and oral bioavailability are increased by approximately 32 and 18%, respectively, when doxazosin mesylate extended-release tablets (Cardura^® XL) are administered with food. Therefore, to provide more consistent systemic exposure to the drug, extended-release tablets should be administered with breakfast.

Doxazosin mesylate extended-release tablets should be swallowed intact and should not be chewed, crushed, or broken. Patients should be advised not to become alarmed if they notice a tablet-like substance in their stools; this is normal since the tablet is designed to release the drug slowly from a nonabsorbable shell during passage through the GI tract.

Dosage

Dosage of doxazosin mesylate is expressed in terms of doxazosin1 and must be adjusted according to the patient's blood pressure response and tolerance.1

Hypertension

Usual Dosage

For the management of hypertension in adults, the usual initial dosage of doxazosin conventional (immediate-release) tablets is 1 mg once daily.1 Because of the risk of postural effects (see Cautions: Postural Effects), it is essential that therapy with the drug not be initiated with higher dosages.1 Patient response (standing blood pressure) should be assessed 2-6 and 24 hours after the initial dose and any subsequent dosage adjustments.1 Because postural effects are most likely to occur 2-6 hours after a dose, it is particularly important that the standing blood pressure response be assessed during this period after the first dose and any increases.1

If blood pressure is not adequately controlled at a doxazosin dosage of 1 mg daily as conventional tablets, the dosage may be increased to 2 mg once daily in adults; subsequent dosage adjustments can be made by doubling the dose until the desired blood pressure control is achieved, the drug is not tolerated, or a maximum dosage of 16 mg once daily is reached.1 Some experts state that the usual adult dosage ranges from 1-16 mg once daily.1200 The manufacturer recommends that dosage increases be made no more frequently than every 2 weeks.1 Doxazosin dosages exceeding 4 mg daily as conventional tablets are associated with an increased likelihood of excessive postural effects including syncope, dizziness, vertigo, and hypotension,1 and those exceeding 16 mg daily are not recommended because of the substantial risk of postural effects.1

If doxazosin is used for the management of hypertension in children†, some experts have recommended an initial dosage of 1 mg once daily as conventional tablets;106 dosage may be increased as necessary to a maximum of 4 mg once daily. (See Cautions: Pediatric Precautions.) For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Extended-release doxazosin tablets (Cardura^® XL) currently are not FDA-labeled for use in the management of hypertension.

Blood Pressure Monitoring and Treatment Goals

Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage adjusted until blood pressure is controlled.1200 If an adequate blood pressure response is not achieved, the dosage may be increased or another antihypertensive agent with demonstrated benefit and preferably with a complementary mechanism of action (e.g., angiotensin-converting enzyme [ACE] inhibitor, angiotensin II receptor antagonist, calcium-channel blocker, thiazide diuretic) may be added; if target blood pressure is still not achieved with the use of 2 antihypertensive agents, a third drug may be added.1200,1216 (See Uses: Hypertension.) In patients who develop unacceptable adverse effects with doxazosin, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.1216

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.1200 However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.505,506,507,508,515,523,530,1201,1207,1209,1222 A 2017 multidisciplinary hypertension guideline from the American College of Cardiology (ACC), American Heart Association (AHA), and a number of other professional organizations generally recommends a blood pressure goal of less than 130/80 mm Hg in all adults, regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.1200,1207 Many patients will require at least 2 drugs from different pharmacologic classes to achieve this blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.1200,1220

For additional information on target levels of blood pressure and on monitoring therapy in the management of hypertension, see Blood Pressure Monitoring and Treatment Goals under Dosage: Hypertension, in Dosage and Administration in the Thiazides General Statement 40:28.20.

Benign Prostatic Hyperplasia

For the management of benign prostatic hyperplasia (BPH), the usual initial adult dosage of doxazosin as conventional (immediate-release) tablets is 1 mg daily, given in the morning or in the evening.1,41,44 Some clinicians state that it is preferable to administer the drug at bedtime to minimize postural effects.35,36 Because of the risk of postural effects (see Cautions: Postural Effects), it is essential that therapy with the drug not be initiated with higher dosages.1

To achieve the desired improvement in symptoms and urodynamics, subsequent doxazosin dosage as conventional tablets may be increased in a stepwise manner to 2, 4, and 8 mg daily as necessary;1,39,40,41,42,43,44 it is recommended that each doubling of dosage occur at intervals of not less than 1-2 weeks.1,41,42,43,44 Although higher dosages (e.g., 16 mg daily) have been used, maximally tolerable and effective dosages have not been established and the manufacturer and most experts recommend that the dosage for BPH not exceed 8 mg daily as conventional tablets.35 Blood pressure should be evaluated routinely in patients receiving doxazosin therapy, particularly with initiation of therapy and subsequent dosage adjustment (see Dosage: Hypertension).1

In a study demonstrating the combined efficacy of an α₁-adrenergic blocker and 5α-reductase inhibitor, doxazosin therapy as conventional tablets was initiated at a dosage of 1 mg daily at bedtime for the first week and then doubled at 1-week intervals until a dosage of 8 mg daily was achieved.84 In patients who could not tolerate the 8-mg dose, dosage was reduced to 4 mg daily as conventional tablets; those unable to tolerate the 4-mg dose were counted as having discontinued the drug.84 Finasteride was administered concomitantly at a dosage of 5 mg daily at bedtime.84

Alternatively, when extended-release tablets are used for the management of BPH, the usual initial dosage is 4 mg once daily with breakfast. This dosage also should be used initially in patients being switched from conventional tablets. Depending on patient response and tolerability, extended-release dosage may be increased to a maximum of 8 mg once daily with breakfast. If extended-release therapy is interrupted, it should be reinitiated at 4 mg once daily.

Dosage in Renal and Hepatic Impairment

Clinically important alterations in the pharmacokinetics of doxazosin in patients with impaired renal function have not been observed to date,1,8 and the manufacturer makes no specific recommendations for modification of dosage in such patients.1

The effect of hepatic impairment on the disposition of doxazosin has not been established in controlled clinical studies.1 However, administration of a single 2-mg dose of doxazosin as conventional tablets to patients with cirrhosis (Child-Pugh class A) resulted in a 40% increase in systemic exposure to the drug.1 Because doxazosin is eliminated almost entirely by metabolism in the liver, the manufacturer states that the drug should be administered cautiously in patients with hepatic impairment.1

Dosage in Geriatric Patients

While the manufacturer makes no specific recommendations for titration of doxazosin dosage in geriatric patients,1 patients in this age group generally are less tolerant of the postural hypotensive effects of α₁-adrenergic blocking agents because of impaired cardiovascular reflexes, and caution should be exercised.7 Therefore, dosage escalation in elderly hypertensive patients generally should be slower than in younger adults.7 Clinically important alterations in the pharmacokinetics of the drug in geriatric patients have not been observed to date.1

Adverse effects occurring most frequently during doxazosin mesylate therapy for hypertension include dizziness, headache, drowsiness, lack of energy (e.g, lethargy, fatigue), nausea, edema, and rhinitis.1,2,3,4,6 In patients receiving the drug for benign prostatic hyperplasia (BPH), the most frequent adverse effects are dizziness, headache, fatigue, edema, dyspnea, abdominal pain, and diarrhea.1 The frequency of adverse effects in controlled clinical trials generally has been lower in patients receiving doxazosin for BPH than in those receiving the drug for hypertension; however, dosages employed for this condition also generally have been lower than those for hypertension.1

While adverse effects occur frequently in patients receiving the drug, most are mild to moderate in severity,1,2,3 and discontinuance of doxazosin secondary to adverse effects was required in only 7% of patients with hypertension during clinical trials.1,2 The principal reasons for discontinuance in patients with hypertension were postural effects in 2% of patients and edema, malaise/fatigue, and heart rate disturbance each in about 0.7% of patients.1 In controlled clinical trials in patients with hypertension, only dizziness (including postural effects), weight gain, somnolence, and malaise/fatigue occurred at rates significantly greater than those for placebo;1 postural effects and edema appeared to be dose related.1 Only dizziness, fatigue, hypotension, edema, and dyspnea occurred significantly more frequently with the drug than placebo in controlled clinical trials for BPH;1 dizziness and dyspnea appeared to be dose-related.1

Postural Effects

Doxazosin, like other α₁-adrenergic blocking agents, can cause marked hypotension, which may be accompanied by syncope and other postural effects.1,2,3,4,6 While syncope is the most severe orthostatic effect of the drug, other less severe symptoms, such as dizziness, lightheadedness, and vertigo, also can be associated with doxazosin-induced reductions in blood pressure.1 Syncope is uncommon when doxazosin dosage is initiated at low levels and titrated slowly, but dizziness and/or lightheadedness are frequent, occurring in about 20 or 16% of patients receiving the drug for hypertension or BPH, respectively, in controlled trials.1,17 Vertigo has been reported in 2%, syncope in 0.7%, and postural hypotension in 0.3% of hypertensive patients in controlled trials.1 In patients receiving the drug for BPH in controlled clinical trials, postural hypotension was reported in 0.3% and syncope in 0.5-0.7% of patients.1

Doxazosin-induced postural effects are dose related, particularly likely in the upright position following an initial dose, and most likely to develop between 2-6 hours after administration.1,2,3,4,6,17 With continued therapy after careful dosage titration, adaptation of reflex mechanisms to α₁-blockade develop and the risk of postural effects generally subsides.6 However, marked hypotension also can occur with subsequent dosage increases or after therapy is interrupted for more than a few days.1 In clinical trials in patients with hypertension, postural effects occurred in 23% of patients receiving the drug and required discontinuance in 2% of patients.1 In clinical trials in patients with BPH receiving doxazosin dosages up to 8 mg daily, discontinuance of the drug for postural effects was required in 3.3% of patients.1 While the adverse effect profiles of doxazosin and prazosin generally appear to be similar,3,4,6 it has been suggested that postural effects may be less likely with doxazosin in part because of the drug's slower onset of action and reduced affinity for α₁-receptors;2,4 however, additional study and experience are needed to elucidate the relative risks of postural effects.17

The risk of first-dose syncope with α₁-adrenergic blocking agents generally can be minimized by initiating therapy at low doses (i.e., 1 mg of doxazosin daily) and lessening the level of salt restriction and avoiding diuretics just prior to initiation of α₁-blocker therapy.1,4,6 It is essential that doxazosin therapy not be initiated at dosages exceeding 1 mg daily and that dosage escalation be slow with patient evaluations.1 In addition, it is important that standing blood pressure be evaluated 2 minutes after standing.1 If syncope develops, the patient should be placed in the recumbent position and treated supportively as necessary.1 Patients should be advised to lie or sit down if they develop any postural symptom (e.g., dizziness, vertigo) and to exercise caution upon standing from a sitting or supine position.2 Patients also should be cautioned to avoid situations, both during the day and through the night, that could result in injury if syncope were to occur.1 Other antihypertensive therapy should added cautiously in patients receiving doxazosin.1,2

In an early dose-ranging study of the safety and tolerance of doxazosin in several normotensive individuals, two-thirds of these individuals could not tolerate dosages exceeding 2 mg daily because of symptomatic postural hypotension.1 In other studies in normotensive individuals, approximately 30% of individuals receiving initial doxazosin dosages of 2 mg daily experienced symptomatic hypotension 0.5-6 hours after the dose,1 and in subsequent trials in hypertensive patients in which doxazosin therapy was initiated at 1 mg daily, postural effects were observed following the initial dose in 4% of patients but were not associated with syncope.1,17 In multiple-dose clinical trials in hypertensive patients involving dosage initiation at 1 mg daily and titration every 1-2 weeks, syncope was reported in less than 1% of patients, occurring in no patients at a dosage of 1 mg daily but in 1.2% of those titrated to 16 mg daily.1 In dose titration trials, the frequency of orthostatic effects could be minimized by initiating therapy at 1 mg daily and titrating dosage no more frequently than every 2 weeks to a maximum of 2.4-8 mg daily.1 The frequency of orthostatic effects in these titration trials in hypertensive patients was about 12% in those receiving 16 mg of doxazosin once daily, 10% in those receiving 8 mg or more once daily, and 5% in those receiving 1-4 mg once daily.1 In controlled trials in patients with BPH, the frequency of orthostatic hypotension was not dose related at dosages up to 8 mg daily, titrated at intervals of 1-2 weeks.1

Nervous System Effects

Besides dizziness (see Cautions: Postural Effects), headache is the most common adverse nervous system effect associated with doxazosin therapy, occurring in about 14 or 10% of patients receiving the drug for hypertension or BPH, respectively.1 Somnolence occurs in 5 or 3% of such patients, respectively, and pain in 2% of patients.1 Nervousness occurs in about 2% of patients receiving doxazosin for hypertension,1 and insomnia1 and anxiety1 occur in 1.2 and 1.1%, respectively, of those receiving the drug for BPH;1 insomnia occurs in 1% of hypertensive patients.1 Adverse nervous system effects occurring in 0.5-1% of patients include paresthesia, kinetic disorders, ataxia, hypertonia, hypoesthesia, agitation, depression, and decreased libido.1 Paresis, tremor, twitching, confusion, migraine, paroniria, amnesia, emotional lability, impaired concentration, abnormal thinking, and depersonalization have been reported in less than 0.5% of patients, but a causal relationship to the drug has not been established.1

GI Effects

Nausea,1,3,6 diarrhea,1,3 and dry mouth1 are the most common adverse GI effects of doxazosin in hypertensive patients, occurring in 3, 2, and 2% of such patients, respectively,1 and abdominal pain,1 diarrhea,1 dyspepsia,1 nausea,1 and dry mouth1 are the most common in those with BPH, occurring in 2.4, 2.3, 1.7, 1.5, and 1.4% of such patients, respectively;1 dyspepsia occurs in 1% of hypertensive patients.1 Constipation and flatulence occur in 1% of patients receiving the drug for hypertension.1,3 Increased appetite, anorexia, fecal incontinence, and gastroenteritis have been reported in less than 0.5% of hypertensive patients but not directly attributed to the drug.1 Vomiting has been reported during postmarketing experience with doxazosin.1

Cardiovascular Effects

Besides postural effects of the drug (see Cautions: Postural Effects), other cardiovascular effects reported in patients receiving doxazosin for hypertension or BPH include edema in 4 or 2.7%, respectively, and palpitation and chest pain in 2 or 1.2% of such patients, respectively.1 Arrhythmia occurs in 1% of hypertensive patients,1 and tachycardia and angina pectoris occur in 0.9 and 0.6%, respectively, of patients with BPH.1 Tachycardia and peripheral ischemia have been reported in 0.3% of hypertensive patients.1 Hot flushes, ischemia, angina pectoris, myocardial infarction, and cerebral vascular accident have been reported in less that 0.5% of hypertensive patients, but a causal relationship has not been established.1 In addition, bradycardia has been reported with doxazosin during postmarketing experience.1

An increased incidence of myocardial necrosis and fibrosis has been observed in Sprague-Dawley rats after 6 months of oral doxazosin dosages of 80 mg/kg daily, and after 12 months of oral dosages of 40 mg/kg daily (AUC exposure in rats was 8 times the human AUC exposure associated with a 12 mg daily dosage).1 Myocardial fibrosis also was observed in both rats and mice receiving an oral dosage of 40 mg/kg daily for 18 months (AUC exposure in rats was 8 times the human exposure and in mice was somewhat equivalent to the human exposure).1 No cardiotoxicity was associated with lower dosages (e.g., 10 or 20 mg/kg daily, depending on the study) in either species, and such effects also were not observed following 12 months of administration in dogs receiving maximum oral doxazosin dosages of 20 mg/kg daily nor in Wistar rats receiving maximum oral dosages of 100 mg/kg daily.1 While the clinical relevance of these findings to human is not known, the manufacturer states that there currently is no evidence that similar lesions occur in humans.1

Dermatologic Effects

Adverse dermatologic effects associated with doxazosin include rash, pruritus, and facial edema.1 In controlled clinical trials, these effects were reported in 1% of hypertensive patients.1 Pallor, alopecia, dry skin, and eczema have been reported in less than 0.5% of hypertensive patients receiving doxazosin, but a causal relationship to the drug has not been established.1

Musculoskeletal Effects

Arthralgia/arthritis, muscle weakness, myalgia, and muscle cramps have been reported in 1% of hypertensive patients receiving doxazosin.1 Back pain was reported in 1.8% or less than 0.5% of patients receiving the drug for BPH or hypertension, respectively.1

Respiratory Effects

Rhinitis occurs in 3% of hypertensive patients receiving doxazosin.1 Dyspnea occurs in 2.6 or 1% of patients with BPH or hypertension, respectively, and respiratory disorder occurs in 1.1% of those with BPH.1 Bronchospasm, sinusitis, cough, and pharyngitis have been reported in less than 0.5% of hypertensive patients but not directly attributed to the drug.1 In addition, aggravated bronchospasm has been reported with doxazosin during postmarketing experience.1

Genitourinary Effects

Polyuria occurs in 2% of hypertensive patients receiving doxazosin and urinary incontinence occurs in 1% of such patients.1 Sexual dysfunction occurred in 2% of hypertensive patients1 and impotence occurred in 1.1% of those with BPH1 receiving the drug. Urinary tract infection and dysuria were reported in 1.4 and 0.5%, respectively, of patients with BPH receiving doxazosin, but they occurred less frequently than with placebo.1 Renal calculus has been reported in less than 0.5% of hypertensive patients, but a causal relationship has not been established.1 Priapism (painful penile erection sustained for hours and unrelieved by sexual intercourse or masturbation) has been reported rarely (probably less frequently than 1 in several thousand patients) in patients receiving an α₁-adrenergic antagonist (e.g., doxazosin).1 Urinary frequency,1 nocturia,1 hematuria,1 and unspecified micturition disorder1 have been reported with doxazosin during postmarketing experience.

Ocular and Otic Effects

Visual abnormalities occur in 2 or 1.4% of patients receiving doxazosin for hypertension of BPH, respectively, and conjunctivitis/ocular pain occurs in 1% of hypertensive patients.1 Tinnitus also occurs in 1% of patients receiving the drug.1 Photophobia, abnormal lacrimation, and earache have been reported in less than 0.5% of hypertensive patients, but these effects have not been directly attributed to the drug.1

Hematologic Effects

Adverse hematologic effects reported with doxazosin include decreased leukocyte and neutrophil counts.1 Mean reductions in these counts relative to placebo were 2.4 and 1%, respectively, in clinical trials in hypertensive patients.1 In clinical trials in patients with BPH, clinically important leukocyte abnormalities occurred in 0.4% of patients receiving doxazosin and in 0% of those receiving placebo, but the difference in incidence between these groups was not statistically different.1 Leukopenia1 and thrombocytopenia1 have been reported with doxazosin during postmarketing experience.

A search by the manufacturer of a database that included information on 2400 hypertensive patients and 665 with BPH revealed 4 cases in the hypertensive group and one case in the BPH group in which doxazosin-related neutropenia could not be ruled out.1 In 2 hypertensive patients, stable, nonprogressive neutropenia of about 1000/mm³ was observed over periods of 20-40 weeks.1 In a patient with BPH, the leukocyte count decreased from 4800 to 2700/mm³ at the end of the study, but there was no evidence of clinical impairment.1 In cases where follow-up was possible, leukocyte and neutrophil counts returned to normal after discontinuance of doxazosin; no cases of symptomatic reductions have been reported to date.1 Similar reductions in leukocyte and neutrophil counts have been observed with other α₁-adrenergic blocking agents.1

Other Adverse Effects

Sweating has been reported in 1.1 or 0.5-1% of patients receiving doxazosin for BPH or hypertension, respectively, and flu-like symptoms have been reported in 1.1 or less than 0.5% of such patients, respectively.1 Weight gain has been reported in 0.5-1% of hypertensive patients receiving the drug and thirst, gout, hypokalemia, lymphadenopathy, purpura, breast pain, taste perversion, parosmia, infection, fever/rigors, and weight loss have been reported in less than 0.5% of patients.1 In addition, gynecomastia,1 hepatitis,1 and cholestatic hepatitis1 have been reported with doxazosin during postmarketing experience.1

Precautions and Contraindications

Patients should be warned of the possibility of doxazosin-induced postural dizziness and measures to take if it develops (e.g., sitting, lying down).1 (See Cautions: Postural Effects.) During initiation of doxazosin therapy, the patient should be cautioned to avoid situations, both day and night, where injury could result if syncope occurs.1 If syncope occurs, the patient should be placed in the recumbent position and treated supportively as necessary.1 Patients who engage in potentially hazardous activities such as operating machinery or driving motor vehicles should be warned about possible drowsiness, dizziness, or lightheadedness.1

Patients also should be advised that priapism has been reported rarely in patients receiving an α₁-adrenergic antagonist (e.g., doxazosin).1 Priapism is a medical emergency that could result in penile tissue damage and permanent loss of potency if not treated immediately; therefore, patients should be advised to report promptly to their clinician or, if their clinician is unavailable, to seek alternative immediate medical attention if an erection occurs that persists longer than several (e.g., 4-6) hours or is painful.1,55,56

Experience to date with doxazosin under controlled conditions is limited to patients with normal liver function.1 However, because the drug is almost completely metabolized in the liver, particular caution should be exercised when using doxazosin in patients with impaired liver function or who are receiving other agents (e.g., cimetidine) that could influence hepatic clearance of the drug.1

The possibility of carcinoma of the prostate and other conditions associated with manifestations that mimic those of BPH should be excluded in any patient for whom doxazosin therapy for presumed BPH is being considered.1 No evidence of an effect on plasma concentrations of prostate specific antigen (PSA) has been observed in patients treated with doxazosin for up to 3 years.1

Doxazosin is contraindicated in patients with known sensitivity to the drug or any other quinazoline derivative (e.g., prazosin, terazosin).1

Pediatric Precautions

The manufacturer states that safety and efficacy of doxazosin in children and adolescents younger than 18 years of age have not been established.1,17 Some experts state that use of centrally acting antihypertensive agents (e.g., doxazosin) should be reserved for children who are not responsive to 2 or more of the preferred classes of antihypertensive agents (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, long-acting calcium-channel blockers, or thiazide diuretics).1150,1230 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Geriatric Precautions

Geriatric patients may be particularly susceptible to postural effects of α₁-adrenergic blocking agents such as doxazosin.7 (See Dosage and Administration: Dosage.) The manufacturer states that certain pharmacokinetic parameters (i.e., plasma half-life, oral clearance) were similar for geriatric individuals 65 years of age or older compared with younger adults.1 In addition, safety and efficacy of the drug in patients with BPH were similar in those 65 years of age or older compared with younger patients.1 Clinical studies of doxazosin in patients with hypertension did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.1 While other clinical experience has not revealed age-related differences in response, drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range.1 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.1

Mutagenicity and Carcinogenicity

The manufacturer states that there was no evidence of mutagenicity associated with doxazosin or its metabolites at the chromosomal or subchromosomal level in mutagenicity studies.1

No evidence of carcinogenicity was seen in rats receiving the maximally tolerated oral doxazosin dosage of 40 mg/kg daily (8 times the human AUC exposure) for up to 24 months.1 There also was no evidence of carcinogenicity in a similarly conducted study in mice receiving oral doxazosin for up to 18 months; however, the relevance, if any, of the findings of this study in mice is unclear since the maximally tolerated dosage was not employed.1

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rabbits and rats using doxazosin dosages up to 41 and 20 mg/kg daily (plasma concentrations 10 and 4 times the peak plasma concentration and AUC exposures of humans receiving a dosage of 12 mg daily) have not revealed evidence of harm to the fetus.1 Postnatal development (weight gain, anatomical features, reflexes) was delayed in some offspring of rats given maternal oral doxazosin dosages of 40-50 mg/kg daily,1 and decreased fetal survival was associated with dosages of 82 mg/kg daily (in rabbits).1 There are no adequate and controlled studies to date using doxazosin in pregnant women, and the drug should be used during pregnancy only when clearly needed.1

Fertility

Reproduction studies in male rats using oral doxazosin dosages of 20 mg/kg daily demonstrated a reversible decrease in fertility; however, oral dosages of 10 mg/kg or less daily were not associated with impaired fertility.1 There have been no reports of adverse effects of the drug on fertility in men.1

Lactation

Since it is not known whether doxazosin is distributed into human milk, the drug should be used with caution in nursing women.1 Accumulation of the drug has been observed in the milk of lactating rats given a single 1-mg/kg oral dose; in these rats, concentrations of radiolabeled doxazosin in milk were about 20 times greater than those in maternal plasma.1

Description

Doxazosin mesylate is a quinazoline-derivative postsynaptic α₁-adrenergic blocking agent.1,2,3,4,5,6 The drug is chemically and pharmacologically related to prazosin and terazosin.1,3,6 On a weight basis, the postsynaptic α₁-adrenergic blocking potency of doxazosin is half that of prazosin,3 and the α₁-receptor selectivity is one-fourth that of terazosin when tested in human prostate adenoma.17,18

Doxazosin reduces peripheral vascular resistance and blood pressure as a result of its vasodilating effects; the drug produces both arterial and venous dilation.1,2,3,4,6 Doxazosin reduces blood pressure in both supine and standing patients; the effect is most pronounced on standing blood pressure, and postural hypotension can occur.1,2,3,4,6 Doxazosin generally causes no change in heart rate or cardiac output in the supine position.1,2,3,4,6 Cardiovascular responses to exercise (e.g., increased heart rate and cardiac output) are maintained during doxazosin therapy.1,2,3,4,6

Effects of doxazosin on the cardiovascular system are mediated by the drug's activity at α₁-receptor sites on vascular smooth muscle.1,2,3,4,6α₁-Adrenergic receptors also are located in nonvascular smooth muscle (e.g., bladder trigone and sphincters, GI tract and sphincters, prostate adenoma and capsule, ureters, uterus)5,6 and in nonmuscular tissues (e.g., CNS, liver, kidneys).1,5 Because of the prevalence of α-receptors on the prostate capsule, prostate adenoma, and the bladder trigone and the relative absence of these receptors on the bladder body, α-blockers decrease urinary outflow resistance in men.1,5

Doxazosin may improve to a limited extent the serum lipid profile (e.g., small increases in high-density lipoprotein cholesterol concentrations [HDL] and HDL/total cholesterol ratio, small decreases in low-density lipoprotein cholesterol [LDL], total cholesterol, and triglyceride concentrations),1,2,3 and can reduce blood glucose and serum insulin concentrations.2 The drug does not appear to affect plasma renin activity appreciably.2,3,4

Commercially available extended-release tablets of doxazosin mesylate (Cardura^® XL) contain the drug in an oral osmotic delivery system formulation (elementary osmotic pump, GI therapeutic system [GITS]). The osmotic delivery system consists of an osmotically active core (comprised of a layer containing the drug and a layer containing osmotically active but pharmacologically inert components) that is surrounded by a semipermeable membrane with a laser-drilled delivery orifice and is designed to deliver the drug at an approximately constant rate over a 24-hour period (approximately zero-order delivery). The inert tablet ingredients remain intact and are eliminated in feces. Oral bioavailability from extended-release tablets at steady state with 4- or 8-mg doses is 54 or 59%, respectively, of that achieved with conventional (immediate-release) tablets. Food increases peak plasma concentrations and bioavailability achieved with extended-release tablets.

Additional Information

SumMon^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the labeling be consulted for information on the usual cautions, precautions, and contraindications concerning potential drug interactions and/or laboratory test interferences and for information on acute toxicity.

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