Pharmacodynamics

Benign Prostatic Hyperplasia (BPH)

Benign prostatic hyperplasia (BPH) is a common cause of urinary outflow obstruction in aging males. Severe BPH may lead to urinary retention and renal damage. A static and a dynamic component contribute to the symptoms and reduced urinary flow rate associated with BPH. The static component is related to an increase in prostate size caused, in part, by a proliferation of smooth muscle cells in the prostatic stroma. However, the severity of BPH symptoms and the degree of urethral obstruction do not correlate well with the size of the prostate. The dynamic component of BPH is associated with an increase in smooth muscle tone in the prostate and bladder neck. The degree of tone in this area is mediated by the alpha1 adrenoceptor, which is present in high density in the prostatic stroma, prostatic capsule and bladder neck. Blockade of the alpha1 receptor decreases urethral resistance and may relieve the obstruction and BPH symptoms. In the human prostate, doxazosin antagonizes phenylephrine (alpha1 agonist)-induced contractions, in vitro, and binds with high affinity to the alpha1c adrenoceptor. The receptor subtype is thought to be the predominant functional type in the prostate. Doxazosin acts within 1 to 2 weeks to decrease the severity of BPH symptoms and improve urinary flow rate. Since alpha1 adrenoceptors are of low density in the urinary bladder (apart from the bladder neck), doxazosin should maintain bladder contractility.

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 1. 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 SUMMARY OF EFFECTIVENESS DATA IN PLACEBO-CONTROLLED TRIALS

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 1) 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.

*p < 0.05 Compared to Placebo;
+p < 0.05 Compared to Baseline;
Doxazosin Titration to Maximum of 8 mg.

In BPH patients (N = 450) treated for up to 2 years in open-label studies, doxazosin therapy resulted in significant improvement above baseline in urinary flow rates and BPH symptoms. The significant effects of doxazosin were maintained over the entire treatment period.

Although blockade of alpha1 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 2). 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%).

TABLE 2 Mean Changes in Blood Pressure from Baseline to the Mean of the Final Efficacy Phase in Normotensives (Diastolic BP < 90 mmHg) in Two Double-blind, Placebo-Controlled U.S. Studies with Doxazosin 1 mg to 8 mg once daily.

	PLACEBO (N=85)		DOXAZOSIN (N=183)
* p ≤ 0.05 compared to placebo
Sitting BP (mmHg)	Baseline	Change	Baseline	Change
Systolic	128.4	-1.4	128.8	-4.9*
Diastolic	79.2	-1.2	79.6	-2.4*
Standing BP (mmHg)	Baseline	Change	Baseline	Change
Systolic	128.5	-0.6	128.5	-5.3*
Diastolic	80.5	-0.7	80.4	-2.6*

Pharmacokinetics

After oral administration of therapeutic doses, peak plasma levels of doxazosin mesylate 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 12 hypertensive subjects. Reductions of 18% in mean maximum plasma concentration and 12% in the area under the concentration-time curve occurred when doxazosin was administered with food. Neither of these differences was statistically or clinically significant.

Doxazosin is extensively metabolized in the liver, mainly by O-demethylation of the quinazoline nucleus or hydroxylation of the benzodioxan moiety. Although several active metabolites of doxazosin have been identified, the pharmacokinetics of these metabolites have not been characterized. 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. At the plasma concentrations achieved by therapeutic doses approximately 98% of the circulating drug is bound to plasma proteins.

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 crossover study in 24 normotensive subjects, the pharmacokinetics and safety of doxazosin were shown to be similar with morning and evening dosing regimens. The area under the curve 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 hr vs. 3.5 hr).

The pharmacokinetics of doxazosin in young (< 65 years) and elderly (≥ 65 years) subjects were similar for plasma half-life values and oral clearance. Pharmacokinetic studies in elderly patients and patients with renal impairment have shown no significant alterations compared to younger patients with normal renal function. Administration of a single 2 mg dose to patients with cirrhosis (Child-Pugh Class A) showed a 40% increase in exposure to doxazosin. There are only limited data on the effects of drugs known to influence the hepatic metabolism of doxazosin [e.g., cimetidine (see PRECAUTIONS: Drug Interactions)]. As with any drug wholly metabolized by the liver, use of doxazosin in patients with altered liver function should be undertaken with caution.

In two placebo-controlled studies, of normotensive and hypertensive BPH patients, in which doxazosin was administered in the morning and the titration interval was two weeks and one week, respectively, trough plasma concentrations of doxazosin were similar in the two populations. Linear kinetics and dose proportionality were observed.

Benign Prostatic Hyperplasia (BPH)

Doxazosin tablets are indicated for the treatment of both the urinary outflow obstruction and obstructive and irritative symptoms associated with BPH: obstructive symptoms (hesitation, intermittency, dribbling, weak urinary stream, incomplete emptying of the bladder) and irritative symptoms (nocturia, daytime frequency, urgency, burning). Doxazosin tablets may be used in all BPH patients whether hypertensive or normotensive. In patients with hypertension and BPH, both conditions were effectively treated with doxazosin tablet monotherapy. Doxazosin tablets provide rapid improvement in symptoms and urinary flow rate in 66% to 71% of patients. Sustained improvements with doxazosin tablets were seen in patients treated for up to 14 weeks in double-blind studies and up to 2 years in open-label studies.

Hypertension

Doxazosin tablets are also indicated for the treatment of hypertension. Doxazosin tablets may be used alone or in combination with diuretics, beta-adrenergic blocking agents, calcium channel blockers or angiotensin-converting enzyme inhibitors.

Syncope and "First-dose" Effect

Doxazosin, like other alpha-adrenergic blocking agents, can cause marked hypotension, especially in the upright position, with syncope and other postural symptoms such as dizziness. Marked orthostatic effects are most common with the first dose but can also occur when there is a dosage increase, or if therapy is interrupted for more than a few days. To decrease the likelihood of excessive hypotension and syncope, it is essential that treatment be initiated with the 1 mg dose. The 2 mg, 4 mg, and 8 mg tablets are not for initial therapy. Dosage should then be adjusted slowly (see DOSAGE AND ADMINISTRATION section) with evaluations and increases in dose every two weeks to the recommended dose. Additional antihypertensive agents should be added with caution.

Patients being titrated with doxazosin should be cautioned to avoid situations where injury could result should syncope occur, during both the day and night.

In an early investigational study of the safety and tolerance of increasing daily doses of doxazosin in normotensives beginning at 1 mg/day, only 2 of 6 subjects could tolerate more than 2 mg/day without experiencing symptomatic postural hypotension. In another study of 24 healthy normotensive male subjects receiving initial doses of 2 mg/day of doxazosin, seven (29%) of the subjects experienced symptomatic postural hypotension between 0.5 and 6 hours after the first dose necessitating termination of the study. In this study, 2 of the normotensive subjects experienced syncope. Subsequent trials in hypertensive patients always began doxazosin dosing at 1 mg/day resulting in a 4% incidence of postural side effects at 1 mg/day with no cases of syncope.

In multiple dose clinical trials in hypertension involving over 1,500 hypertensive patients with dose titration every one to two weeks, syncope was reported in 0.7% of patients. None of these events occurred at the starting dose of 1 mg and 1.2% (8/664) occurred at 16 mg/day.

In placebo-controlled, clinical trials in BPH, 3 out of 665 patients (0.5%) taking doxazosin reported syncope. Two of the patients were taking 1 mg doxazosin, while one patient was taking 2 mg doxazosin when syncope occurred. In the open-label, long-term extension follow-up of approximately 450 BPH patients, there were 3 reports of syncope (0.7%). One patient was taking 2 mg, one patient was taking 8 mg and one patient was taking 12 mg when syncope occurred. In a clinical pharmacology study, one subject receiving 2 mg experienced syncope.

If syncope occurs, the patient should be placed in a recumbent position and treated supportively as necessary.

Priapism

Rarely (probably less frequently than once in every several thousand patients), alpha1 antagonists, including doxazosin, have been associated with priapism (painful penile erection, sustained for hours and unrelieved by sexual intercourse or masturbation). Because this condition can lead to permanent impotence if not promptly treated, patients must be advised about the seriousness of the condition (see PRECAUTIONS: Information for Patients).

General

Information for Patients

(See Patient Leaflet)

Patients should be made aware of the possibility of syncopal and orthostatic symptoms, especially at the initiation of therapy, and urged to avoid driving or hazardous tasks for 24 hours after the first dose, after a dosage increase, and after interruption of therapy when treatment is resumed. They should be cautioned to avoid situations where injury could result should syncope occur during initiation of doxazosin therapy. They should also be advised of the need to sit or lie down when symptoms of lowered blood pressure occur, although these symptoms are not always orthostatic, and to be careful when rising from a sitting or lying position. If dizziness, lightheadedness, or palpitations are bothersome they should be reported to the physician, so that dose adjustment can be considered. Patients should also be told that drowsiness or somnolence can occur with doxazosin or any selective alpha1 adrenoceptor antagonist, requiring caution in people who must drive or operate heavy machinery.

Patients should be advised about the possibility of priapism as a result of treatment with alpha1 antagonists. Patients should know that this adverse event is very rare. If they experience priapism, it should be brought to immediate medical attention for if not treated promptly it can lead to permanent erectile dysfunction (impotence).

Drug/Laboratory Test Interactions

Doxazosin does not affect the plasma concentration of prostate specific antigen in patients treated for up to 3 years. Both doxazosin, an alpha1 inhibitor, and finasteride, a 5-alpha reductase inhibitor, are highly protein bound and hepatically metabolized. There is no definitive controlled clinical experience on the concomitant use of alpha1 inhibitors and 5-alpha reductase inhibitors at this time.

Impaired Liver Function

Doxazosin should be administered with caution to patients with evidence of impaired hepatic function or to patients receiving drugs known to influence hepatic metabolism (see CLINICAL PHARMACOLOGY: Pharmacokinetics).

Leukopenia/Neutropenia

Analysis of hematologic data from hypertensive patients receiving doxazosin in controlled hypertension clinical trials showed that the mean WBC (N = 474) and mean neutrophil counts (N = 419) were decreased by 2.4% and 1%, respectively, compared to placebo, a phenomenon seen with other alpha blocking drugs. In BPH patients the incidence of clinically significant WBC abnormalities was 0.4% (2/459) with doxazosin and 0% (0/147) with placebo, with no statistically significant difference between the two treatment groups. A search through a data base of 2,400 hypertensive patients and 665 BPH patients revealed 4 hypertensives in which drug-related neutropenia could not be ruled out and one BPH patient in which drug-related leukopenia could not be ruled out. Two hypertensives had a single low value on the last day of treatment. Two hypertensives had stable, non-progressive neutrophil counts in the 1000/mm3 range over periods of 20 and 40 weeks. One BPH patient had a decrease from WBC count of 4800/mm3 to 2700/mm3 at the end of the study; there was no evidence of clinical impairment. In cases where follow-up was available the WBCs and neutrophil counts returned to normal after discontinuation of doxazosin. No patients became symptomatic as a result of the low WBC or neutrophil counts.

Drug Interactions

Most (98%) of plasma doxazosin is protein bound. In vitro data in human plasma indicate that doxazosin has no effect on protein binding of digoxin, warfarin, phenytoin or indomethacin. There is no information on the effect of other highly plasma protein bound drugs on doxazosin binding. Doxazosin has been administered without any evidence of an adverse drug interaction to patients receiving thiazide diuretics, beta-blocking agents, and nonsteroidal anti-inflammatory drugs. In a placebo-controlled trial in normal volunteers, the administration of a single 1 mg dose of doxazosin on day 1 of a 4-day regimen of oral cimetidine (400 mg twice daily) resulted in a 10% increase in mean AUC of doxazosin (p = 0.006), and a slight but not statistically significant increase in mean Cmax and mean half-life of doxazosin. The clinical significance of this increase in doxazosin AUC is unknown.

In clinical trials, doxazosin tablets have been administered to patients on a variety of concomitant medications; while no formal interaction studies have been conducted, no interactions were observed. Doxazosin tablets have been used with the following drugs or drug classes: 1) analgesic/anti-inflammatory (e.g., acetaminophen, aspirin, codeine and codeine combinations, ibuprofen, indomethacin); 2) antibiotics (e.g., erythromycin, trimethoprim and sulfamethoxazole, amoxicillin); 3) antihistamines (e.g., chlorpheniramine); 4) cardiovascular agents (e.g., atenolol, hydrochlorothiazide, propranolol); 5) corticosteroids; 6) gastrointestinal agents (e.g., antacids); 7) hypoglycemics and endocrine drugs; 8) sedatives and tranquilizers (e.g., diazepam); 9) cold and flu remedies.

Concomitant administration of doxazosin tablets with a phosphodiesterase-5 (PDE-5) inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension (see DOSAGE AND ADMINISTRATION).

Cardiac Toxicity in Animals

An increased incidence of myocardial necrosis or fibrosis was displayed by Sprague-Dawley rats after 6 months of dietary administration at concentrations calculated to provide 80 mg doxazosin/kg/day and after 12 months of dietary administration at concentrations calculated to provide 40 mg doxazosin/kg/day (AUC exposure in rats 8 times the human AUC exposure with a 12 mg/day therapeutic dose). Myocardial fibrosis was observed in both rats and mice treated in the same manner with 40 mg doxazosin/kg/day for 18 months (exposure 8 times human AUC exposure in rats and somewhat equivalent to human Cmax exposure in mice). No cardiotoxicity was observed at lower doses (up to 10 or 20 mg/kg/day, depending on the study) in either species. These lesions were not observed after 12 months of oral dosing in dogs at maximum doses of 20 mg/kg/day [maximum plasma concentrations (Cmax) in dogs 14 times the Cmax exposure in humans receiving a 12 mg/day therapeutic dose] and in Wistar rats at doses of 100 mg/kg/day (Cmax exposures 15 times human Cmax exposure with a 12 mg/day therapeutic dose). There is no evidence that similar lesions occur in humans.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

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.

Pregnancy

Nursing Mothers

Studies in lactating rats given a single oral dose of 1 mg/kg of [2-14C]-doxazosin indicate that doxazosin accumulates in rat breast milk with a maximum concentration about 20 times greater than the maternal plasma concentration. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when doxazosin is administered to a nursing mother.

Pediatric Use

The safety and effectiveness of doxazosin as an antihypertensive agent have not been established in children.

Geriatric Use

The safety and effectiveness profile of doxazosin in BPH was similar in the elderly (age ≥ 65 years) and younger (age < 65 years) patients.

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 3) 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. The adverse events when the incidence in the doxazosin group was at least 1% are summarized in Table 3. No significant difference in the incidence of adverse events compared to placebo was seen except for dizziness, fatigue, hypotension, edema and dyspnea. Dizziness and dyspnea appeared to be dose-related.

In these placebo-controlled studies of 665 doxazosin patients, treated for a mean of 85 days, additional adverse reactions have been reported. These are less than 1% and not distinguishable from those that occurred in the placebo group. Adverse reactions with an incidence of less than 1% but of clinical interest are (doxazosin vs. placebo): Cardiovascular System: angina pectoris (0.6% vs. 0.7%), postural hypotension (0.3% vs. 0.3%), syncope (0.5% vs. 0%), tachycardia (0.9% vs. 0%); Urogenital System: dysuria (0.5% vs. 1.3%), and Psychiatric Disorders: libido decreased (0.8% vs. 0.3%). The safety profile in patients treated for up to three years was similar to that in the placebo-controlled studies.

The majority of adverse experiences with doxazosin were mild.

Hypertension

Doxazosin mesylate has been administered to approximately 4,000 hypertensive patients, of whom 1,679 were included in the hypertension clinical development program. In that program, minor adverse effects were frequent, but led to discontinuation of treatment in only 7% of patients. In placebo-controlled studies adverse effects 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. The major reasons for discontinuation were postural effects (2%), edema, malaise/fatigue, and some heart rate disturbance, each about 0.7%.

In controlled hypertension clinical trials directly comparing doxazosin to placebo there was no significant difference in the incidence of side effects, except for dizziness (including postural), weight gain, somnolence and fatigue/malaise. 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 4 summarizes those adverse experiences (possibly/probably related) reported for patients in these hypertension studies where the prevalence rate in the doxazosin group was at least 0.5% or where the reaction is of particular interest.

Additional adverse reactions have been reported, but these are, in general, not distinguishable from symptoms that might have occurred in the absence of exposure to doxazosin. The following adverse reactions occurred with a frequency of between 0.5% and 1%: syncope, hypoesthesia, increased sweating, agitation, increased weight. The following additional adverse reactions were reported by < 0.5% of 3,960 patients who received doxazosin in controlled or open, short- or long-term clinical studies, including international studies. Cardiovascular System: angina pectoris, myocardial infarction, cerebrovascular accident; Autonomic Nervous System: pallor; Metabolic: thirst, gout, hypokalemia; Hematopoietic: lymphadenopathy, purpura; Reproductive System: breast pain; Skin Disorders: alopecia, dry skin, eczema; Central Nervous System: paresis, tremor, twitching, confusion, migraine, impaired concentration; Psychiatric: paroniria, amnesia, emotional lability, abnormal thinking, depersonalization; Special Senses: parosmia, earache, taste perversion, photophobia, abnormal lacrimation; Gastrointestinal System: increased appetite, anorexia, fecal incontinence, gastroenteritis; Respiratory System: bronchospasm, sinusitis, coughing, pharyngitis; Urinary System: renal calculus; General Body System: hot flushes, back pain, infection, fever/rigors, decreased weight, influenza-like symptoms.

Doxazosin has not been associated with any clinically significant changes in routine biochemical tests. No clinically relevant adverse effects were noted on serum potassium, serum glucose, uric acid, blood urea nitrogen, creatinine or liver function tests. Doxazosin has been associated with decreases in white blood cell counts (see PRECAUTIONS: Leukopenia/Neutropenia).

In post-marketing experience the following additional adverse reactions have been reported: Autonomic Nervous System: priapism; Central Nervous System: hypoesthesia; Endocrine System: gynecomastia; Gastrointestinal System: vomiting; General Body System: allergic reaction; Heart Rate/Rhythm: bradycardia; Hematopoietic: leukopenia, thrombocytopenia; Liver/Biliary System: hepatitis, hepatitis cholestatic; Respiratory System: bronchospasm aggravated; Skin Disorders: urticaria; Special Senses: Intraoperative Floppy Iris Syndrome (see PRECAUTIONS: General: Cataract Surgery); Urinary System: hematuria, micturition disorder, micturition frequency, nocturia.

Benign Prostatic Hyperplasia 1 mg to 8 mg Once Daily

The initial dosage of doxazosin tablets is 1 mg, given once daily in the a.m. or p.m. Depending on the individual patient's urodynamics and BPH symptomatology, dosage may then be increased to 2 mg and thereafter to 4 mg and 8 mg once daily, the maximum recommended dose for BPH. The recommended titration interval is 1 to 2 weeks. Blood pressure should be evaluated routinely in these patients.

Hypertension 1 mg to 16 mg Once Daily

The initial dosage of doxazosin tablets is 1 mg given once daily. Depending on the individual patient's standing blood pressure response (based on measurements taken at 2 to 6 hours post-dose and 24 hours post-dose), dosage may then be increased to 2 mg and thereafter if necessary to 4 mg, 8 mg and 16 mg to achieve the desired reduction in blood pressure. Increases in dose beyond 4 mg increase the likelihood of excessive postural effects including syncope, postural dizziness/vertigo and postural hypotension. At a titrated dose of 16 mg once daily the frequency of postural effects is about 12% compared to 3% for placebo.