Doxazosin-1 Product Monograph

INDICATIONS AND CLINICAL USE

Hypertension

DOXAZOSIN (doxazosin mesylate) is indicated in the treatment of mild to moderate essential hypertension. It is employed in a general treatment program in association with a thiazide diuretic and/or other antihypertensive agents, as needed, for proper patient response.

DOXAZOSIN may be tried as a sole therapy in those patients for whom treatment with other agents caused adverse effects or is inappropriate.

Benign Prostatic Hyperplasia (BPH)

DOXAZOSIN is also indicated for the treatment of symptoms of benign prostatic hyperplasia

(BPH). The onset of effect is rapid, with improvement in peak flow and symptoms observed within 1 to 2 weeks. The effect on these variables was maintained over the entire study duration

(up to 4 years). DOXAZOSIN may be used in BPH patients who are either hypertensive or normotensive. While the reduction in blood pressure in normotensive patients with BPH is clinically insignificant, patients with hypertension and BPH have both conditions effectively treated with doxazosin monotherapy (see DOSAGE AND ADMINISTRATION for dosage regimens).

A number of clinical conditions can mimic symptomatic BPH (i.e., stricture of urethra, stricture of bladder neck, urinary bladder stones, neurogenic bladder dysfunction secondary to diabetes,

Parkinsonism, etc.). These conditions should therefore be ruled out before doxazosin therapy is initiated.

CONTRAINDICATIONS

It is contraindicated in patients with a known sensitivity to doxazosin mesylate or quinazolines.

WARNINGS

Syncope and “First Dose” Effect

DOXAZOSIN (doxazosin mesylate) can cause marked hypotension, especially postural hypotension and syncope in association with the first dose or first few doses of therapy. A similar effect can occur if therapy is reinstated following interruption for more than a few doses.

Postural effects are most likely to occur between 2 and 6 hours after dose.

In controlled studies of doxazosin mesylate the incidence of syncopal episodes was 0.7%. An initial dose of 1 mg/day resulted in a 4% incidence of postural side effects with no cases of syncope. In controlled clinical trials for BPH in normotensive patients, there was a 0.2% occurrence of syncope with doxazosin mesylate. In controlled trials in patients with both BPH and hypertension receiving doxazosin mesylate, the incidence of syncope was 0.8%.

The likelihood of syncopal episodes or excessive hypotension can be minimized by limiting the initial dose of DOXAZOSIN to 1 mg, by increasing the dosage slowly, and by introducing any additional antihypertensive drugs into the patient's regimen with caution (see DOSAGE AND

ADMINISTRATION).

Patients should be advised of the possibility of syncopal and orthostatic symptoms, and to avoid driving or hazardous tasks for 24 hours: after the initial dose of DOXAZOSIN, after the dose is increased, and after interruption of therapy when treatment is resumed. They should be cautioned to avoid situations where injury could result should syncope occur.

If syncope occurs, the patient should be placed in the supine position. If this measure is inadequate, volume expansion with intravenous fluids or vasopressor therapy may be used. A transient hypotensive response is not a contraindication to further doses of doxazosin mesylate.

Orthostatic Hypotension

While syncope is the most severe orthostatic effect of doxazosin mesylate, other symptoms of lowered blood pressure such as dizziness, lightheadedness or vertigo can occur. These were common in clinical trials in hypertension, occurring in up to 23% of all patients treated and

causing discontinuation of therapy in about 2%. In placebo-controlled titration trials, there was an increased frequency of orthostatic effects in patients given 8 mg or more (10%) compared to patients given 1 to 4 mg (5%) or placebo (3%).

In placebo-controlled trials in BPH, the incidence of orthostatic hypotension with doxazosin mesylate was ≤1%. With maintenance doses of up to 8 mg/day in normotensive patients with

BPH, the average decreases in both sitting and standing blood pressure were small: 5/2 mm Hg with doxazosin mesylate and 1/1 mm Hg with placebo.

Patients with occupations in which such events represent potential problems should be treated with particular caution.

Concomitant administration of doxazosin with a PDE-5 inhibitor such as sildenafil, tadalafil or vardenafil, should be used with caution as it may lead to symptomatic hypotension.

Patients should be advised of the need to lie down when symptoms of lowered blood pressure occur, and to be careful when arising from a 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 mesylate, requiring caution in people who must drive or operate heavy machinery.

If hypotension occurs, place the patient in the recumbent position and institute supportive measures as necessary.

Priapism

Rarely (probably less frequently than once in every several thousand patients), α₁-antagonists such as doxazosin have been associated with priapism. Because this condition can lead to permanent impotence if not promptly treated, patients should be advised about the seriousness of the condition.

Hematological Events

Analysis of hematologic data from patients receiving doxazosin mesylate in controlled clinical trials showed that the mean white blood cell (WBC) (n=474) and mean neutrophil counts

(n=419) were decreased by 2.4% and 1.0% respectively, compared to placebo. A search through a database of 2,400 patients revealed 4 cases in which drug-related neutropenia could not be ruled out. Two had a single low value on the last day of treatment. Two had stable, non-progressive neutrophil counts in the 1000/mm³ range over periods of 20 and 40 weeks. No patients became symptomatic as a result of the low WBC or neutrophil counts.

In BPH patients treated with doxazosin, the incidence of clinically significant WBC abnormalities was 0.4%.

In post-marketing experience, rare cases of hematopoietic events such as leukopenia and thrombocytopenia have been reported.

Hepatic Events

In post-marketing experience, rare cases of abnormal liver function tests, cholestasis, jaundice and hepatitis have been reported.

Peripheral Edema

Fluid retention resulting in weight gain may occur during doxazosin mesylate therapy. In placebo-controlled monotherapy trials, patients receiving doxazosin mesylate gained a mean of

0.6 kg compared to a mean loss of 0.1 kg for placebo-treated patients. The overall incidence of body weight gain reported as a side effect in controlled clinical trials was 0.8%.

PRECAUTIONS

General

Doxazosin mesylate therapy does not modify the natural history of benign prostatic hyperplasia

(BPH). It does not retard or stop the progression of BPH, nor does it improve urine flow sufficiently to significantly reduce the residual urine volume. However, significant reduction of

the mean residual volume have been shown in patients with baseline residual volumes of

>50 mL. The patient may continue to be at risk of developing urinary retention and other BPH complications during doxazosin therapy.

Long-term Safety and Efficacy

The long-term safety and efficacy (i.e., >4 years) has not yet been established for the use of doxazosin in the treatment of benign prostatic hyperplasia.

Prostatic Cancer

Carcinoma of the prostate and BPH cause many of the same symptoms. These two diseases frequently coexist. Therefore, patients thought to have BPH should be examined prior to starting

DOXAZOSIN therapy to rule out the presence of carcinoma of the prostate.

DOXAZOSIN should not be used in patients with PSA >10 ng/mL unless cancer of the prostate has been ruled out.

Ophthalmologic

The Intraoperative Floppy Iris Syndrome (IFIS, a variant of small pupil syndrome) has been observed during cataract surgery in some patients on or previously treated with alpha₁ blockers.

As IFIS may lead to increased procedural complications during the operation, current or past use of alpha blockers should be made known to the ophthalmologic surgeon in advance of surgery.

Use in Patients with Impaired Liver Function

As with any drug wholly metabolized by the liver, DOXAZOSIN should be administered with caution to patients with evidence of impaired hepatic function or to patients receiving drugs known to influence hepatic metabolism.

Use in Patients with Impaired Renal Function

The use of DOXAZOSIN in patients with impaired renal function requires careful monitoring.

Clinical studies indicate that the disposition of doxazosin mesylate in patients with renal insufficiency is similar to that in patients with normal renal function, however accumulation of the drug with chronic dosing may occur. Less than 10% of the dose of doxazosin is excreted in the urine as unchanged drug and metabolites.

Concomitant Conditions

Doxazosin should not be prescribed to patients with symptomatic BPH who have the following concomitant conditions:

Chronic urinary retention, high residual urine (over 200 mL), peak urine flow of 5 mL/s or less, history of prior prostatic surgery, chronic fibrous or granulomatous prostatitis, urethral stricture, history of pelvic irradiation, presence of prostatic calculi, presence of large median lobe of prostate, presence of calculi in urinary bladder, recent history of epididymitis, gross hematuria, presence of neurogenic bladder dysfunction (diabetes mellitus, Parkinsonism, uninhibited neurogenic bladder, etc.), hydronephrosis, presence of carcinoma of the prostate. Nor should doxazosin be prescribed to patients having experienced a myocardial infarction, transient ischemic attacks, or cerebrovascular accident within the past 6 months.

Use in Pregnancy

There are no studies in pregnant women. DOXAZOSIN is not recommended in pregnant women unless the potential benefit outweighs the potential risk to mother and fetus.

Doxazosin mesylate crosses the placental barrier.

Studies in pregnant rabbits and rats at daily oral doses of up to 40 and 20 mg/kg, respectively, have revealed no evidence of teratogenic effect. A dosage regimen of 82 mg/kg/day in the rabbit was associated with reduced fetal survival, an increase in embryomortality as well as increases in fetal and placental weights.

In peri- and post-post-natal studies in rats, postnatal development at maternal doses of 40 or

50 mg/kg/day of doxazosin was delayed as evidenced by slower body weight gain and a slightly later appearance of anatomical features and reflexes.

Use in Nursing Mothers

Studies in lactating rats indicate that doxazosin accumulates in rat breast milk. It is not known whether this drug is excreted in human milk. Caution should be exercised when DOXAZOSIN is administered to a nursing mother and in general, nursing should be interrupted.

Use in Children

The use of DOXAZOSIN is not recommended in children since safety and efficacy have not been established.

Use in Elderly

DOXAZOSIN should be used cautiously in elderly patients because of the possibility of postural hypotension. There was an age-related trend towards an increased incidence of postural hypotension and postural dizziness in elderly hypertensive patients treated with this drug.

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.

Myocardial fibrosis was observed in both rats and mice treated in the same manner with 40 mg doxazosin/kg/day for 18 months. 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 and Wistar rats at maximum doses of 20 and 100 mg/kg/day, respectively. There is no evidence that similar lesions occur in humans.

Drug Interactions

Doxazosin is highly (98%) bound to plasma protein. In vitro data in human plasma indicates that doxazosin mesylate has no effect on protein binding of digoxin, warfarin, phenytoin or indomethacin.

Doxazosin mesylate has been administered to patients receiving thiazide diuretics, beta-adrenergic blocking agents and non-steroidal anti-inflammatory drugs. No unexpected interactions were reported. An additive hypotensive effect was observed when doxazosin mesylate was co-administered with thiazide diuretics and beta-adrenergic blocking agents. There is limited experience with doxazosin mesylate in combination with ACE inhibitors or calcium channel blockers.

Digoxin

Serum digoxin concentrations were not affected by treatment with doxazosin.

Cimetidine

In a randomized, open-label, placebo-controlled, cross-over study in 22 healthy male subjects, the single co-administration of 1 mg doxazosin with 400 mg b.i.d. cimetidine resulted in a 10% increase in mean AUC of doxazosin (p=0.006), and a slight but not statistically significant increase in mean C_max and mean half-life of doxazosin. The effect of further administration of cimetidine has not been studied.

PDE-5 Inhibitors

Symptomatic hypotension has been reported during the concomitant use of PDE-5 inhibitors

(e.g. sildenafil, tadalafil, vardenafil) and doxazosin mesylate (see WARNINGS).

ADVERSE REACTIONS

Hypertension

Doxazosin mesylate has been administered to approximately 4,000 patients in clinical trials of

whom 1,679 patients were included in controlled trials. The most serious adverse event occurring in the controlled clinical trials was syncope occurring in 0.7% of patients and resulting in a discontinuation rate of 0.2%.

The most frequent adverse events in controlled clinical trials were: headache (16.5%), fatigue/malaise (14.8%), dizziness (14.6%), postural dizziness (8.7%) and edema (6.6%).

Discontinuation of doxazosin mesylate due to adverse events was required in 7% of patients.

Adverse events which occurred with an incidence of ≥1% in the controlled clinical trials in patients with mild to moderate essential hypertension were as shown in the following table.

The following other adverse events occurred in hypertensive patients with an incidence of <1% in controlled clinical trials (n=1,679): postural hypotension, arrhythmia, syncope, pruritus, arthralgia, agitation, flushing, tremor, paroniria, tinnitus, vomiting, epistaxis, sinusitis, bronchospasm/bronchitis, urinary incontinence, urinary disorder, face edema, weight increase, general edema, angina pectoris, peripheral ischemia, hypotension, paresis, twitching, migraine, amnesia, movement disorders, emotional lability, abnormal thinking, depersonalization, pallor, hypertonia, ataxia, thirst, gout, hypokalemia, lymphadenopathy, purpura, breast pain, alopecia, dry skin, eczema, taste perversion, photophobia, abnormal lacrimation, increased appetite, anorexia, fecal incontinence, coughing, pharyngitis, hot flushes, back pain, infection, fever/rigors and muscle weakness.

Benign Prostatic Hyperplasia

Doxazosin mesylate has been administered once daily to 665 both hypertensive and normotensive patients with BPH in controlled clinical trials. The most serious adverse event occurring in the controlled trials was syncope (0.5%).

The most frequent adverse events in controlled trials were dizziness (15.6%), headache (9.8%)

and fatigue (8%).

Discontinuation rate of doxazosin mesylate due to adverse events was 9%.

Adverse events which occurred with an incidence of ≥1% in the controlled clinical trials in

normotensive or hypertensive patients with BPH were as shown in the following table.

*Placebo-controlled clinical trials; treated with doxazosin from 1 to 203 days.

**Open label extension of 3 placebo-controlled clinical trials; treated for up to 50 months.

The following other adverse events occurred in normotensive or hypertensive patients with BPH with an incidence of <1% in short-term controlled clinical trials (n=665): tachycardia, angina, syncope, postural hypotension, pruritus, rash, myalgia, paresthesia, flushing, conjunctivitis, tinnitus, decreased libido, depression, nervousness, flatulence, rhinitis, epistaxis, carcinoma, dysuria, asthenia, influenza-like symptoms, viral infection, fever, weight increase, malaise, myocardial infarction, bradycardia, sudden death, pallor, hyperglycemia, gout, lymphadenopathy, prostatic disorder, ejaculation failure, epididymitis, dry skin, genital pruritus, urticaria, maculopapular rash, erythematous rash, aggravated psoriasis, eczema, hypoesthesia, hypertonia, leg cramps, confusion, speech disorder, ataxia, abnormal thinking, depersonalization, paroniria, emotional lability, impaired concentration, amnesia, earache, taste perversion, eye pain, visual field defect, cataract, melena, constipation, vomiting, gingivitis, increased appetite, coughing, bronchospasm, bronchitis, upper respiratory tract infection, sinusitis, pneumonia, urinary retention, micturition disorder, abnormal urine, renal pain, urinary incontinence, cystitis, arthritis, tendon disorder, arthalgia, hernia, rigors, hot flushes, allergy, sepsis, fungal infection, hematuria and subarachnoid hemorrhage.

The following other adverse events occurred in normotensive or hypertensive patients with BPH with an incidence of <1% in long-term controlled clinical trials (n=450): convulsions, encephalopathy, hypokinesia, migraine, fever, malaise, rigor, enlarged abdomen, allergic reaction/allergy, weight increase, nervousness, amnesia, anxiety, depersonalization, impaired concentration, abnormal thinking, flatulence, melena, vomiting, rectal hemorrhage, abnormal semen, tooth disorder, increased appetite, diverticulitis, esophagitis, gastric ulcer, tenesmus, tongue disorder, tooth hypoplasia, syncope, aneurysm, cardiac failure, abnormal ECG, hypertension, epistaxis, pharyngitis, rhinitis, bronchitis, pulmonary carcinoma, epididymitis, perineal pain, cystitis, dysuria, polyuria, urinary incontinence, oliguria, abnormal urine, increased sweating, seborrhea, maculopapular rash, skin disorder, nail disorder, photosensitivity reaction, pruritus, skin hypertrophy, urticaria, conjunctivitis, diplopia, eye abnormality, eye pain, myopia, visual field defect, myalgia, arthritis, polymyalgia rheumatica, atrial fibrillation, tachycardia, extra systoles, angina pectoris, myocardial ischemia, flushing, dry mouth, aggravated hypertension, sexual dysfunction, purpura, deafness, earache, cerebrovascular

disorder/accident, intermittent claudication, carcinoma, herpes simplex, herpes zoster, fungal infection, otitis media, dehydration, hyperglycemia, hyperuricemia, cholelithiasis, SGOT increase, SGPT increase and breast neoplasm.

Data from long-term (up to 50 months), open BPH studies (n=450) indicate higher rates of dizziness in younger hypertensive (27%) and normotensive (22%) patients, impotence in younger hypertensive (8%) patients, and discontinuation rates in patients due to adverse events

(16.7%) compared to data from short-term placebo-controlled BPH studies (n=665).

Uncontrolled Trials and Post-Marketing Experience

The following additional adverse events have also been reported in patients with essential hypertension and in normotensive or hypertensive patients with BPH: parosmia, renal calculus, priapism, ejaculation disorders such as retrograde ejaculation, jaundice, cholestasis and hepatitis.

Intraoperative Floppy Iris Syndrome (see PRECAUTIONS, Ophthalmologic) and gynecomastia.

Laboratory Abnormalities

No clinically relevant adverse effects were noted on serum potassium, serum glucose, uric acid, blood urea nitrogen or creatinine. Decreases in white blood cells, neutrophils, platelets (see

WARNINGS), hemoglobin and hematocrit have been reported. Abnormal liver function tests have occurred.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

No data are available regarding overdosage with doxazosin mesylate in humans.

Should administration of doxazosin mesylate lead to hypotension, support of the cardiovascular system is of first importance. Restoration of blood pressure and normalization of heart rate may be accomplished by keeping the patient in the supine position. If this measure is inadequate,

shock should first be treated with volume expanders. If necessary, vasopressors should be used.

Renal function should be monitored and supported as needed. As doxazosin mesylate is highly protein bound, dialysis may not be of benefit.

DOSAGE AND ADMINISTRATION

Dosage must be individualized. DOXAZOSIN (doxazosin mesylate) may be administered either in the morning or in the evening.

The absorption of DOXAZOSIN is not affected by food.

When DOXAZOSIN is being added to existing antihypertensive therapy, the patient should be carefully monitored for the occurrence of hypotension (see WARNINGS – Syncope and “First

Dose” Effect). If a diuretic or other antihypertensive agent is being added to a DOXAZOSIN regimen, reducing the dose of DOXAZOSIN and retitration, with careful monitoring, may be necessary.

If DOXAZOSIN administration is discontinued for several days, or longer, therapy should be reinstituted using the initial dosing regimen.

Hypertension - 1 to 16 mg Once Daily

The initial dose of DOXAZOSIN in patients with hypertension is 1 mg given once daily and this dose should not be exceeded. This starting dose is intended to minimize postural hypotensive effects. The maximum reduction in blood pressure normally occurs between 2 and 6 hours after a dose.

The dose may be slowly increased to achieve the desired blood pressure response. The usual dose range is 1 to 8 mg once daily. The maximum recommended daily dose is 16 mg once daily.

Increases in dose beyond 4 mg increased 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.

Benign Prostatic Hyperplasia - 1 to 8 mg Once Daily

The initial dosage of DOXAZOSIN is 1 mg given once daily (see WARNINGS – Syncope and

“First Dose” Effect). 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. The recommended titration interval is 1 to 2 weeks.

Blood pressure should be evaluated routinely in these patients.

DOXAZOSIN should be discontinued if the drug has been increased to the maximum tolerated dose and improvement in urinary flowmetry is less than 25%, or if doxazosin side effects are more bothersome than BPH symptoms, or if the patient develops a urinary complication secondary to BPH while on doxazosin therapy.

PHARMACEUTICAL INFORMATION

Trade Name: DOXAZOSIN

Proper Name: Doxazosin mesylate

Chemical Name: 1-(4-Amino-6,7-dimethyoxy-2-quinazolinyl)-4-(1,4-benzodioxan-2 ylcarbonyl) piperazine methanesulfonate

Structural Formula:

Molecular Formula: C₂₃H₂₅N₅O₅CH₄SO₃

Molecular Weight: 547.6 g/mol

Description: Doxazosin mesylate is a white to off-white crystalline solid of uniform appearance. It is freely soluble in dimethylsulphoxide, soluble in dimethylformamide, slightly soluble in methanol, ethanol, and water

(0.8% w/v at 25°C), and very slightly soluble in acetone and methylene chloride. The pKa of the doxazosin moiety is 6.93 at 25°C and the melting point of doxazosin mesylate is 273.7°C.

Stability and Storage Recommendations

Store between 15°C and 30°C.

AVAILABILITY OF DOSAGE FORMS

1 mg: Each white, round tablet, imprinted “DOXA 1” on one side and plain on the other side, contains: Doxazosin mesylate equivalent to doxazosin 1 mg. Non-medicinal ingredients:

lactose, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate and sodium starch glycolate. Available in HDPE bottles of 100.

2 mg: Each white, oblong tablet, imprinted “DOXA” on one side and score “2” on the other side, contains: Doxazosin mesylate equivalent to doxazosin 2 mg. Non-medicinal ingredients: lactose, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate and sodium starch glycolate. Available in HDPE bottles of 100.

4 mg: Each white, lozenge-shaped tablet, imprinted “DOXA” on one side and score “4” on the other side, contains: Doxazosin mesylate equivalent to doxazosin 4 mg. Non-medicinal ingredients: lactose, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate and sodium starch glycolate. Available in HDPE bottles of 100.

PHARMACOLOGY

Animal Pharmacology - In Vivo

In anaesthetized cats, doxazosin caused adrenaline reversal and was more effective in antagonizing pressor responses to phenylephrine (ED₅₀=0.06 mg/kg, i.v.) than to noradrenaline,

(ED₅₀<10 mg/kg, i.v.) indicating selective effect on post-junctional alpha₁- as opposed to alpha₂-adrenoceptors. This was confirmed by the lack of effect of doxazosin on the alpha₂-mediated pressor responses induced by alpha-methylnor-adrenaline. The lack of effect of doxazosin on pre-junctional alpha₂-adrenoceptors was confirmed in anaesthetized dogs.

Animal Pharmacology - In Vitro

In the perfused isolated rabbit ear artery and in the rabbit pulmonary artery rings, doxazosin had a selective effect on post-synaptic alpha₁-adrenoceptors. The superfused rabbit pulmonary artery preparation was used to show that doxazosin is highly selective (pre-synaptic activity

EC₂₀=2 x 10^-5 M vs. post-synaptic activity EC₂₀=2.4 x 10^-8 M); for the post- as opposed to the pre-junctional alpha receptors in this tissue.

Miscellaneous Actions

At high doses, doxazosin increased both alcohol and pentobarbitone sleeping time in mice and may possess mild CNS sedative activity per se, increased basal gastric acid secretion and gastrointestinal motility in rats, and had antidiuretic activity in normotensive rats and dogs.

Human Pharmacology

Hypertension

A comparison of the blood pressure lowering effect of doxazosin mesylate in patients 65 years and over (n=204), and those below 65 years (n= 1,344) show similar falls in blood pressure. The changes in standing systolic/diastolic pressures were -15/-12 mm Hg for the elderly and -13/-

11 mm Hg for the under 65-years groups, respectively.

Pharmacokinetic studies at steady state in hypertensive patients given doxazosin doses of 2 to

16 mg once daily showed linear kinetics and dose proportionality. In two studies, following the

administration of 2 mg orally once daily, the mean accumulation ratios (steady state AUC vs.

first dose AUC) were 1.2 and 1.7.

Benign Prostatic Hyperplasia (BPH)

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 mesylate.

The results from the three placebo-controlled studies (n=609) showing significant efficacy with

4 mg and 8 mg doxazosin are summarized in Table 2. In all three studies, doxazosin mesylate 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 mesylate in Studies 1 and 2, compared to 0.1 to 0.7 mL/sec with placebo.

Table 2. Summary of effectiveness data in placebo controlled trials

^a AUA questionnaire (range 0 to 30) in studies 1 and 3. Modified Boyarsky Questionnaire (range 7 to 39) in study 2. ^b Change is to endpoint.

^c Change is to fixed-dose efficacy phase, 22 to 26 hours post-date for study 2.

^d Study in hypertensives with BPH.

^e 36 patients received a dose of 8 mg of doxazosin mesylate. *(**) p<0.05 (0.01) compared to placebo mean change.

In one fixed dose study (study 2) of dozaxosin mesylate therapy (4 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 2) compared to placebo (0.1 mL/sec). In this study, the only study in which weekly evaluations were made, significant improvement with dozaxosin mesylate 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 mesylate (34 to 42%) than placebo (13 to 17%). A significantly greater improvement was also seen in average flow rate with doxazosin mesylate (1.5 mL/sec) than with placebo (0.2 mL/sec).

The onset and time course of symptom relief and increased urinary flow from study 1 are illustrated in Figure 1.

Figure 1

In BPH patients (n=450) treated for up to 4 years in open-label studies, doxazosin mesylate therapy resulted in significant improvement above baseline in urinary flow rates and BPH symptoms. The significant effects of doxazosin mesylate were maintained over the entire treatment period, as shown in Figure 2.

Figure 2

Mean change in total symptom score from baseline, in normotensive patients.

Mean increase in maximum flow rate (mL/sec) from baseline.

P=0.0001, **: P=0.001, ***: P=<0.05

Although blockade of α₁-adrenoceptors also lowers blood pressure in hypertensive patients with increased peripheral vascular resistance, doxazosin mesylate treatment of normotensive men with BPH did not result in a clinically significant blood pressure lowering effect (Table

3). The proportion of normotensive patients with a sitting systolic blood pressure less than

90 mm Hg and/or diastolic blood pressure less than 60 mm Hg at any time during treatment with doxazosin mesylate 1 to 8 mg once daily was 6.7% and not statistically significantly different from that with placebo (5%).

Table 3 Mean Changes in Blood Pressure from Baseline to the Mean of the Final Efficacy Phase in Normotensive (Diastolic BP<90mm Hg) in All Double-Blind, Placebo-Controlled U.S. Studies.

Group n Baseline Mean Change

Systolic BP Doxazosin Mesylate 183 128.8 -4.9* Sitting (mm Hg) Placebo 85 128.4 -1.4 Diastolic BP Doxazosin Mesylate 183 79.6 -2.4* Sitting (mm Hg) Placebo 85 79.2 -1.2

*p≤0.05 compared to placebo

TOXICOLOGY

Acute Toxicology

SPECIES SEX ROUTE LD₅₀

(Confidence Limits)

mg/base/kg Mice M p.o. > 1,000 F p.o. > 1,000 Rats M p.o. > 1,200 F p.o. > 1,200

After oral administration of the drug, the animals displayed vulval opening (females), ptosis and prostration, with the signs lasting up to two days depending on dose level. The 3 deaths which occurred were between days 2 and 5.

Toxicology

Mutagenicity studies revealed no drug or metabolite related effects at either chromosomal or subchromosomal levels.

Carcinogenicity

Chronic dietary administration (up to 24 months) of doxazosin mesylate at maximally tolerated concentrations (highest dose 40 mg/kg/day) revealed no evidence of carcinogenicity in rats.

Doxazosin was also administered for up to 18 months in the diet of mice, at doses up to

40 mg/kg/day, with no evidence of carcinogenicity observed. This mouse study however, was compromised by the failure to use a maximally tolerated dose of doxazosin. A subsequent 24-month dietary study of doxazosin mesylate, at maximally tolerated concentrations (highest dose

120 mg/kg/day), showed no carcinogenic effect in mice. 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.

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.

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    September 18, 2012, Control number: 156309