Doxazosin

DOXAZOSIN- doxazosin mesylate tablet
Aidarex Pharmaceuticals LLC

DESCRIPTION

Doxazosin mesylate is a quinazoline compound that is a selective inhibitor of the alpha1 subtype of alpha adrenergic receptors. The chemical name of doxazosin mesylate is 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(1,4-benzodioxan-2-ylcarbonyl) piperazine methanesulfonate. The molecular formula for doxazosin mesylate is C23 H25 N5 O5 • CH4 O3 S and the molecular weight is 547.6. It has the following structure:

Structural Formula
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Doxazosin mesylate is freely soluble in dimethylsulfoxide, soluble in dimethylformamide, slightly soluble in methanol, ethanol, and water (0.8% at 25°C), and very slightly soluble in acetone and methylene chloride.

Doxazosin Tablets, USP for oral administration, contain 1 mg, 2 mg, 4 mg or 8 mg of doxazosin as doxazosin mesylate, USP. In addition, each tablet also contains the following inactive ingredients: anhydrous lactose, colloidal silicon, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate and sodium starch glycolate. The 2 mg tablets also contain D&C Red No. 30 Aluminum Lake, the 4 mg tablets contain FD&C Blue No. 2 Aluminum Lake, and the 8 mg tablets contain D&C Red No. 30 Aluminum Lake and FD&C Blue No. 2 Aluminum Lake.

CLINICAL PHARMACOLOGY

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
Table 1
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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.

Figure 1
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*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)BaselineChangeBaselineChange
Systolic 128.4 -1.4 128.8 -4.9*
Diastolic 79.2 -1.2 79.6 -2.4*
Standing BP (mmHg)BaselineChangeBaselineChange
Systolic 128.5 -0.6 128.5 -5.3*
Diastolic 80.5 -0.7 80.4 -2.6*

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