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Description

Doxazosin mesylate is a quinazoline compound that is a selective inhibitor of the alpha₁subtype 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 C₂₃H₂₅N₅O₅· CH₄O₃S and the molecular weight is 547.6. It has the following structure:

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. Each doxazosin mesylate tablet (colored) for oral administration, contains 1 mg (gray), 2 mg (yellow), 4 mg (pink) and 8 mg (blue) of doxazosin as the free base.

Inactive Ingredients: hydrated alumina, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate and sodium starch glycolate. The 1 mg tablet also contains FD&C Blue No. 2 aluminum lake, FD&C Red No. 40 aluminum lake and FD&C Yellow No. 6 aluminum lake; the 2 mg tablet also contains D&C Yellow No. 10 aluminum lake. The 4 mg tablet also contains D&C Red No. 27 aluminum lake and D&C Red No. 30 aluminum lake. The 8 mg tablet also contains FD&C Blue No. 2 aluminum lake.

Clinical Pharmacology

Pharmacodynamics

A. 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 alpha_1c adrenoceptor. The receptor subtype is thought to be the predominant functional type in the prostate. Doxazosin acts within 1-2 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 mesylate tablet treatment was superior to placebo in improving patient symptoms and urinary flow rate. Significant relief with doxazosin mesylate tablets was seen as early as one week into the treatment regimen, with doxazosin mesylate tablets 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 66-71% of patients, improvements above baseline were seen in both symptoms and maximum urinary flow rate.

In three placebo-controlled studies of 14-16 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 (2-6 hours post-dose) and/or trough (24 hours post-dose) plasma concentrations of doxazosin mesylate tablets..

The results from the three placebo-controlled studies (N=609) showing significant efficacy with 4 mg and 8 mg doxazosin mesylate are summarized in Table 1. In all three studies, doxazosin mesylate tablets resulted in statistically significant relief of obstructive and irritative symptoms compared to placebo. Statistically significant improvements of 2.3-3.3 mL/sec in maximum flow rate were seen with doxazosin mesylate tablets in Studies 1 and 2, compared to 0.1-0.7 mL/sec with placebo.

TABLE 1 SUMMARY OF EFFECTIVENESS DATA INPLACEBO-CONTROLLED TRIALS

		SYMPTOM SCOREa			MAXIMUM FLOW RATE (mL/sec)
	N	MeanBaseline	MeanbChange	N	Mean Baseline	MeancChange
STUDY 1 (Titration to maximum dose of 8 mg)e
Placebo	47	15.6	-2.3	41	9.7	+0.7
Doxazosin Mesylate	49	14.5	-4.9**	41	9.8	+2.9**
STUDY 2 (titration to fixed dose 14 weeks)d
Placebo	37	20.7	-2.5	30	10.6	+0.1
Doxazosin Mesylate 4 mg	38	21.2	-5.0**	32	9.8	+2.3*
Doxazosin Mesylate 8 mg	42	19.9	-4.2*	36	10.5	+3.3**
STUDY 3 (Titration to fixed dose-12 weeks)
Placebo	47	14.9	-4.7	44	9.9	+2.1
Doxazosin Mesylate 4 mg	46	16.6	-6.1*	46	9.6	+2.6

      STUDY 2Maximum Flow Rate



In one fixed dose study (study 2) doxazosin mesylate tablet therapy ( 4-8 mg, once daily) resulted in a significant and sustained improvement in maximum urinary flow rate of 2.3-3.3 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 mesylate tablets 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 mestylate tablets (34-42%) than placebo (13-17%). A significantly greater improvement was also seen in average flow rate with doxazosin mesylate tablets (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.



In BPH patients (N=450) treated for up to 2 years in open-label studies, doxazosin mesylate tablet 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 mesylate tablets 1-8 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 Mesylate Tablets 1-8 mg once daily.

	PLACEBO(N=85)		Doxazosin Mesylate(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*

B. Hypertension

The mechanism of action of doxazosin mesylate tabltes is selective blockade of the alpha₁ (postjunctional) subtype of adrenergic receptors. Studies in normal human subjects have shown that doxazosin competitively antagonized the pressor effects of phenylephrine (an alpha₁ agonist) and the systolic pressor effect of norepinephrine. Doxazosin and prazosin have similar abilities to antagonize phenylephrine. The antihypertensive effect of doxazosin mesylate tablets results from a decrease in systemic vascular resistance. The parent compound doxazosin is primarily responsible for the antihypertensive activity. The low plasma concentrations of known active and inactive metabolites of doxazosin (2-piperazinyl, 6'- and 7'-hydroxy and 6-and 7-O-desmethyl compounds) compared to parent drug indicate that the contribution of even the most potent compound (6'-hydroxy) to the antihypertensive effect of doxazosin in man is probably small. The 6'- and 7'-hydroxy metabolites have demonstrated antioxidant properties at concentrations of 5 µM, in vitro.

Administration of doxazosin mesylate tablets results in a reduction in systemic vascular resistance. In patients with hypertension there is little change in cardiac output. Maximum reductions in blood pressure usually occur 2-6 hours after dosing and are associated with a small increase in standing heart rate. Like other alpha₁-adrenergic blocking agents, doxazosin has a greater effect on blood pressure and heart rate in the standing position.

In a pooled analysis of placebo-controlled hypertension studies with about 300 hypertensive patients per treatment group, doxazosin, at doses of 1-16 mg given once daily, lowered blood pressure at 24 hours by about 10/8 mmHg compared to placebo in the standing position and about 9/5 mmHg in the supine position. Peak blood pressure effects (1-6 hours) were larger by about 50-75% (i.e., trough values were about 55-70% of peak effect), with the larger peak-trough differences seen in systolic pressures. There was no apparent difference in the blood pressure response of Caucasians and Afro-Americans or of patients above and below age 65. In these predominantly normocholesterolemic patients doxazosin produced small reductions in total serum cholesterol (2-3%), LDL cholesterol (4%), and a similarly small increase in HDL/total cholesterol ratio (4%). The clinical significance of these findings is uncertain. In the same patient population, patients receiving doxazosin mesylate tablets gained a mean of 0.6 kg compared to a mean loss of 0.1 kg for placebo patients.

Pharmacokinetics

After oral administration of therapeutic doses, peak plasma levels of doxazosin mesylate tablets occur at about 2-3 hours. Bioavailability is approximately 65%, reflecting first pass metabolism of doxazosin by the liver. The effect of food on the pharmacokinetics of doxazosin mesylate tablets was examined in a crossover study with twelve hypertensive subjects. Reductions of 18% in mean maximum plasma concentration and 12% in the area under the concentration-time curve occurred when doxazosin mesylate tablets was administered with food. Neither of these differences was statistically or clinically significant.

Doxazosin mesylate tablets are 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 2-16 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 mesylate tablets 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)). As with any drug wholly metabolized by the liver, use of doxazosin mesylate tablets 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 mesylate tablets were similar in the two populations. Linear kinetics and dose proportionality were observed.