DOXAZOSIN MESYLATE- doxazosin mesylate tablet
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-dimethyoxy-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 tablet, for oral administration, contains doxazosin mesylate equivalent to 1 mg, 2 mg, 4 mg or 8 mg doxazosin as the free base. In addition, each doxazosin mesylate tablet contains the following inactive ingredients: lactose anhydrous, magnesium stearate, microcrystalline cellulose, sodium lauryl sulphate, and sodium starch glycolate.
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 mesylate 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 mesylate 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 mesylate should maintain bladder contractility.
The efficacy of doxazosin mesylate was evaluated extensively in over 900 patients with BPH in double-blind, placebo-controlled trials. Doxazosin mesylate treatment was superior to placebo in improving patient symptoms and urinary flow rate. Significant relief with doxazosin mesylate was seen as early as one week into the treatment regimen, with doxazosin mesylate 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 mesylate.
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 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.
a AUA questionnaire (range 0-30) in studies 1 and 3. Modified Boyarsky Questionnaire (range 7-39) in study 2.
b Change is to endpoint.
c Change is fixed-dose efficacy phase, 22-26 hours post-dose for studies 1 and 3 and 2-6 hours post-dose for study 2.
d Study in hypertensives with BPH.
e 36 patients received a dose of 8 mg doxazosin mesylate.
* (**) p<0.05 (0.01) compared to placebo mean change.
|Symptom Score a|| |
Maximum Flow Rate(mL/sec)
Study 1 (Titration tomaximum dose of 8 mg)e
Study 2 (Titration tofixed dose — 14 weeks)d
|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 tofixed dose — 12 weeks)
|Doxazosin mesylate 4 mg||46||16.6||-6.1*||46||9.6||+2.6|
In one fixed dose study (study 2) doxazosin 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 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 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 (1.6 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 Mesylate Titration to Maximum of 8 mg.
In BPH patients (N=450) treated for up to 2 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.
Although blockade of alpha1 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 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 1 to 8 mg once daily was 6.7% with doxazosin mesylate and not significantly different (statistically) from that with placebo (5%).
|*p ≤ 0.05 compared to placebo|
The mechanism of action of doxazosin mesylate is selective blockade of the alpha1 (postjunctional) subtype of adrenergic receptors. Studies in normal human subjects have shown that doxazosin mesylate competitively antagonized the pressor effects of phenylephrine (an alpha1 agonist) and the systolic pressor effect of norepinephrine. Doxazosin mesylate and prazosin have similar abilities to antagonize phenylephrine. The antihypertensive effect of doxazosin mesylate results from a decrease in systemic vascular resistance. The parent compound doxazosin mesylate is primarily responsible for the antihypertensive activity. The low plasma concentrations of known active and inactive metabolites of doxazosin mesylate (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 mesylate 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 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 to 6 hours after dosing and are associated with a small increase in standing heart rate. Like other alpha1-adrenergic blocking agents, doxazosin mesylate 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 mesylate, at doses of 1 to 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 to 6 hours) were larger by about 50 to 75% (i.e., trough values were about 55 to 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 blacks or of patients above and below age 65. In these predominantly normocholesterolemic patients doxazosin mesylate produced small reductions in total serum cholesterol (2 to 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 gained a mean of 0.6 kg compared to a mean loss of 0.1 kg for placebo patients.
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 mesylate by the liver. The effect of food on the pharmacokinetics of doxazosin mesylate 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 was administered with food. Neither of these differences was statistically or clinically significant.
Doxazosin mesylate 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 mesylate have been identified, the pharmacokinetics of these metabolites have not been characterized. In a study of two subjects administered radiolabelled doxazosin mesylate 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 mesylate is biphasic, with a terminal elimination half-life of about 22 hours. Steady-state studies in hypertensive patients given doxazosin mesylate 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. Enterohepatic recycling is suggested by secondary peaking of plasma doxazosin mesylate concentrations. In a crossover study in 24 normotensive subjects, the pharmacokinetics and safety of doxazosin mesylate were shown to be similar with morning and evening dosing regimens. The area under the curve after the 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 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 mesylate. There are only limited data on the effects of drugs known to influence the hepatic metabolism of doxazosin mesylate [e.g., cimetidine (see PRECAUTIONS)]. As with any drug wholly metabolized by the liver, use of doxazosin mesylate 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 mesylate was administered in the morning and the titration interval was two weeks and one week, respectively, trough plasma concentrations of doxazosin mesylate were similar in the two populations. Linear kinetics and dose proportionality were observed.
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