Doxazosin 2 mg Tablet, 100-count — NDC 68382-784-01 (Billing 68382-0784-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Benign Prostatic Hyperplasia (BPH) The symptoms associated with benign prostatic hyperplasia (BPH), such as urinary frequency, nocturia, weak stream, hesitancy, and incomplete emptying are related to two components, anatomical (static) and functional (dynamic). 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 alpha 1 adrenoceptor, which is present in high density in the prostatic stroma, prostatic capsule and bladder neck. Blockade of the alpha 1 receptor decreases urethral resistance and may relieve the obstruction and BPH symptoms and improve urine flow.

Hypertension The mechanism of action of doxazosin is selective blockade of the alpha 1 (postjunctional) subtype of adrenergic receptors. Studies in normal human subjects have shown that doxazosin competitively antagonized the pressor effects of phenylephrine (an alpha 1 agonist) and the systolic pressor effect of norepinephrine. Doxazosin and prazosin have similar abilities to antagonize phenylephrine.

The antihypertensive effect of doxazosin 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 .

12.2Pharmacodynamics Benign Prostatic Hyperplasia (BPH) Administration of doxazosin to patients with symptomatic BPH resulted in a statistically significant improvement in maximum urinary flow rate [see Clinical Studies ( 14.1 )] . Effect on Normotensive Patients with Benign Prostatic Hyperplasia (BPH) Although blockade of alpha 1 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 4).

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 1to 8 mg once daily was 6.7% with doxazosin and not significantly different (statistically) from that with placebo (5%). Hypertension Administration of doxazosin 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 alpha 1 -adrenergic blocking agents, doxazosin has a greater effect on blood pressure and heart rate in the standing position.

12.3Pharmacokinetics Absorption After oral administration of therapeutic doses, peak plasma levels of doxazosin 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 twelve hypertensive subjects.

Reductions of 18% in mean maximum plasma concentration (C max ) and 12% in the area under the concentration-time curve (AUC) occurred when doxazosin was administered with food. Neither of these differences is clinically significant. In a crossover s… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Benign Prostatic Hyperplasia (BPH) The symptoms associated with benign prostatic hyperplasia (BPH), such as urinary frequency, nocturia, weak stream, hesitancy, and incomplete emptying are related to two components, anatomical (static) and functional (dynamic). 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 alpha 1 adrenoceptor, which is present in high density in the prostatic stroma, prostatic capsule and bladder neck. Blockade of the alpha 1 receptor decreases urethral resistance and may relieve the obstruction and BPH symptoms and improve urine flow.

Hypertension The mechanism of action of doxazosin is selective blockade of the alpha 1 (postjunctional) subtype of adrenergic receptors. Studies in normal human subjects have shown that doxazosin competitively antagonized the pressor effects of phenylephrine (an alpha 1 agonist) and the systolic pressor effect of norepinephrine. Doxazosin and prazosin have similar abilities to antagonize phenylephrine.

The antihypertensive effect of doxazosin 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 .

12.3Pharmacokinetics Absorption After oral administration of therapeutic doses, peak plasma levels of doxazosin 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 twelve hypertensive subjects.

Reductions of 18% in mean maximum plasma concentration (C max ) and 12% in the area under the concentration-time curve (AUC) occurred when doxazosin was administered with food. Neither of these differences is clinically significant. 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 AUC 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 vs. 3.5 hours). Distribution At the plasma concentrations achieved by therapeutic doses, approximately 98% of the circulating drug is bound to plasma proteins.

Metabolism Doxazosin is extensively metabolized in the liver, mainly by O-demethylation of the quinazoline nucleus or hydroxylation of the benzodioxan moiety. In vitro studies suggest that the primary pathway for elimination is via CYP 3A4; however, CYP 2D6 and CYP 2C9 metabolic pathways are also involved to a lesser extent. Although several active metabolites of doxazosin have been identified, the pharmacokinetics of these metabolites have not been characterized.

Excretion 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 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 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.

Specific Populations Geriatric The pharmacokinetics of doxazosin in young (<65 years) and elderly (≥65 years) subjects were similar for plasma half-life values and oral clearance. Renal Impairment Pharmacokinetic studies in elderly patients and patients with renal impairment have shown no significant alterations compared to younger patients with normal renal function. Hepatic Impairment Administration of a single 2 mg dose to patients with cirrhosis (Child-Pugh Class A) showed a 40% increase in exposure to doxazosin.

The impact of moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment on the pharmacokinetics of doxazosin is not known [see Use in Specific Populations ( 8.6 )] . Drug Interactions There are only limited data on the effects of drugs known to influence the hepatic metabolism of doxazosin (e.g., cimetidine). Cimetidine: In healthy volunteers, the administration of a single 1 mg dose of doxazosin on day 1 of a four-day regimen of oral cimetidine (400 mg twice daily) resulted in a 10% increase in mean AUC of doxazosin, and a slight but not significant increase in mean C max and mean half-life of doxazosin.

In vitro data in human plasma indicate that doxazosin has no effect on protein binding of digoxin, warfarin, phenytoin, or indomethacin.

12.2Pharmacodynamics Benign Prostatic Hyperplasia (BPH) Administration of doxazosin to patients with symptomatic BPH resulted in a statistically significant improvement in maximum urinary flow rate [see Clinical Studies ( 14.1 )] . Effect on Normotensive Patients with Benign Prostatic Hyperplasia (BPH) Although blockade of alpha 1 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 4).

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 1to 8 mg once daily was 6.7% with doxazosin and not significantly different (statistically) from that with placebo (5%). Hypertension Administration of doxazosin 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 alpha 1 -adrenergic blocking agents, doxazosin has a greater effect on blood pressure and heart rate in the standing position.

14 CLINICAL STUDIES

14.1Benign Prostatic Hyperplasia (BPH) 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 3. 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 3 SUMMARY OF EFFECTIVENESS DATA IN PLACEBO-CONTROLLED TRIALS In one fixed-dose study (Study 2), doxazosin 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 3) 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 – Study 1

14.2Hypertension In a pooled analysis of placebo-controlled hypertension studies with about 300 hypertensive patients per treatment group, doxazosin, 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 the same patient population, patients receiving doxazosin gained a mean of 0.6 kg compared to a mean loss of 0.1 kg for placebo patients. TABLE 4Mean 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 to 8 mg once daily. * p ≤0.05 compared to placebo PLACEBO ( N = 85 ) DOXAZOSIN ( N = 183 ) Sitting BP ( mm Hg ) 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… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis and Mutagenesis: 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.

Fertility in Males: 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.

13.2Animal Toxicology and Pharmacology An increased incidence of myocardial necrosis or fibrosis was observed in long-term (6-12 months) studies in rats and mice (exposure 8 times human AUC exposure in rats and somewhat equivalent to human C max exposure in mice). Findings were not seen at lower doses. In dogs no cardiotoxicity was observed following 12 months of oral dosing at doses that resulted in maximum plasma concentrations (C max ) 14 times the C max exposure in humans receiving a 12 mg/day therapeutic dose or in Wistar rats at C max exposures 15 times human C max exposure.

There is no evidence that similar lesions occur in humans.