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Doxazosin mesylate (Tablet)
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DOSAGE MUST BE INDIVIDUALIZED.The initial dosage of doxazosin mesylate tablets in patients with hypertension and/or BPH is 1 mg given once daily in the a.m. or p.m. This starting dose is intended to minimize the frequency of postural hypotension and first dose syncope associated with doxazosin mesylate tablets. Postural effects are most likely to occur between 2 and 6 hours after a dose. Therefore blood pressure measurements should be taken during this time period after the first dose and with each increase in dose. If doxazosin mesylate tablet administration is discontinued for several days, therapy should be restarted using the initial dosing regimen. A. BENIGN PROSTATIC HYPERPLASIA 1-8 mg once daily. The initial dosage of doxazosin mesylate tablets is 1 mg, given once daily in the a.m. or p.m. 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 for BPH. The recommended titration interval is 1-2 weeks. Blood pressure should be evaluated routinely in these patients. B. HYPERTENSION 1-16 mg once daily The initial dosage of doxazosin mesylate tablet is 1 mg given once daily. Depending on the individual patient's standing blood pressure response (based on measurements taken at 2-6 hours post-dose and 24 hours post-dose), dosage may then be increased to 2 mg and thereafter if necessary to 4 mg, 8 mg and 16 mg to achieve the desired reduction in blood pressure. Increases in dose beyond 4 mg increase 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.
dailymed-instance:clinicalP...
Pharmacodynamics:<br/>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 BPHis 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 alphaadrenoceptor, which is present in high density in the prostatic stroma, prostatic capsule and bladder neck. Blockade of the alphareceptor decreases urethral resistance and may relieve the obstruction and BPH symptoms. In the human prostate, doxazosin antagonizes phenylephrine (alphaagonist)-induced contractions, in vitro, and binds with high affinity to the alphaadrenoceptor. 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 alphaadrenoceptors 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. 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 alphaadrenoceptors 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%).<br/>B. Hypertension: The mechanism of action of doxazosin mesylate tabltes is selective blockade of the alpha(postjunctional) subtype of adrenergic receptors. Studies in normal human subjects have shown that doxazosin competitively antagonized the pressor effects of phenylephrine (an alphaagonist) 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��M, 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 alpha-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 increasein 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.<br/>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 meanmaximum 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 issuggested 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 dataon 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.
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Doxazosin mesylate 1 mg tablets are gray, capsule-shaped tablets, debossed���ETH266���on one side and���1���bisect���mg���on the other side, packaged as follows: NDC 58177-266-04 bottle of 100 tabletsNDC 58177-266-08 bottle of 500 tabletsNDC 58177-266-22 unit dose cartons of 30 tablets Doxazosin mesylate 2 mg tablets are yellow, capsule-shaped tablets, debossed���ETH267���on one side and���2���bisect���mg���on the other side, packaged as follows: NDC 58177-267-04 bottle of 100 tabletsNDC 58177-267-08 bottle of 500 tabletsNDC 58177-267-22 unit dose cartons of 30 tablets Doxazosin mesylate 4 mg tablets are pink, capsule-shaped tablets, debossed���ETH268���on one side and���4���bisect���mg���on the other side, packaged as follows: NDC 58177-268-04 bottle of 100 tabletsNDC 58177-268-08 bottle of 500 tabletsNDC 58177-268-22 unit dose cartons of 30 tablets Doxazosin mesylate 8 mg tablets are blue, capsule-shaped tablets, debossed���ETH269���on one side and���1���bisect���mg���on the other side, packaged as follows: NDC 58177-269-04 bottle of 100 tabletsNDC 58177-269-08 bottle of 500 tabletsNDC 58177-269-22 unit dose cartons of 30 tablets Recommended Storage: Store at controlled room temperature 15��C���30��C (59��- 86��C) (see USP). Manufactured byKV Pharmaceutical Co. forETHEX CorporationSt. Louis, Missouri 63043-2413 P3949-1 07/06 Doxazosin MesylateTabletsPatient Package Insert
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Doxazosin mesylate
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Doxazosin mesylate (Tablet)
dailymed-instance:adverseRe...
A. Benign Prostatic Hyperplasia: The incidence of adverse events has been ascertained from worldwide clinical trials in 965 BPH patients. The incidence rates presented below (Table 3) are based on combined data from seven placebo-controlled trials involving once daily administration of doxazosin in doses of 1-16 mg in hypertensives and 0.5-8 mg in normotensives. The adverse events when the incidence in the doxazosin group was at least 1% are summarized in Table 3. No significant difference in the incidence of adverse events compared to placebo was seen except for dizziness, fatigue, hypotension, edema and dyspnea. Dizziness and dyspnea appeared to be dose-related. In these placebo-controlled studies of 665 doxazosin mesylate tablet patients, treated for a mean of 85 days, additional adverse reactions have been reported. These are less than 1% and not distinguishable from those that occurred in the placebo group. Adverse reactions with an incidence of less than 1% but of clinical interest are (doxazosin mesylate tablets vs. placebo): Cardiovascular system: angina pectoris (0.6% vs. 0.7%), postural hypotension (0.3% vs. 0.3%), syncope (0.5% vs. 0.0%), tachycardia (0.9% vs. 0.0%); Urogenital system: dysuria (0.5% vs. 1.3%), and Psychiatric disorders: libido decreased (0.8% vs. 0.3%). The safety profile in patients treated for up to three years was similar to that in the placebo-controlled studies. The majority of adverse experiences with doxazosin mesylate tablets were mild.<br/>B. Hypertension: Doxazosin mesylate tablets have been administered to approximately 4000 hypertensive patients, of whom 1679 were included in the hypertension clinical development program. In that program, minor adverse effects were frequent, but led to discontinuation of treatment in only 7% of patients. In placebo-controlled studies adverse effects occurred in 49% and 40% of patients in the doxazosin and placebo groups, respectively, and led to discontinuation in 2% of patients in each group. The major reasons for discontinuation were postural effects (2%), edema, malaise/fatigue, and some heart rate disturbance, each about 0.7%. In controlled hypertension clinical trials directly comparing doxazosin mesylate tabletsto placebo there was no significant difference in the incidence of side effects, except for dizziness (including postural), weight gain, somnolence and fatigue/malaise. Postural effects and edema appeared to be dose related. The prevalence rates presented below are based on combined data from placebo-controlled studies involving once daily administration of doxazosin at doses ranging from 1-16 mg. Table 4 summarizes those adverse experiences (possibly/probably related) reported for patients in these hypertension studies where the prevalence rate in the doxazosin group was at least 0.5% or where the reaction isof particular interest. Additional adverse reactions have been reported, but these are, in general, not distinguishable from symptoms that might have occurred in the absence of exposure to doxazosin. The following adverse reactions occurred with a frequency of between 0.5% and 1%: syncope, hypoesthesia, increased sweating, agitation, increased weight. The following additional adverse reactions were reported by<0.5% of 3960 patients who received doxazosin in controlled or open, short- or long- term clinical studies, including international studies. Cardiovascular System: angina pectoris, myocardial infarction, cerebrovascular accident; Autonomic Nervous System: pallor; Metabolic: thirst, gout, hypokalemia; Hematopoietic: lymphadenopathy, purpura; Reproductive System: breast pain; Skin Disorders: alopecia, dry skin, eczema; Central Nervous System: paresis, tremor, twitching, confusion, migraine, impaired concentration; Psychiatric: paroniria, amnesia, emotional lability, abnormal thinking, depersonalization; Special Senses: parosmia, earache, taste perversion, photophobia, abnormal lacrimation; Gastrointestinal System: increased appetite, anorexia, fecal incontinence, gastroenteritis; Respiratory System: bronchospasm, sinusitis, coughing, pharyngitis; Urinary System: renal calculus; General Body System: hot flushes, back pain, infection, fever/rigors, decreased weight, influenza-like symptoms. Doxazosin mesylate tablets have not been associated with any clinically significant changes in routine biochemical tests. No clinically relevant adverse effects were noted on serum potassium, serum glucose, uric acid, blood urea nitrogen, creatinine or liver function tests. Doxazosin mesylate tablets have been associated with decreases in white blood cell counts . In post-marketing experience the following additional adverse reactions have been reported: Autonomic Nervous System: priapism; Central Nervous System: hypoesthesia; Endocrine System: gynecomastia; Gastrointestinal System: vomiting; General Body System: allergic reaction; Heart Rate/Rhythm: bradycardia; Hematopoietic: leukopenia, thrombocytopenia; Liver/Billiary System: hepatitis, hepatitis cholestatic; Respiratory System: bronchospasm aggravated; Skin Disorders: urticaria; Special Senses: Intraoperative Floppy Iris Syndrome ; Urinary System: hematuria, micturition disorder, micturition frequency, nocturia.
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A. Benign Prostatic Hyperplasia (BPH) Doxazosin mesylate tablets are indicated for the treatment of both the urinary outflow obstruction and obstructive and irritative symptoms associated with BPH: obstructive symptoms (hesitation, intermittency, dribbling, weak urinary stream, incomplete emptying of the bladder) and irritative symptoms (nocturia, daytime frequency, urgency, burning). Doxazosin mesylate tablets may be used in all BPH patients whether hypertensive ornormotensive. In patients with hypertension and BPH, both conditions were effectively treated with doxazosin mesylate tablet monotherapy. Doxazosin mesylate tablets provides rapid improvement in symptoms and urinary flow rate in 66-71% of patients. Sustained improvements with doxazosin mesylate tablets were seen in patients treated for up to 14 weeks in double-blind studies and up to 2 years in open-label studies. B. Hypertension Doxazosin mesylate tablets are also indicated for the treatment of hypertension. Doxazosin mesylate tablets may be used alone or in combination with diuretics, beta-adrenergic blocking agents, calcium channel blockers or angiotensin-converting enzyme inhibitors.
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Doxazosin mesylate