Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/950
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Doxazosin (Tablet)
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DOSAGE MUST BE INDIVIDUALIZED. The initial dosage of doxazosin 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. 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 tablets administration is discontinued for several days, therapy should be restarted using the initial dosing regimen.<br/>Benign Prostatic Hyperplasia 1 to 8 mg Once Daily: The initial dosage of doxazosin 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 to 2 weeks. Blood pressure should be evaluated routinely in these patients.<br/>Hypertension 1 to 16 mg Once Daily: The initial dosage of doxazosin is 1 mg given once daily. Depending on the individual patient's standing blood pressure response (based on measurements taken at 2 to 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.
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Doxazosin mesylate is a quinazoline compound that is a selective inhibitor of
the alphasubtype 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 CHNO���CHOS
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. Doxazosin Tablets, USP for oral administration, contain 1 mg, 2 mg, 4 mg or 8 mg of doxazosin as doxazosin mesylate. 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.
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Pharmacodynamics:<br/>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 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 to 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 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. 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 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. *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 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 1 to 8 mg once daily was 6.7% with doxazosin and not significantly different (statistically) from that with placebo (5%).<br/>Hypertension: The mechanism of action of doxazosin mesylate 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 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 mcM, in vitro. 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-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 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 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 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 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 12 hypertensive subjects. Reductions of 18% in mean maximum plasma concentration and 12% in the area under the concentration-time curve occurred when doxazosin was administered with food. Neither of these differences was statistically or clinically significant. Doxazosin 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 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 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 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 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 ]. As with any drug wholly metabolized by the liver, use of doxazosin 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 were similar in the two populations. Linear kinetics and dose proportionality were observed.
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Doxazosin tablets are contraindicated in patients with a known sensitivity to quinazolines (e.g., prazosin, terazosin), doxazosin, or any of the inert ingredients.
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Doxazosin Tablets, USP are available as tablets for oral administration. Each tablet contains doxazosin mesylate equivalent to 1 mg, 2 mg, 4 mg or 8 mg of doxazosin. The 1 mg are available as white to off-white, round, biconvex tablets debossed with M over D9 on one side of the tablet and scored on the other side. They are available as follows: NDC 0378-4021-01bottles of 100 tablets The 2 mg are available as pink, round, biconvex tablets debossed with M over D10 on one side of the tablet and scored on the other side. They are available as follows: NDC 0378-4022-01bottles of 100 tablets NDC 0378-4022-05bottles of 500 tablets The 4 mg are available as blue, round, biconvex tablets debossed with M over D11 on one side of the tablet and scored on the other side. They are available as follows: NDC 0378-4024-01bottles of 100 tablets NDC 0378-4024-05bottles of 500 tablets The 8 mg are available as purple, round, biconvex tablets debossed with M over D12 on one side of the tablet and scored on the other side. They are available as follows: NDC 0378-4028-01bottles of 100 tablets Store at 20��to 25��C (68��to 77��F). [See USP for Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. PHARMACIST: Detach Patient Information Leaflet at each perforation and give leaflet to patient.
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General:<br/>Prostate Cancer: Carcinoma of the prostate causes many of the
symptoms associated with BPH and the two disorders frequently co-exist. Carcinoma of the
prostate should therefore be ruled out prior to commencing therapy with doxazosin.<br/>Cataract Surgery: Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients on or previously treated with alphablockers. This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient's surgeon should be prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alphablocker therapy prior to cataract surgery.<br/>Orthostatic Hypotension: While syncope is the most severe orthostatic effect of doxazosin, other symptoms of lowered blood pressure, such as dizziness, lightheadedness, or vertigo can occur, especially at initiation of therapy or at the time of dose increases.<br/>Information for Patients: (See Patient Leaflet) Patients should be made aware of the possibility
of syncopal and orthostatic symptoms, especially at the initiation of therapy, and urged
to avoid driving or hazardous tasks for 24 hours after the first dose, after a dosage increase,
and after interruption of therapy when treatment is resumed. They should be cautioned to avoid
situations where injury could result should syncope occur during initiation of doxazosin therapy.
They should also be advised of the need to sit or lie down when symptoms of lowered blood
pressure occur, although these symptoms are not always orthostatic, and to be careful when
rising from a sitting or lying position. If dizziness, lightheadedness, or palpitations are bothersome
they should be reported to the physician, so that dose adjustment can be considered.
Patients should also be told that drowsiness or somnolence can occur with doxazosin or any
selective alphaadrenoceptor antagonist, requiring caution in people who must drive or operate heavy machinery. Patients should be advised about the possibility of priapism as a result of treatment with alphaantagonists. Patients should know that this adverse event is very rare. If they experience priapism, it should be brought to immediate medical attention for if not treated promptly it can lead to permanent erectile dysfunction (impotence).<br/>Drug/Laboratory Test Interactions: Doxazosin does not affect the plasma concentration of
prostate specific antigen in patients treated for up to 3 years. Both doxazosin, an alphainhibitor,
and finasteride, a 5-alpha reductase inhibitor, are highly protein bound and hepatically
metabolized. There is no definitive controlled clinical experience on the concomitant use
of alphainhibitors and 5-alpha reductase inhibitors at this time.<br/>Impaired Liver Function: Doxazosin should be administered with caution to patients with evidence of impaired hepatic function or to patients receiving drugs known to influence hepatic metabolism .<br/>Leukopenia/Neutropenia: Analysis of hematologic data from hypertensive patients receiving
doxazosin in controlled hypertension clinical trials showed that the mean WBC (N = 474) and
mean neutrophil counts (N = 419) were decreased by 2.4% and 1%, respectively, compared to
placebo, a phenomenon seen with other alpha blocking drugs. In BPH patients the incidence of
clinically significant WBC abnormalities was 0.4% (2/459) with doxazosin and 0% (0/147) with
placebo, with no statistically significant difference between the two treatment groups. A search
through a data base of 2,400 hypertensive patients and 665 BPH patients revealed 4 hypertensives
in which drug-related neutropenia could not be ruled out and one BPH patient in which
drug-related leukopenia could not be ruled out. Two hypertensives had a single low value on the
last day of treatment. Two hypertensives had stable, non-progressive neutrophil counts in the
1000/mmrange over periods of 20 and 40 weeks. One BPH patient had a decrease from WBC
count of 4800/mmto 2700/mmat the end of the study; there was no evidence of clinical
impairment. In cases where follow-up was available the WBCs and neutrophil counts returned
to normal after discontinuation of doxazosin. No patients became symptomatic as a result of the
low WBC or neutrophil counts.<br/>Drug Interactions: Most (98%) of plasma doxazosin is protein bound. In vitro data in human plasma indicate that doxazosin has no effect on protein binding of digoxin, warfarin, phenytoin or indomethacin. There is no information on the effect of other highly plasma protein
bound drugs on doxazosin binding. Doxazosin has been administered without any evidence of
an adverse drug interaction to patients receiving thiazide diuretics, beta-blocking agents, and
nonsteroidal anti-inflammatory drugs. In a placebo-controlled trial in normal volunteers, the
administration of a single 1 mg dose of doxazosin on day 1 of a 4-day regimen of oral cimetidine
(400 mg twice daily) resulted in a 10% increase in mean AUC of doxazosin (p = 0.006),
and a slight but not statistically significant increase in mean Cand mean half-life of doxazosin.
The clinical significance of this increase in doxazosin AUC is unknown. In clinical trials, doxazosin tablets have been administered to patients on a variety of concomitant medications; while no formal interaction studies have been conducted, no interactions
were observed. Doxazosin tablets have been used with the following drugs or drug classes:
1) analgesic/anti-inflammatory (e.g., acetaminophen, aspirin, codeine and codeine combinations,
ibuprofen, indomethacin); 2) antibiotics (e.g., erythromycin, trimethoprim and sulfamethoxazole,
amoxicillin); 3) antihistamines (e.g., chlorpheniramine); 4) cardiovascular
agents (e.g., atenolol, hydrochlorothiazide, propranolol); 5) corticosteroids; 6) gastrointestinal
agents (e.g., antacids); 7) hypoglycemics and endocrine drugs; 8) sedatives and tranquilizers
(e.g., diazepam); 9) cold and flu remedies.<br/>Cardiac Toxicity in Animals: An increased incidence of myocardial necrosis or fibrosis was displayed
by Sprague-Dawley rats after 6 months of dietary administration at concentrations calculated
to provide 80 mg doxazosin/kg/day and after 12 months of dietary administration at
concentrations calculated to provide 40 mg doxazosin/kg/day (AUC exposure in rats 8 times the
human AUC exposure with a 12 mg/day therapeutic dose). Myocardial fibrosis was observed in
both rats and mice treated in the same manner with 40 mg doxazosin/kg/day for 18 months
(exposure 8 times human AUC exposure in rats and somewhat equivalent to human Cexposure
in mice). No cardiotoxicity was observed at lower doses (up to 10 or 20 mg/kg/day, depending
on the study) in either species. These lesions were not observed after 12 months of oral dosing
in dogs at maximum doses of 20 mg/kg/day [maximum plasma concentrations (C) in
dogs 14 times the Cexposure in humans receiving a 12 mg/day therapeutic dose] and in
Wistar rats at doses of 100 mg/kg/day (Cexposures 15 times human Cexposure with a 12 mg/day therapeutic dose). There is no evidence that similar lesions occur in humans.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: 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. 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.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nonteratogenic Effects: In peri-postnatal studies in rats, postnatal development at maternal
doses of 40 or 50 mg/kg/day of doxazosin (8 times human AUC exposure with a 12 mg/day
therapeutic dose) was delayed as evidenced by slower body weight gain and a slightly later
appearance of anatomical features and reflexes.<br/>Nursing Mothers: Studies in lactating rats given a single oral dose of 1 mg/kg of [2-C]-doxazosin indicate that doxazosin accumulates in rat breast milk with a maximum concentration
about 20 times greater than the maternal plasma concentration. It is not known
whether this drug is excreted in human milk. Because many drugs are excreted in human
milk, caution should be exercised when doxazosin is administered to a nursing mother.<br/>Pediatric Use: The safety and effectiveness of doxazosin as an antihypertensive agent have
not been established in pediatric patients.<br/>Geriatric Use: The safety and effectiveness profile of doxazosin in BPH was similar in the elderly
(age���65 years) and younger (age<65 years) patients. Clinical studies of doxazosin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low
end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy.
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Experience with doxazosin overdosage is limited. Two adolescents who each intentionally ingested 40 mg doxazosin with diclofenac or acetaminophen, were treated with gastric lavage with activated charcoal and made full recoveries. A two-year-old child who accidentally ingested 4 mg doxazosin was treated with gastric lavage and remained normotensive during the five-hour emergency room observation period. A six-month-old child accidentally received a crushed 1 mg tablet of doxazosin and was reported to have been drowsy. A 32-year-old female with chronic renal failure, epilepsy and depression intentionally ingested 60 mg doxazosin (blood level 0.9 mcg/mL; normal values in hypertensives= 0.02 mcg/mL); death was attributed to a grand mal seizure resulting from hypotension. A 39-year-old female who ingested 70 mg doxazosin,
alcohol and flurazepam developed hypotension which responded to fluid therapy. The oral LDof doxazosin is greater than 1000 mg/kg in mice and rats. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of fluid. As doxazosin is highly protein bound, dialysis would not be indicated.
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Doxazosin mesylate
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Doxazosin (Tablet)
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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 to 16 mg in hypertensives and 0.5 to 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 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 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 were mild.<br/>Hypertension: Doxazosin mesylate has been administered to approximately 4,000 hypertensive
patients, of whom 1,679 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 to 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 to 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 is of 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 3,960 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 has 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 has 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/Biliary 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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Syncope and "First-dose" Effect: Doxazosin, like other alpha-adrenergic blocking agents, can cause marked hypotension, especially in the upright position, with syncope and other postural symptoms such as dizziness. Marked orthostatic effects are most common with the first dose but can also occur when there is a dosage increase, or if therapy is interrupted for more than a few days. To decrease the likelihood of excessive hypotension and syncope, it is essential that treatment be initiated with the 1 mg dose. The 2, 4, and 8 mg tablets are not for initial therapy. Dosage should then be adjusted slowly with evaluations and increases in dose every two weeks to the recommended dose. Additional antihypertensive agents should be added with caution. Patients being titrated with doxazosin should be cautioned to avoid situations where injury could result should syncope occur, during both the day and night. In an early investigational study of the safety and tolerance of increasing daily doses of
doxazosin in normotensives beginning at 1 mg/day, only 2 of 6 subjects could tolerate more
than 2 mg/day without experiencing symptomatic postural hypotension. In another study of 24 healthy normotensive male subjects receiving initial doses of 2 mg/day of doxazosin, seven (29%) of the subjects experienced symptomatic postural hypotension between 0.5 and 6 hours after the first dose necessitating termination of the study. In this study, 2 of the normotensive subjects experienced syncope. Subsequent trials in hypertensive patients always began doxazosin dosing at 1 mg/day resulting in a 4% incidence of postural side effects at 1 mg/day with no cases of syncope. In multiple dose clinical trials in hypertension involving over 1,500 hypertensive patients with dose titration every one to two weeks, syncope was reported in 0.7% of patients. None of these events occurred at the starting dose of 1 mg and 1.2% (8/664) occurred at 16 mg/day. In placebo-controlled, clinical trials in BPH, 3 out of 665 patients (0.5%) taking doxazosin reported syncope. Two of the patients were taking 1 mg doxazosin, while one patient was taking 2 mg doxazosin when syncope occurred. In the open-label, long-term extension follow-up of approximately 450 BPH patients, there were 3 reports of syncope (0.7%). One patient was taking 2 mg, one patient was taking 8 mg and one patient was taking 12 mg when syncope occurred. In a clinical pharmacology study, one subject receiving 2 mg experienced syncope. If syncope occurs, the patient should be placed in a recumbent position and treated supportively as necessary.<br/>Priapism: Rarely (probably less frequently than once in every several thousand patients), alphaantagonists, including doxazosin, have been associated with priapism (painful penile erection, sustained for hours and unrelieved by sexual intercourse or masturbation). Because this condition can lead to permanent impotence if not promptly treated, patients must be advised about the seriousness of the condition .
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Benign Prostatic Hyperplasia (BPH): Doxazosin 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 may be used in all BPH patients whether hypertensive or normotensive. In patients with hypertension and BPH, both conditions were effectively treated with doxazosin monotherapy. Doxazosin provides rapid improvement in symptoms and urinary flow rate in 66 to 71% of patients. Sustained improvements with doxazosin were seen in patients treated for up to 14 weeks in double-blind studies and up to 2 years in open-label studies.<br/>Hypertension: Doxazosin tablets are also indicated for the treatment of hypertension. Doxazosin
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
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