NDC 54868-4895 Doxazosin

NDC Product Code 54868-4895

NDC CODE: 54868-4895

Proprietary Name: Doxazosin What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Product Characteristics

Color(s):
WHITE (C48325 - WHITE TO OFF-WHITE)
Shape: ROUND (C48348)
Size(s):
9 MM
Imprint(s):
M;D9
Score: 2

NDC Code Structure

NDC 54868-4895-0

Package Description: 30 TABLET in 1 BOTTLE, PLASTIC

NDC 54868-4895-1

Package Description: 100 TABLET in 1 BOTTLE, PLASTIC

This product is EXCLUDED from the official NDC directory because the listing data was inactivated by the FDA.

NDC Product Information

Doxazosin with NDC 54868-4895 is a product labeled by Physicians Total Care, Inc.. The generic name of Doxazosin is . The product's dosage form is and is administered via form.

Labeler Name: Physicians Total Care, Inc.

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)
  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)
  • SODIUM LAURYL SULFATE (UNII: 368GB5141J)
  • SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Physicians Total Care, Inc.
Labeler Code: 54868
Start Marketing Date: 08-14-2003 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2017 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: I - INACTIVATED, the listing data was inactivated by the FDA. What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

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Information for Patients

Doxazosin

Doxazosin is pronounced as (dox ay' zoe sin)

Why is doxazosin medication prescribed?
Doxazosin is used in men to treat the symptoms of an enlarged prostate (benign prostatic hyperplasia or BPH), which include difficulty urinating (hesitation, dribbling, w...
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* Please review the disclaimer below.

Doxazosin Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Other

1 mg, 2 mg, 4 mg and 8 mg1Rx only1 (Each  tablet contains doxazosin mesylate equivalent to 1 mg, 2 mg, 4 mg or 8 mg of
doxazosin)

Description

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-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.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.

Clinical Pharmacology

PharmacodynamicsBenign 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 alpha1c adrenoceptor. 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 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 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.TABLE 1 SUMMARY OF EFFECTIVENESS DATA IN PLACEBO-CONTROLLED TRIALSIn 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 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 1 to 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 1 to 8 mg once
daily.PLACEBO(N=85)DOXAZOSIN(N=183)Sitting BP (mmHg)BaselineChangeBaselineChangeSystolic 128.4-1.4128.8-4.9*Diastolic 79.2-1.279.6-2.4*Standing BP (mmHg)BaselineChangeBaselineChangeSystolic128.5-0.6128.5-5.3*Diastolic80.5-0.780.4-2.6**p < 0.05 compared to placeboHypertensionThe 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
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 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 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 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.PharmacokineticsAfter 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 (see PRECAUTIONS)]. 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.

Indications And Usage

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.HypertensionDoxazosin 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.

Contraindications

Doxazosin tablets are contraindicated in patients with a known
sensitivity to quinazolines (e.g., prazosin, terazosin), doxazosin, or any of
the inert ingredients.

Warnings

Syncope and "First-dose" EffectDoxazosin, 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 (see DOSAGE AND ADMINISTRATION section) 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.PriapismRarely (probably less frequently than once in every several
thousand patients), alpha1 antagonists, 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 (see PRECAUTIONS: Information for Patients).

Precautions

GeneralProstate CancerCarcinoma 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.Cataract SurgeryIntraoperative Floppy Iris Syndrome (IFIS) has been observed
during cataract surgery in some patients on or previously treated with
alpha1 blockers. 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 alpha1
blocker therapy prior to cataract surgery.Orthostatic HypotensionWhile 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.HypertensionThese symptoms were common in clinical trials in hypertension,
occurring in up to 23% of all patients treated and causing discontinuation of
therapy in about 2%.In placebo-controlled titration trials in hypertension, orthostatic effects
were minimized by beginning therapy at 1 mg per day and titrating every two
weeks to 2, 4, or 8 mg per day. There was an increased frequency of orthostatic
effects in patients given 8 mg or more, 10%, compared to 5% at 1 to 4 mg and 3%
in the placebo group.Benign Prostatic HyperplasiaIn placebo-controlled trials in BPH, the incidence of orthostatic
hypotension with doxazosin was 0.3% and did not increase with increasing dosage
(to 8 mg/day). The incidence of discontinuations due to hypotensive or
orthostatic symptoms was 3.3% with doxazosin and 1% with placebo. The titration
interval in these studies was one to two weeks.Patients in occupations in which orthostatic hypotension could be dangerous
should be treated with particular caution. As alpha1
antagonists can cause orthostatic effects, it is important to evaluate standing
blood pressure two minutes after standing and patients should be advised to
exercise care when arising from a supine or sitting position.If hypotension occurs, the patient should be placed in the supine position
and, if this measure is inadequate, volume expansion with intravenous fluids or
vasopressor therapy may be used. A transient hypotensive response is not a
contraindication to further doses of doxazosin.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 alpha1 adrenoceptor
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 alpha1 antagonists. 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).Drug/Laboratory Test InteractionsDoxazosin does not affect the plasma concentration of prostate
specific antigen in patients treated for up to 3 years. Both doxazosin, an
alpha1 inhibitor, 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 alpha1 inhibitors and 5-alpha reductase inhibitors at this
time.Impaired Liver FunctionDoxazosin should be administered with caution to patients with
evidence of impaired hepatic function or to patients receiving drugs known to
influence hepatic metabolism (see CLINICAL
PHARMACOLOGY).Leukopenia/NeutropeniaAnalysis 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/mm3 range over periods of 20 and 40 weeks. One BPH patient had a
decrease from WBC count of 4800/mm3 to 2700/mm3 at 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.Drug InteractionsMost (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 Cmax and 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.Cardiac Toxicity in AnimalsAn 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 Cmax exposure 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 (Cmax) in dogs 14 times the Cmax exposure
in humans receiving a 12 mg/day therapeutic dose] and in Wistar rats at doses of
100 mg/kg/day (Cmax exposures 15 times human Cmax exposure with a 12 mg/day therapeutic dose). There is no
evidence that similar lesions occur in humans.Carcinogenesis, Mutagenesis, Impairment of
FertilityChronic 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.PregnancyTeratogenic EffectsPregnancy Category CStudies in pregnant rabbits and rats at daily oral doses of up to
41 and 20 mg/kg, respectively (plasma drug concentrations 10 and 4 times human
Cmax and AUC exposures with a 12 mg/day therapeutic
dose), have revealed no evidence of harm to the fetus. A dosage regimen of 82
mg/kg/day in the rabbit was associated with reduced fetal survival. There are no
adequate and well-controlled studies in pregnant women. Because animal
reproduction studies are not always predictive of human response, doxazosin
should be used during pregnancy only if clearly needed.Radioactivity was found to cross the placenta following oral administration
of labeled doxazosin to pregnant rats.Nonteratogenic EffectsIn 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.Nursing MothersStudies in lactating rats given a single oral dose of 1 mg/kg of
[2-14C]-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.Pediatric UseThe safety and effectiveness of doxazosin as an antihypertensive
agent have not been established in pediatric patients.Geriatric UseThe 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.

Adverse Reactions

Benign Prostatic HyperplasiaThe 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.TABLE 3 ADVERSE REACTIONS DURING PLACEBO-CONTROLLED STUDIESBENIGN PROSTATIC HYPERPLASIABody SystemDOXAZOSIN(N=665)PLACEBO(N=300)BODY AS A WHOLEBack pain1.8%2.0%Chest Pain1.2%0.7%Fatigue8.0%*1.7%Headache9.9%9.0%Influenza-like symptoms1.1%1.0%Pain2.0%1.0%CARDIOVASCULAR SYSTEMHypotension1.7%*0.0%Palpitation1.2%0.3%DIGESTIVE SYSTEMAbdominal Pain2.4%2.0%Diarrhea2.3%2.0%Dyspepsia1.7%1.7%Nausea1.5%0.7%METABOLIC AND NUTRITIONAL DISORDERSEdema2.7%*0.7%NERVOUS SYSTEMDizziness†15.6%*9.0%Mouth Dry1.4%0.3%Somnolence3.0%1.0%RESPIRATORY SYSTEMDyspnea2.6%*0.3%Respiratory Disorder1.1%0.7%SPECIAL SENSESVision Abnormal 1.4%0.7%UROGENITAL SYSTEMImpotence1.1%1.0%Urinary Tract Infection1.4%2.3%SKIN & APPENDAGESSweating Increased1.1%1.0%PSYCHIATRIC DISORDERSAnxiety1.1%0.3%Insomnia1.2%0.3%*p < 0.05 for treatment differences†Includes vertigoIn 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.HypertensionDoxazosin 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.TABLE 4 ADVERSE REACTIONS DURING PLACEBO-CONTROLLED STUDIESHYPERTENSIONDOXAZOSIN(N=339)PLACEBO(N=336)CARDIOVASCULAR SYSTEM  Dizziness19%9%  Vertigo2%1%  Postural Hypotension0.3%0%  Edema4%3%  Palpitation2%3%  Arrhythmia1%0%  Hypotension1%0%  Tachycardia0.3%1%  Peripheral Ischemia0.3%0%SKIN & APPENDAGES  Rash1%1%  Pruritus1%1%MUSCULOSKELETAL SYSTEM  Arthralgia/Arthritis1%0%  Muscle Weakness1%0%  Myalgia1%0%CENTRAL & PERIPHERAL N.S.  Headache14%16%  Paresthesia1%1%  Kinetic Disorders1%0%  Ataxia1%0%  Hypertonia1%0%  Muscle Cramps1%0%AUTONOMIC  Mouth Dry2%2%  Flushing1%0%SPECIAL SENSES  Vision Abnormal 2%1%  Conjunctivitis/Eye Pain 1%1%  Tinnitus 1%0.3%PSYCHIATRIC  Somnolence 5%1%  Nervousness 2%2%  Depression 1%1%  Insomnia 1%1%  Sexual Dysfunction 2%1%GASTROINTESTINAL  Nausea 3%4%  Diarrhea 2%3%  Constipation 1%1%  Dyspepsia 1%1%  Flatulence 1%1%  Abdominal Pain 0%2%  Vomiting0%1%RESPIRATORY  Rhinitis 3%1%  Dyspnea 1%1%  Epistaxis 1%0%URINARY  Polyuria 2%0%  Urinary Incontinence 1%0%  Micturition Frequency 0%2%GENERAL  Fatigue/Malaise12%6%  Chest Pain 2%2%  Asthenia 1%1%  Face Edema 1%0%  Pain 2%2%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 (see PRECAUTIONS).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 (see PRECAUTIONS: General: Cataract Surgery); Urinary System: hematuria, micturition disorder,
micturition frequency, nocturia.

Overdosage

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 LD50 of 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.

Dosage And Administration

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.Benign Prostatic Hyperplasia 1 to 8 mg Once
DailyThe 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.Hypertension 1 to 16 mg Once DailyThe 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.

How Supplied/Storage And Handling

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.1 mg:  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:Bottles of 30NDC 54868-4895-0Bottles of 100NDC 54868-4895-12 mg:  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:Bottles of 30NDC 54868-4801-0Bottles of 60NDC 54868-4801-2Bottles of 90NDC 54868-4801-3Bottles of 100NDC 54868-4801-14 mg:  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:Bottles of 25NDC 54868-4802-3Bottles of 30NDC 54868-4802-0Bottles of 60NDC 54868-4802-2Bottles of 90NDC 54868-4802-4Bottles of 100NDC 54868-4802-18 mg:  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:Bottles of 30NDC 54868-4767-0Bottles of 90NDC 54868-4767-2Bottles of 100NDC 54868-4767-1Store 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.Mylan Pharmaceuticals Inc.Morgantown, WV 26505REVISED AUGUST 2007DXZN:R6pRelabeling and Repackaging by:Physicians Total Care, Inc.Tulsa, OK       74146

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