SIDE EFFECTS
Benign Prostatic Hyperplasia
The incidence of adverse events has been ascertained
from worldwide clinical trials in 965 BPH patients. The
incidence rates presented in TABLE 3 are based on combined
data from seven placebo-controlled trials involving once
daily administration of doxazosin mesylate in doses of
1-16 mg in hypertensives and 0.5-8 mg in normotensives.
The adverse events when the incidence in the doxazosin
mesylate 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 Studies
Benign Prostatic Hyperplasia |
| Body System |
Doxazosin Mesylate (N=665) |
Placebo (N=300) |
| Body
as a Whole |
|
|
1.8% |
2.0% |
|
|
1.2% |
0.7% |
|
|
8.0%* |
1.7% |
|
|
9.9% |
9.0% |
|
|
1.1% |
1.0% |
|
|
2.0% |
1.0% |
| Cardiovascular
System |
|
|
1.7%* |
0.0% |
|
|
1.2% |
0.3% |
| Digestive
System |
|
|
2.4% |
2.0% |
|
|
2.3% |
2.0% |
|
|
1.7% |
1.7% |
|
|
1.5% |
0.7% |
| Metabolic
and Nutritional Disorders |
|
|
2.7%* |
0.7% |
| Nervous
System |
|
|
15.6%* |
9.0% |
|
|
1.4% |
0.3% |
|
|
3.0% |
1.0% |
| Respiratory
System |
|
|
2.6%* |
0.3% |
|
|
1.1% |
0.7% |
| Special
Senses |
|
|
1.4% |
0.7% |
| Urogenital
System |
|
|
1.1% |
1.0% |
|
|
1.4% |
2.3% |
| Skin
& Appendages |
|
|
1.1% |
1.0% |
| Psychiatric
Disorders |
|
|
1.1% |
0.3% |
|
|
1.2% |
0.3% |
| * p £
0.05 for treatment differences. |
| † Includes
vertigo. |
In these placebo-controlled studies of 665 doxazosin mesylate
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 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%).
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
were mild.
Hypertension
Doxazosin mesylate has 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 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 1-16 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 Studies |
| |
Hypertension |
| |
Doxazosin (N=339) |
Placebo (N=336) |
| Cardiovascular
System |
|
|
19% |
9% |
|
|
2% |
1% |
|
|
0.3% |
0% |
|
|
4% |
3% |
|
|
2% |
3% |
|
|
1% |
0% |
|
|
1% |
0% |
|
|
0.3% |
1% |
|
|
0.3% |
0% |
| Skin
& Appendages |
|
|
1% |
1% |
|
|
1% |
1% |
| Musculoskeletal
System |
|
|
1% |
0% |
|
|
1% |
0% |
|
|
1% |
0% |
| Central
& Peripheral N.S. |
|
|
14% |
16% |
|
|
1% |
1% |
|
|
1% |
0% |
|
|
1% |
0% |
|
|
1% |
0% |
|
|
1% |
0% |
| Autonomic |
|
|
2% |
2% |
|
|
1% |
0% |
| Special
Seneses |
|
|
2% |
1% |
|
|
1% |
1% |
|
|
1% |
0.3% |
| Psychiatric |
|
|
5% |
1% |
|
|
2% |
2% |
|
|
1% |
1% |
|
|
1% |
1% |
|
|
2% |
1% |
| Gastrointestinal |
|
|
3% |
4% |
|
|
2% |
3% |
|
|
1% |
1% |
|
|
1% |
1% |
|
|
1% |
1% |
|
|
0% |
2% |
|
|
0% |
1% |
| Respiratory |
|
|
3% |
1% |
|
|
1% |
1% |
|
|
1% |
0% |
| Urinary |
|
|
2% |
0% |
|
|
1% |
0% |
|
|
0% |
2% |
| General |
|
|
12% |
6% |
|
|
2% |
2% |
|
|
1% |
1% |
|
|
1% |
0% |
|
|
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 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 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 mesylate has been associated
with decreases in white blood cell counts (see PRECAUTIONS).
DRUG INTERACTIONS
Most (98%) of plasma doxazosin is protein bound. In vitro
data in human plasma indicate that doxazosin mesylate
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 mesylate 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 four-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 mesylate 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 mesylate 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.
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