WARNINGS
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 (see DOSAGE AND ADMINISTRATION) 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 1500 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.
Priapism: Rarely (probably less frequently
than once in every several thousand patients), alpha1
antagonists such as 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 the Patient).
PRECAUTIONS
General
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 mesylate.
Orthostatic Hypotension
While syncope is the most severe orthostatic effect of
doxazosin mesylate, 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.
Hypertension: These 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 1-4 mg and 3% in the placebo group.
Benign Prostatic Hyperplasia: In 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
mesylate.
Information for the Patient
(See PATIENT PACKAGE INSERT). 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 mesylate 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 Interactions
Doxazosin mesylate 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 Function
Doxazosin mesylate 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/Neutropenia
Analysis of hematologic data from hypertensive patients
receiving doxazosin mesylate in controlled hypertension
clinical trials showed that the mean WBC (N=474) and mean
neutrophil counts (N=419) were decreased by 2.4% and 1.0%,
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 mesylate and 0% (0/147) with placebo, with
no statistically significant difference between the two
treatment groups. A search through a data base of 2400
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 a 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 mesylate. No patients became symptomatic
as a result of the low WBC or neutrophil counts.
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 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, and 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.
Pregnancy, Teratogenic Effects, Pregnancy Category
C
Studies 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 mesylate should
be used during pregnancy only if clearly needed.
Radioactivity was found to cross the placenta following
oral administration of labelled doxazosin to pregnant
rats.
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 slightly later appearance of anatomical features and
reflexes.
Nursing Mothers
Studies in lactating rats given a single oral dose of
1 mg/kg of [2-14C]-doxazosin mesylate 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 mesylate is administered
to a nursing mother.
Pediatric Use
The safety and effectiveness of doxazosin mesylate as
an antihypertensive agent have not been established in
children.
Geriatric Use
The safety and effectiveness profile of doxazosin mesylate
in BPH was similar in the elderly (age ³ 65 years)
and younger (age <65 years) patients.
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