PRECAUTIONSGeneralProstate 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.
Cataract Surgery
Intraoperative 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 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.
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 to 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.
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 Interactions
Doxazosin 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 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 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 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 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 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, 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.
PregnancyTeratogenic EffectsPregnancy 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
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 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.
Nursing Mothers
Studies 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 Use
The safety and effectiveness of doxazosin as an antihypertensive
agent have not been established in pediatric patients.
Geriatric Use
The safety and effectiveness profile of doxazosin in BPH was
similar in the elderly (age ≥ 65 years) and younger (age less 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.
