PRAZOSIN
DESCRIPTION:
MINIPRESS(R) (prazosin hydrochloride), a quinazoline derivative, is the first of
a new chemical class of antihypertensives. It is the hydrochloride salt of 1-(4-
amino-6,7-dimethoxy- 2-quinazolinyl)-4-(2-furoyl) piperazine.
It is a white, crystalline substance, slightly soluble in water and isotonic
saline, and has a molecular weight of 419.87. Each 1 mg capsule of MINIPRESS for
oral use contains drug equivalent to 1 mg free base.
ACTIONS/CLINICAL PHARMACOLOGY:
The exact mechanism of the hypotensive action of prazosin is unknown. Prazosin
causes a decrease in total peripheral resistance and was originally thought to
have a direct relaxant action on vascular smooth muscle. Recent animal studies,
however, have suggested that the vasodilator effect of prazosin is also related
to blockade of postsynaptic Alpha-adrenoceptors. The results of dog forelimb
experiments demonstrate that the peripheral vasodilator effect of prazosin is
confined mainly to the level of the resistance vessels (arterioles). Unlike
conventional Alpha- blockers, the antihypertensive action of prazosin is usually
not accompanied by a reflex tachycardia. Tolerance has not been observed to
develop in long term therapy.
Hemodynamic studies have been carried out in man following acute single dose
administration and during the course of long term maintenance therapy. The
results confirm that the therapeutic effect is a fall in blood pressure
unaccompanied by a clinically significant change in cardiac output, heart rate,
renal blood flow and glomerular filtration rate. There is no measurable negative
chronotropic effect.
In clinical studies to date, MINIPRESS (prazosin hydrochloride) has not
increased plasma renin activity.
In man, blood pressure is lowered in both the supine and standing positions.
This effect is most pronounced on the diastolic blood pressure.
Following oral administration, human plasma concentrations reach a peak at about
three hours with a plasma half-life of two to three hours. The drug is highly
bound to plasma protein. Bioavailability studies have demonstrated that the
total absorption relative to the drug in a 20% alcoholic solution is 90%,
resulting in peak levels approximately 65% of that of the drug in solution.
Animal studies indicate that MINIPRESS (prazosin hydrochloride) is extensively
metabolized, primarily by demethylation and conjugation, and excreted mainly via
bile and feces. Less extensive human studies suggest similar metabolism and
excretion in man.
In clinical studies in which lipid profiles were followed, there were generally
no adverse changes noted between pre- and post-treatment lipid levels.
INDICATIONS AND USAGE:
MINIPRESS (prazosin hydrochloride) is indicated in the treatment of
hypertension. It can be used alone or in combination with other antihypertensive
drugs such as diuretics or beta- adrenergic blocking agents.
CONTRAINDICATIONS:
None known.
WARNINGS:
MINIPRESS (PRAZOSIN HYDROCHLORIDE) MAY CAUSE SYNCOPE WITH SUDDEN LOSS OF
CONSCIOUSNESS. IN MOST CASES THIS IS BELIEVED TO BE DUE TO AN EXCESSIVE POSTURAL
HYPOTENSIVE EFFECT, ALTHOUGH OCCASIONALLY THE SYNCOPAL EPISODE HAS BEEN PRECEDED
BY A BOUT OF SEVERE TACHYCARDIA WITH HEART RATES OF 120-160 BEATS PER MINUTE.
SYNCOPAL EPISODES HAVE USUALLY OCCURRED WITHIN 30 TO 90 MINUTES OF THE INITIAL
DOSE OF THE DRUG; OCCASIONALLY THEY HAVE BEEN REPORTED IN ASSOCIATION WITH RAPID
DOSAGE INCREASES OR THE INTRODUCTION OF ANOTHER ANTIHYPERTENSIVE DRUG INTO THE
REGIMEN OF A PATIENT TAKING HIGH DOSES OF MINIPRESS (PRAZOSIN HYDROCHLORIDE).
THE INCIDENCE OF SYNCOPAL EPISODES IS APPROXIMATELY 1% IN PATIENTS GIVEN AN
INITIAL DOSE OF 2 MG OR GREATER. CLINICAL TRIALS CONDUCTED DURING THE
INVESTIGATIONAL PHASE OF THIS DRUG SUGGEST THAT SYNCOPAL EPISODES CAN BE
MINIMIZED BY LIMITING THE INITIAL DOSE OF THE DRUG TO 1 MG, BY SUBSEQUENTLY
INCREASING THE DOSAGE SLOWLY, AND BY INTRODUCING ANY ADDITIONAL ANTIHYPERTENSIVE
DRUGS INTO THE PATIENT'S REGIMEN WITH CAUTION (SEE DOSAGE AND ADMINISTRATION).
HYPOTENSION MAY DEVELOP IN PATIENTS GIVEN MINIPRESS WHO ARE ALSO RECEIVING A
BETA-BLOCKER SUCH AS PROPRANOLOL.
If syncope occurs, the patient should be placed in the recumbent position and
treated supportively as necessary. This adverse effect is self-limiting and in
most cases does not recur after the initial period of therapy or during
subsequent dose titration.
Patients should always be started on the 1 mg capsules of MINIPRESS (prazosin
hydrochloride). The 2 and 5 mg capsules are not indicated for initial therapy.
More common than loss of consciousness are the symptoms often associated with
lowering of the blood pressure, namely, dizziness and lightheadedness. The
patient should be cautioned about these possible adverse effects and advised
what measures to take should they develop. The patient should also be cautioned
to avoid situations where injury could result should syncope occur during the
initiation of MINIPRESS (prazosin hydrochloride) therapy.
PRECAUTIONS:
INFORMATION FOR PATIENTS: Dizziness or drowsiness may occur after the first dose
of this medicine. Avoid driving or performing hazardous tasks for the first 24
hours after taking this medicine or when the dose is increased. Dizziness,
lightheadedness or fainting may occur, especially when rising from a lying or
sitting position. Getting up slowly may help lessen the problem. These effects
may also occur if you drink alcohol, stand for long periods of time, exercise,
or if the weather is hot. While taking MINIPRESS, be careful in the amount of
alcohol you drink. Also, use extra care during exercise or hot weather, or if
standing for long periods. Check with your physician if you have any questions.
DRUG INTERACTIONS
MINIPRESS (prazosin hydrochloride) has been administered without any adverse
drug interaction in limited clinical experience to date with the following: (1)
cardiac glycosides-- digitalis and digoxin; (2) hypoglycemics--insulin,
chlorpropamide, phenformin, tolazamide, and tolbutamide; (3) tranquilizers and
sedatives- -chlordiazepoxide, diazepam, and phenobarbital; (4) antigout--
allopurinol, colchicine, and probenecid; (5) antiarrhythmics--procainamide,
propranolol (see WARNINGS however), and quinidine; and (6) analgesics,
antipyretics and anti-inflammatories--propoxyphene, aspirin, indomethacin, and
phenylbutazone.
Addition of a diuretic or other antihypertensive agent to MINIPRESS has been
shown to cause an additive hypotensive effect. This effect can be minimized by
reducing the MINIPRESS dose to 1 to 2 mg three times a day, by introducing
additional antihypertensive drugs cautiously and then by retitrating MINIPRESS
based on clinical response.
DRUG/LABORATORY TEST INTERACTIONS
In a study on five patients given from 12 to 24 mg of prazosin per day for 10 to
14 days, there was an average increase of 42% in the urinary metabolite of
norepinephrine and an average increase in urinary VMA of 17%. Therefore, false
positive results may occur in screening tests for pheochromocytoma in patients
who are being treated with prazosin. If an elevated VMA is found, prazosin
should be discontinued and the patient retested after a month.
LABORATORY TESTS
In clinical studies in which lipid profiles were followed, there were generally
no adverse changes noted between pre- and post-treatment lipid levels.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: No carcinogenic potential
was demonstrated in an 18 month study in rats with MINIPRESS at dose levels more
than 225 times the usual maximum recommended human dose of 20 mg per day.
MINIPRESS was not mutagenic in In Vivo genetic toxicology studies. In a
fertility and general reproductive performance study in rats, both males and
females, treated with 75 mg/kg (225 times the usual maximum recommended human
dose), demonstrated decreased fertility while those treated with 25 mg/kg (75
times the usual maximum recommended human dose) did not.
In chronic studies (one year or more) of MINIPRESS in rats and dogs, testicular
changes consisting of atrophy and necrosis occurred at 25mg/kg/day (75 times the
usual maximum recommended human dose). No testicular changes were seen in rats
or dogs at 10 mg/kg/day (30 times the usual maximum recommended human dose). In
view of the testicular changes observed in animals, 105 patients on long term
MINIPRESS therapy were monitored for 17-ketosteroid excretion and no changes
indicating a drug effect were observed. In addition, 27 males on MINIPRESS for
up to 51 months did not have changes in sperm morphology suggestive of drug
effect.
USAGE IN PREGNANCY: Category C. MINIPRESS has been shown to be associated with
decreased litter size at birth, 1, 4, and 21 days of age in rats when given
doses more than 225 times the usual maximum recommended human dose. No evidence
of drug-related external, visceral, or skeletal fetal abnormalities were
observed. No drug- related external, visceral, or skeletal abnormalities were
observed in fetuses of pregnant rabbits and pregnant monkeys at doses more than
225 times and 12 times the usual maximum recommended human dose respectively.
The use of prazosin and a beta-blocker for the control of severe hypertension in
44 pregnant women revealed no drug-related fetal abnormalities or adverse
effects. Therapy with prazosin was continued for as long as 14 weeks. (REF. 1)
Prazosin has also been used alone or in combination with other hypotensive
agents in severe hypertension of pregnancy by other investigators. No fetal or
neonatal abnormalities have been reported with the use of prazosin. (REF. 2)
There are no adequate and well controlled studies which establish the safety of
MINIPRESS (prazosin hydrochloride) in pregnant women. MINIPRESS should be used
during pregnancy only if the potential benefit justifies the potential risk to
the mother and fetus.
NURSING MOTHERS: MINIPRESS has been shown to be excreted in small amounts in
human milk. Caution should be exercised when MINIPRESS is administered to a
nursing woman.
USAGE IN CHILDREN: Safety and effectiveness in children have not been
established.
DRUG INTERACTIONS:
MINIPRESS has been administered without any adverse drug interaction in limited
clinical experience to date with the following: (1) cardiac glycosides--
digitalis and digoxin; (2) hypoglycemics--insulin, chlorpropamide, phenformin,
tolazamide, and tolbutamide; (3) tranquilizers and sedatives--chlordiazepoxide,
diazepam, and phenobarbital; (4) antigout- -allopurinol, colchicine, and
probenecid; (5) antiarrhythmics--procainamide, propranolol (see WARNINGS
however), and quinidine; and (6) analgesics, antipyretics and anti-
inflammatories- -propoxyphene, aspirin, indomethacin, and phenylbutazone.
Addition of a diuretic or other antihypertensive agent to MINIPRESS has been
shown to cause an additive hypotensive effect. This effect can be minimized by
reducing the MINIPRESS dose to 1 to 2 mg three times a day, by introducing
additional antihypertensive drugs cautiously and then by retitrating MINIPRESS
based on clinical response.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
Clinical trials were conducted on more than 900 patients. During these trials
and subsequent marketing experience, the most frequent reactions associated with
MINIPRESS therapy are: dizziness 10.3%, headache 7.8%, drowsiness 7.6%, lack of
energy 6.9%, weakness 6.5%, palpitations 5.3%, and nausea 4.9%. In most
instances side effects have disappeared with continued therapy or have been
tolerated with no decrease in dose of drug.
Less frequent adverse reactions which are reported to occur in 1-4% of patients
are:
Gastrointestinal: vomiting, diarrhea, constipation.
Cardiovascular: edema, orthostatic hypotension, dyspnea, syncope.
Central Nervous System: vertigo, depression, nervousness.
Dermatologic: rash.
Genitourinary: urinary frequency.
EENT: blurred vision, reddened sclera, epistaxis, dry mouth, nasal congestion.
In addition, fewer than 1% of patients have reported the following (in some
instances, exact causal relationships have not been established):
Gastrointestinal: abdominal discomfort and/or pain, liver function
abnormalities, pancreatitis.
Cardiovascular: tachycardia.
Central Nervous System: paresthesia, hallucinations.
Dermatologic: pruritus, alopecia, lichen planus.
Genitourinary: incontinence, impotence, priapism.
EENT: tinnitus.
Other: diaphoresis, fever, positive ANA titer, arthralgia.
Single reports of pigmentary mottling and serous retinopathy, and a few reports
of cataract development or disappearance have been reported. In these instances,
the exact causal relationship has not been established because the baseline
observations were frequently inadequate.
In more specific slit-lamp and funduscopic studies, which included adequate
baseline examinations, no drug-related abnormal ophthalmological findings have
been reported.
Literature reports exist associating MINIPRESS therapy with a worsening of pre-
existing narcolepsy. A causal relationship is uncertain in these cases.
OVERDOSAGE:
Accidental ingestion of at least 50 mg of MINIPRESS (prazosin hydrochloride) in
a two year old child resulted in profound drowsiness and depressed reflexes. No
decrease in blood pressure was noted. Recovery was uneventful.
Should overdosage lead to hypotension, support of the cardiovascular system is
of first importance. Restoration of blood pressure and normalization of heart
rate may be accomplished by keeping the patient in the supine position. If this
measure is inadequate, shock should first be treated with volume expanders. If
necessary, vasopressors should then be used. Renal function should be monitored
and supported as needed. Laboratory data indicate MINIPRESS is not dialysable
because it is protein bound.
DOSAGE AND ADMINISTRATION:
The dose of MINIPRESS should be adjusted according to the patient's individual
blood pressure response. The following is a guide to its administration:
INITIAL DOSE
1 mg two or three times a day. (See WARNINGS)
MAINTENANCE DOSE
Dosage may be slowly increased to a total daily dose of 20 mg given in divided
doses. The therapeutic dosages most commonly employed have ranged from 6 mg to
15 mg daily given in divided doses. Doses higher than 20 mg usually do not
increase efficacy, however a few patients may benefit from further increases up
to a daily dose of 40 mg given in divided doses. After initial titration some
patients can be maintained adequately on a twice daily dosage regimen.
USE WITH OTHER DRUGS
When adding a diuretic or other antihypertensive agent, the dose of MINIPRESS
should be reduced to 1 mg or 2 mg three times a day and retitration then carried
out.
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