Canada - English - Health Canada
1.0, 2.0 and 5.0 mg Tablets
Teva Canada Limited
Date of Preparation:
30 Novopharm Court
September 28, 2011
Canada M1B 2K9
Submission Control#: 149916
1.0, 2.0 and 5.0 mg Tablets
ACTION AND CLINICAL PHARMACOLOGY
TEVA-PRAZOSIN (prazosin hydrochloride) is a sympatholytic antihypertensive agent. Its
primary mechanism of action is the competitive blockade of the vascular postsynaptic alpha-
adrenoceptors. Prazosin acts preferentially on post-synaptic alpha
blocking the contractile response of vascular smooth muscle to norepinephrine without
interfering with its activity at alpha
-receptors. Abrupt termination of prazosin treatment does
not appear to cause a rebound elevation in blood pressure. Tolerance to prazosin does not
appear to develop.
Hemodynamic studies have shown that the decrease in blood pressure is not accompanied by
any significant changes in renal blood flow or glomerular filtration rate.
A comparative three-way bioavailability study was conducted in order to compare TEVA-
PRAZOSIN 1 mg and 2 mg Tablets with MINIPRESS
2 mg Tablets. The pharmacokinetic
data (mean ± standard deviation) calculated for TEVA-PRAZOSIN and MINIPRESS
Arithmetic Mean (C.V.)
1 x 2 mg
2 x 1 mg
1 x 2 mg
For the T
parameters these are the arithmetic means (standard deviation).
A comparative, two-way bioavailability study was conducted to compare TEVA-PRAZOSIN
5 mg Tablets and MINIPRESS
5 mg Tablets. The pharmacokinetic data (mean ± standard
deviation) calculated for TEVA-PRAZOSIN and MINIPRESS
are tabulated below:
Arithmetic Mean (C.V.)
1 x 5 mg
1 x 5 mg
For the T
parameters these are the arithmetic means (standard deviation).
Following oral administration of prazosin hydrochloride, plasma concentrations of the drug
reach a peak in 1 to 3 hours in most fasting patients. Blood pressure begins to decrease within
2 hours after oral dosing with the maximal decrease occurring in 2 to 4 hours. A period of 4
to 6 weeks at a maintenance dose level may be required before the full effect of the drug is
INDICATIONS AND CLINICAL USE
TEVA-PRAZOSIN (prazosin hydrochloride) is indicated in the treatment of hypertension. It
has mild to moderate antihypertensive activity. Prazosin is employed in a general treatment
program in conjunction with other antihypertensive agents and/or diuretic drugs, depending
on the needs of the patient. In cases of mild hypertension, TEVA-PRAZOSIN can be
employed as the initial treatment if the physician feels that treatment should be initiated with
a sympatholytic rather than a diuretic agent.
TEVA-PRAZOSIN (prazosin hydrochloride) is contraindicated in patients with a known
hypersensitivity to the drug.
TEVA-PRAZOSIN (prazosin hydrochloride) can cause syncope with a sudden loss of
consciousness. This is believed to be the result of an excessive postural hypotensive effect in
most cases. Occasionally, however, syncopal episodes have been associated with a bout of
severe tachycardia with heart rates between 120 and 160 beats per minute. When the dose is
increased gradually, as described under dosage and administration, the occurrence of syncope
is rare. If the initial dose exceeds 0.5 mg, however, the risk of syncope is increased. Syncope
episodes have occurred with 30 to 90 minutes of the initial dose. Syncope has also been
reported in association with the introduction of prazosin hydrochloride into the treatment
regimen of patients already taking a diuretic or another antihypertensive agent, as well as
with dosage increases. It is therefore advisable to limit the initial dosage to 0.5 mg bid or tid
and to make gradual increases. Caution should also be exercised when any additional
hypertensive drugs are added to the treatment regimen.
The addition of TEVA-PRAZOSIN into the regimen of patients whose blood pressure is not
adequately controlled by large doses of beta-adrenergic blocking agents, such as propranolol,
may result in acute hypotension. The dose of the beta-adrenergic blocking agent should,
therefore, be reduced prior to the administration of TEVA-PRAZOSIN in order to minimize
the risk of acute hypotension in these patients. It is also strongly recommended that TEVA-
PRAZOSIN administration be initiated at a low dosage (see DOSAGE AND
If syncope occurs, the patient should be placed in the recumbent position and supportive
measures should be instituted. Syncope is self-limiting, and in most cases, does not recur
once a steady maintenance level is initiated. Patients should be advised to avoid situations
where injury could result should syncope occur. This is especially important during the initial
dose adjustment period.
The symptoms associated with a decrease in blood pressure, namely dizziness and
lightheadedness, are more common than loss of consciousness. Patients should be warned
about the possible adverse effects and advised on what measures to take should these
Use During Pregnancy
TEVA-PRAZOSIN (prazosin hydrochloride) is not recommended for use in pregnant women
or nursing mothers unless the potential benefit out weighs the possible risk to the mother and
child. Although animal studies have not revealed any teratogenic effects; the safety of
prazosin hydrochloride has not been established in this patient group.
Use for Children
The safety of TEVA-PRAZOSIN (prazosin hydrochloride) has not been established in
pediatric patients, therefore, it is not recommended for use in children under 12 years of age,
Use in Patients with Moderate to Severe Grades of Renal Impairment:
Patients with moderate to severe grades of renal impairment have, in some cases, responded
to smaller than usual doses of prazosin hydrochloride. It is recommended, therefore, that
treatment with TEVA-PRAZOSIN (prazosin hydrochloride) be initiated at 0.5 mg daily and
that any increases in dose be instituted with caution.
When prazosin is used with diuretics or other hypotensive agents, particularly beta-
adrenergic blocking agents, the hypotensive effect of prazosin may be increased. Careful
adjustment of dosage is, therefore, necessary when these drugs are used concomitantly. (See
DOSAGE AND ADMINISTRATION: Use with Other Drugs)
Prazosin hydrochloride has been administered without any adverse drug interaction in the
limited clinical experience to date with the following (1) cardiac glycosides digitalis and
digoxin; (2) hypoglycemic agents - insulin, chlorpropamide, phenformin, tolazamide and
tolbutamide; (3) tranquilizers and sedatives - chlordiazepoxide, diazepam and phenobarbital;
(4) agents for the treatment of gout - allopurinol, colchicine and probenecid; (5)
antiarrhythmic agents – procainamide and quinidine; and (6) analgesic, antipyretic and anti-
inflammatory agents - propoxyphene, aspirin, indomethacin and phenylbutazone.
The most common reactions associated with prazosin hydrochloride are: postural dizziness
(10.3%), nausea (4.9%); drowsiness (7.6%), headache (7.8%), palpitations (5.3%), weakness
(6.5%) and fatigue/malaise (6.9%). In most cases, the side effects disappear with continued
therapy, or can be tolerated without a decrease in dosage. The following reactions have also
been observed during prazosin hydrochloride administration, some of them rarely:
vomiting, diarrhea, constipation, abdominal discomfort and/or pain, liver
function abnormalities, pancreatitis.
syncope (see WARNINGS), edema, dyspnea, tachycardia.
Nervous System: nervousness, vertigo, depression, paresthesia, hallucinations.
rash, pruritus, alopecia, lichen planus.
urinary frequency, incontinence, impotence, priapism.
blurred vision, reddened sclera, epistaxis, tinnitus, dry mouth, nasal
Single reports of pigmentary mottling and serious retinopathy, and a few reports of cataract
development have been reported. In these instances, the exact causal relationship has not
been established because the baseline observations were frequently inadequate.
No drug related abnormal ophthalmological findings were reported in slit-lamp and
fundoscopic studies which included adequate baseline examinations.
SYMPTOMS AND TREATMENT OF OVERDOSAGE
A 2-year old child accidentally ingested at least 50 mg of prazosin hydrochloride. The
resulting symptoms were profound drowsiness and depressed reflexes. No decrease in blood
pressure was noted and recovery was uneventful.
If hypotension occurs as a result of the overdose, support of the cardiovascular system is of
primary importance. By placing the patient in the supine position, the heart rate may be
normalized and normal blood pressure can be restored. Vasopressors should be used if
required and if necessary, volume expanders should be used to treat shock. Renal function
should be monitored and supported if necessary. Laboratory data indicates that since prazosin
is protein bound, it is not dialyzable.
DOSAGE AND ADMINISTRATION
When TEVA-PRAZOSIN (prazosin hydrochloride) tablets are used for titration, it
is necessary to split the 1.0 mg scored tablet in order to obtain the 0.5 mg starting
The initial dose of 0.5 mg should be taken with food, preferably with the evening meal, and
at least 2 to 3 hours before retiring. The dose should be increased gradually, with 0.5 mg,
taken bid or tid, for at least 3 days. Depending on the blood pressure lowering effect, and the
occurrence of adverse effects, the dose should be increased to 1.0 mg b.i.d or tid for at least
another 3 days.
The dose should then be increased gradually, depending on the patient’s response to the
blood pressure lowering effect. If a response is to occur at any particular dose, it will usually
be seen within 1 to 14 days. Once a response is seen, therapy should be continued at that dose
until the response has reached the optimum. The dosage can then be increased gradually until
the desired effect is obtained, or until a maximum dose of 20 mg/day is reached.
The maintenance dose may be given as a twice daily dosage regimen.
It is recommended that for patients with moderate to severe renal impairment, therapy be
initiated at 0.5 mg daily, and that dosage increases be made gradually.
USE WITH OTHER DRUGS
Patients Receiving Diuretic Therapy:
TEVA-PRAZOSIN (prazosin hydrochloride) should be initiated at 0.5 mg bid or tid after the
diuretic has been reduced to a maintenance dose level. After an initial period of observation,
the TEVA-PRAZOSIN dose should be increased gradually, according to the patient’s
Patients Receiving Other Antihypertensive Agents:
Some additive effect is anticipated, therefore; the dose of the other agent (for example,
propranolol* or other beta-adrenergic blocking agents*, alpha methyldopa, reserpine,
clonidine*, etc.) should be reduced and TEVA-PRAZOSIN (prazosin hydrochloride) should
be initiated at 0.5 mg bid or tid. Any dosage increase should be made depending on the
response of the patient.
*Appropriate precautions should be taken when the dosage of these other antihypertensive
agents is reduced.
Patients on TEVA-PRAZOSIN to Whom Other Antihypertensive Agents Are Added:
TEVA-PRAZOSIN (prazosin hydrochloride) should be reduced to 1 or 2 mg bid or tid before
adding another antihypertensive agent or a diuretic drug. The patient should then be re-
Molecular Weight: 419.87
Prazosin hydrochloride is a white crystalline substance which is
slightly soluble in water and isotonic saline.
STABILITY AND STORAGE RECOMMENDATIONS:
Store between 15°-30°C and protect from light. Unit dose strips should be stored between
15°-25°C and protected from light and high humidity.
AVAILABILITY OF DOSAGE FORMS
TEVA-PRAZOSIN is available as:
1.0 mg -
Orange coloured, capsule-shaped, bi-convex, compressed tablets engraved
no|vo on one side and ‘1’ on the reverse, containing prazosin hydrochloride
equivalent to 1 mg prazosin.
2.0 mg -
White, round, biconvex, compressed tablets engraved novo on one side and 2
between broken vertical scorelines on the reverse, containing prazosin
hydrochloride equivalent to 2.0 mg prazosin.
5.0 mg -
White, diamond-shaped, biconvex, compressed tablets; engraved no|vo on one
side and 5 on the reverse, containing prazosin hydrochloride equivalent to 5
Bottles of 100 and 500 and boxes of 100 as unit dose strips.
The hypotensive action of prazosin hydrochloride has been studied using both in vitro and in
vivo methodology. Prolonged hypotension and a reduction in the total peripheral resistance
resulted when prazosin was administered intravenously in dogs. There was also a transient
increase in cardiac output, heart rate and blood flow in the femoral, renal and splanchnic
vascular beds. When electrical stimulation was applied to the cardioaccelerator nerves, no
depression of cardiac responses was seen, nor was there any blockade of the sympathetic
ganglion or adrenergic neurons. Prazosin hydrochloride reversed the epinephrine pressor
response in intact animals, but when the vessels were deprived of sympathetic tone, through
ganglionic blockade, the vasodilator activity was only slightly diminished.
It is believed that the hypotensive effect of prazosin hydrochloride is the result of
vasodilation, which is dependent on both direct reaction of vascular smooth muscle, and
peripheral sympatholytic activity. in vitro analysis of sympatholytic activity shows that
prazosin hydrochloride modulates the function of alpha-adrenergic receptors in a manner
which does not involve occupancy blockade. It has been suggested that prazosin
hydrochloride acts at a site distal to the alpha-adrenergic receptors in a manner which
preserves compensatory reflexes.
The hypotensive effect of prazosin hydrochloride, administered intravenously in the dog, can
be reversed through intravenous infusion of metaraminol and norepinephrine.
Prazosin hydrochloride has mild CNS depressant activity, when administered to rats at doses
which are considerably higher than those required for antihypertensive activity. At these
elevated doses it also decreases heart norepinephrine and is hyperglycemic in rats. Prazosin
caused diuresis when administered to dogs, but resulted in fluid retention when the same
dose was given orally to dogs and mice.
Clinical studies to date, indicate that plasma renin activity is not increased by prazosin
In humans, the maximum drug levels attained, following oral administration of prazosin
hydrochloride, are generally low and variable. Peak serum concentrations of approximately
23 ± 10.5 ng/mL have been reported 1 to 3 hours after a single 2 mg oral dose.
Prazosin hydrochloride is highly protein bound in human plasma (97%), yet disappears
rapidly with a plasma half-life of 1.77 to 4.55 hours. There is no apparent drug accumulation
after chronic administration, nor is there any decreases in plasma concentrations.
There was no correlation between maximum plasma drug levels and decrease in blood
pressure, between rates of use and fail in drug levels and the mean arterial pressure response,
or between the total plasma drug concentration and the biological effect. The relationship
between plasma drug concentrations and biological response is somewhat obscure, and drug
activity persists for approximately 10 hours which is longer than would be expected from the
short plasma half-life.
Urinary excretion, measured by chemical assay, was low since not all of the drug related
metabolites can be detected. Also, the preferred biliary elimination, noted in rats and dogs,
probably occurs in man as well. Rats, dogs and man all appear to excrete similar metabolites.
Routes of prazosin hydrochloride metabolism involve 0-demethylation, hydrolysis of the
amide linkage glucuronide formation and, to a lesser extent, piperazine opening and N-
dealkylation. It appears that 0-dealkylation and glucuronide formation occur more readily
and that the metabolism of the piperazine moiety is of minor importance. Free 6 -0-demethyl
prazosin and its glucuronide conjugate are the major excretion products along with smaller
amounts of 7-0-demethyl prazosin and its glucuronide conjugate.
The results of single-dose acute toxicity studies on prazosin hydrochloride are as follows:
LD50 (95% Confidence Limits) mg/kg
M & F
84 (62 – 113)
M & F
141 (121 – 165)
The signs of toxicity observed following the administration of prazosin hydrochloride
included depression, decreased respiration, ptosis, writhing, ataxia, tremors and convulsions.
These were, for the most part, common to both mice and rats by both routes of
A 30 day oral toxicity study employing prazosin doses of 2, 10 and 40 mg/kg 7 days per
week was conducted in beagles. All of the animals survived. Dose related ptosis, ataxia and
relaxation of the nictitating membrane were observed in the mid and high dose groups.
Emesis, diarrhea and decreased activity were also observed in all of the treated animals and
all dosed animals showed spiked EKG T-waves. The pupillary reflex was decreased in the
mid and high dose animals and there was a dose dependent decrease in the thymus weight
and an increase in spleen weight. Gross and histological examinations revealed that the
spleens of the mid and high dose animals were congested with dilated vessels containing
blood. The hepatic vessels were dilated and pericentral hepatocellular degenerative changes
were seen in the high dose animals.
A chronic toxicity study was conducted in beagle dogs of both sexes with oral doses of
prazosin 2, 10 and 25 mg/kg administered 7 days per week for 1 year. Testicular atrophy and
degeneration were observed in all of the male animals in the high dose group and this was
accompanied by prostatic atrophy and fibrosis in 2 of the 4 animals. In addition, splenic
enlargement which was probably drug related was observed in all of the treated animals.
(In human clinical studies, urinary 17-ketosteroid excretion was monitored in 105 patients for
any possible effect on testicular function. No drug effects were observed. No semen
abnormalities were revealed by routine semen analysis in 27 male patients receiving prazosin
hydrochloride alone for up to 51 months).
An 18 month oral toxicity study was conducted in rats during which prazosin was
administered in the diet at doses of 5, 25, 75 and 150 mg/kg/day. Drug related toxic effects
included testicular atrophy and/or degeneration with accompanying inguinal and/or scrotal
adhesions; bilateral cataracts and retinitis proliferans; and hepatic degeneration and/or
necrosis. The effects on the testes were dose related and were evident at all dose levels
except 5 mg/kg. Ocular toxicity occurred only at the 75 and 150 mg/kg dosage level.
Retinitis proliferans showed a drug, but not dose relationship, and cataracts showed a dose
response. Significant degrees of hepatic degeneration and or necrosis occurred only at 75 and
150 mg/kg and this effect was dose related.
Male rats received prazosin 0, 25 and 75 mg/kg/day in the diet for 7 months and females
were given the same dosages for 14 days prior to mating and to day 13 of gestation. Another
group of females received 0, 5, 25 and 75 mg/kg/day to day 21 of gestation. Fertility was
decreased in the high dose group (30% compared to 80% in the controls) and the number of
pups per litter on days 1, 4 and 21 after birth was slightly decreased in the dosed groups. No
gross, visceral or skeletal anomalies were noted in the pups that died; however, pup weight
21 days after birth was decreased in the prazosin groups compared to controls.
Rats were given oral doses of 0, 25 and 75 mg/kg from days 5 through 15 of gestation and
rabbits were given oral doses of 0, 25 and 75 mg/kg on days 5 through 18 of gestation. No
gross external visceral or stained skeletal abnormalities were observed except for one low
dose rabbit pup that had craniochiasis.
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