Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/4025
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HYTRIN (Tablet)
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If HYTRIN administration is discontinued for several
days, therapy should be reinstituted using the initial dosing regimen.<br/>Benign Prostatic Hyperplasia:<br/>Initial Dose: 1 mg at bedtime is the starting dose for all patients,
and this dose should not be exceeded as an initial dose. Patients should
be closely followed during initial administration in order to minimize the
risk of severe hypotensive response.<br/>Subsequent Doses: The dose should be increased in a stepwise fashion
to 2 mg, 5 mg, or 10 mg once daily to achieve the desired improvement of symptoms
and/or flow rates. Doses of 10 mg once daily are generally required for the
clinical response. Therefore, treatment with 10 mg for a minimum of 4���6
weeks may be required to assess whether a beneficial response has been achieved.
Some patients may not achieve a clinical response despite appropriate titration.
Although some additional patients responded at a 20 mg daily dose, there was
an insufficient number of patients studied to draw definitive conclusions
about this dose. There are insufficient data to support the use of higher
doses for those patients who show inadequate or no response to 20 mg daily.<br/>Use with Other Drugs: Caution should be observed when HYTRIN tablets are
administered concomitantly with other antihypertensive agents, especially
the calcium channel blocker verapamil, to avoid the possibility of developing
significant hypotension. When using HYTRIN tablets and other antihypertensive
agents concomitantly, dosage reduction and retitration of either agent may
be necessary (see PRECAUTIONS). Hypotension
has been reported when Hytrin has been used with phosphodiesterase-5 (PDE-5)
inhibitors.<br/>Hypertension: The dose of HYTRIN and the dose interval (12 or
24 hours) should be adjusted according to the patient's individual blood
pressure response. The following is a guide to its administration:<br/>Initial Dose: 1 mg at bedtime is the starting dose for all patients,
and this dose should not be exceeded. This initial dosing regimen should
be strictly observed to minimize the potential for severe hypotensive effects.<br/>Subsequent Doses: The dose may be slowly increased to achieve the
desired blood pressure response. The usual recommended dose range is 1 mg
to 5 mg administered once a day; however, some patients may benefit from doses
as high as 20 mg per day. Doses over 20 mg do not appear to provide further
blood pressure effect and doses over 40 mg have not been studied. Blood pressure
should be monitored at the end of the dosing interval to be sure control is
maintained throughout the interval. It may also be helpful to measure blood
pressure 2-3 hours after dosing to see if the maximum and minimum responses
are similar, and to evaluate symptoms such as dizziness or palpitations which
can result from excessive hypotensive response. If response is substantially
diminished at 24 hours an increased dose or use of a twice daily regimen can
be considered. If terazosin administration is discontinued
for several days or longer, therapy should be reinstituted using the initial
dosing regimen. In clinical trials, except for the initial dose,
the dose was given in the morning.<br/>Use With Other Drugs (see above):
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HYTRIN (terazosin hydrochloride), an alpha-1-selective
adrenoceptor blocking agent, is a quinazoline derivative represented by the
following chemical name and structural formula: (RS)-Piperazine,
1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(tetra-hydro-2-furanyl)carbonyl]-,
monohydrochloride, dihydrate. Terazosin hydrochloride is a white, crystalline substance,
freely soluble in water and isotonic saline and has a molecular weight of
459.93. HYTRIN tablets (terazosin hydrochloride tablets) for oral ingestion
are supplied in four dosage strengths containing terazosin hydrochloride equivalent
to 1 mg, 2 mg, 5 mg, or 10 mg of terazosin.<br/>Inactive Ingredients: 1 mg tablet: corn starch, lactose, magnesium stearate,
povidone and talc. 2 mg tablet: corn starch,
FD&C Yellow No. 6, lactose, magnesium stearate, povidone and talc. 5 mg tablet: corn starch, iron oxide, lactose, magnesium
stearate, povidone and talc. 10 mg tablet:
corn starch, D&C Yellow No. 10, FD&C Blue No. 2, lactose, magnesium
stearate, povidone and talc.
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Pharmacodynamics:<br/>A. Benign Prostatic Hyperplasia (BPH): The symptoms associated with BPH are related to
bladder outlet obstruction, which is comprised of two underlying components:
a static component and a dynamic component. The static component is a consequence
of an increase in prostate size. Over time, the prostate will continue to
enlarge. However, clinical studies have demonstrated that the size of the
prostate does not correlate with the severity of BPH symptoms or the degree
of urinary obstruction.The dynamic component is a function of
an increase in smooth muscle tone in the prostate and bladder neck, leading
to constriction of the bladder outlet. Smooth muscle tone is mediated by sympathetic
nervous stimulation of alpha-l adrenoceptors, which are abundant in the prostate,
prostatic capsule and bladderneck. The reduction in symptoms and improvement
in urine flow rates following administration of terazosin is related to relaxation
of smooth muscle produced by blockade of alpha-l adrenoceptors in the bladder
neck and prostate. Because there are relatively few alpha-l adrenoceptors
in the bladder body, terazosin is able to reduce the bladder outlet obstruction
without affecting bladder contractility. Terazosin
has been extensively studied in 1222 men with symptomatic BPH. In three placebo-controlled
studies, symptom evaluation and uroflowmetric measurements were performed
approximately 24 hours following dosing. Symptoms were systematically quantified
using the Boyarsky Index. The questionnaire evaluated both obstructive (hesitancy,
intermittency, terminal dribbling, impairment of size and force of stream,
sensation of incomplete bladder emptying) and irritative (nocturia, daytime
frequency, urgency, dysuria) symptoms by rating each of the 9 symptoms from
0-3, for a total score of 27 points. Results from these studies indicated
that terazosin statistically significantly improved symptoms and peak urine
flow rates over placebo as follows: In all three studies, both symptom scores and
peak urine flow rates showed statistically significant improvement from baseline
in patients treated with HYTRIN from week 2 (or the first clinic visit) and
throughout the study duration. Analysis of
the effect of HYTRIN on individual urinary symptoms demonstrated that compared
to placebo, HYTRIN significantly improved the symptoms of hesitancy, intermittency,
impairment in size and force of urinary stream, sensation of incomplete emptying,
terminal dribbling, daytime frequency and nocturia. Global
assessments of overall urinary function and symptoms were also performed by
investigators who were blinded to patient treatment assignment. In studies
1 and 3, patients treated with HYTRIN had a significantly (p���0.001)
greater overall improvement compared to placebo treated patients. In a short term study (Study 1), patients were randomized
to either 2, 5 or 10 mg of HYTRIN or placebo. Patients randomized to the 10
mg group achieved a statistically significant response in both symptoms and
peak flow rate compared to placebo (Figure 1). In a long-term, open-label, non-placebo controlled
clinical trial, 181 men were followed for 2 years and 58 of these men were
followed for 30 months. The effect of HYTRIN on urinary symptom scores and
peak flow rates was maintained throughout the study duration (Figures 2 and
3): * p���0.05 vs. baseline mean baseline = 10.7 * p���0.05 vs. baseline mean baseline
= 9.9 In this long-term trial, both symptom
scores and peak urinary flow rates showed statistically significant improvement
suggesting a relaxation of smooth muscle cells. Although
blockade of alpha-1 adrenoceptors also lowers blood pressure in hypertensive
patients with increased peripheral vascular resistance, terazosin treatment
of normotensive men with BPH did not result in a clinically significant blood
pressure lowering effect:<br/>B. Hypertension: In animals, terazosin causes a decrease in blood
pressure by decreasing total peripheral vascular resistance. The vasodilatory
hypotensive action of terazosin appears to be produced mainly by blockade
of alpha-1 adrenoceptors. Terazosin decreases blood pressure gradually within
15 minutes following oral administration. Patients
in clinical trials of terazosin were administered once daily (the great majority)
and twice daily regimens with total doses usually in the range of 5-20 mg/day,
and had mild (about 77%, diastolic pressure 95-105 mmHg) or moderate (23%,
diastolic pressure 105-115 mmHg) hypertension. Because terazosin, like all
alpha antagonists, can cause unusually large falls in blood pressure after
the first dose or first few doses, the initial dose was 1 mg in virtually
all trials, with subsequent titration to a specified fixed dose or titration
to some specified blood pressure end point (usually a supine diastolic pressure
of 90 mmHg). Blood pressure responses were
measured at the end of the dosing interval (usually 24 hours) and effects
were shown to persist throughout the interval, with the usual supine responses
5-10 mmHg systolic and 3.5-8 mmHg diastolic greater than placebo. The responses
in the standing position tended to be somewhat larger, by 1-3 mmHg, although
this was not true in all studies. The magnitude of the blood pressure responses
was similar to prazosin and less than hydrochlorothiazide (in a single study
of hypertensive patients). In measurements 24 hours after dosing, heart rate
was unchanged. Limited measurements of peak
response (2-3 hours after dosing) during chronic terazosin administration
indicate that it is greater than about twice the trough (24 hour) response,
suggesting some attenuation of response at 24 hours, presumably due to a fall
in blood terazosin concentrations at the end of the dose interval. This explanation
is not established with certainty, however, and is not consistent with the
similarity of blood pressure response to once daily and twice daily dosing
and with the absence of an observed dose-response relationship over a range
of 5-20 mg, i.e., if blood concentrations had fallen to the point of providing
less than full effect at 24 hours, a shorter dosing interval or larger dose
should have led to increased response. Further
dose response and dose duration studies are being carried out. Blood pressure
should be measured at the end of the dose interval; if response is not satisfactory,
patients may be tried on a larger dose or twice daily dosing regimen. The
latter should also be considered if possibly blood pressure-related side effects,
such as dizziness, palpitations, or orthostatic complaints,are seen within
a few hours after dosing. The greater blood
pressure effect associated with peak plasma concentrations (first few hours
after dosing) appears somewhat more position-dependent (greater in the erect
position) than the effect of terazosin at 24 hours and in the erect position
there is also a 6-10 beat per minute increase in heart rate in the first few
hours after dosing. During the first 3 hours after dosing 12.5% of patients
had a systolic pressure fall of 30 mmHg or more from supine to standing, or
standing systolic pressure below 90 mmHg with a fall of at least 20 mmHg,
compared to 4% of a placebo group. There
was a tendency for patients to gain weight during terazosin therapy. In placebo-controlled
monotherapy trials, male and female patients receiving terazosin gained a
mean of 1.7 and 2.2 pounds respectively, compared to losses of 0.2 and 1.2
pounds respectively in the placebo group. Both differences were statistically
significant. During controlled clinical trials,
patients receiving terazosin monotherapy had a small but statistically significant
decrease (a 3% fall) compared to placebo in total cholesterol and the combined
low-density and very-low-density lipoprotein fractions. No significant changes
were observed in high-density lipoprotein fraction and triglycerides compared
to placebo. Analysis of clinical laboratory
data following administration of terazosin suggested the possibility of hemodilution
based on decreases in hematocrit, hemoglobin, white blood cells, total protein
and albumin. Decreases in hematocrit and total protein have been observed
with alpha-blockade and are attributed to hemodilution.<br/>Pharmacokinetics: Relative to solution, terazosin hydrochloride administered
as HYTRIN tablets is essentially completely absorbed in man. Food had little
or no effect on the extent of absorption but food delayed the time to peak
concentration by about 1 hour. Terazosin has been shown to undergo minimal
hepatic first-pass metabolism and nearly all of the circulating dose is in
the form of parent drug. The plasma levels peak about one hour after dosing,
and then decline with a half-life of approximately 12 hours. In a study that
evaluated the effect of age on terazosin pharmacokinetics, the mean plasma
half-lives were 14.0 and 11.4 hours for the age group���70 years and
the age group of 20-39 years, respectively. After oral administration the
plasma clearance was decreased by 31.7% in patients 70 years of age or older
compared to that in patients 20-39 years of age. The
drug is highly bound to plasma proteins and binding is constant over the clinically
observed concentration range. Approximately 10% of an orally administered
dose is excreted as parent drug in the urine and approximately 20% is excreted
in the feces. The remainder is eliminated as metabolites. Impaired renal function
had no significant effect on the elimination of terazosin, and dosage adjustment
of terazosin to compensate for the drug removal during hemodialysis (approximately
10%) does not appear to be necessary. Overall, approximately 40% of the administered
dose is excreted in the urine and approximately 60% in the feces. The disposition
of the compound in animals is qualitatively similar to that in man.
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HYTRIN tablets are contraindicated in patients known
to be hypersensitive to terazosin hydrochloride.
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HYTRIN tablets (terazosin hydrochloride tablets) are
available in four dosage strengths: 1 mg, white
tablets (bears the Abbott���A���logo and the Abbo-Code DF): Bottles of
100 (NDC 0074-3322-13). 2 mg, orange tablets (bears the Abbott���A���logo and the Abbo-Code DH): Bottles
of 100 (NDC 0074-3323-13). 5 mg, tan tablets (bears the Abbott���A���logo and the Abbo-Code DJ): Bottles
of 100 (NDC 0074-3324-13). 10 mg, green tablets (bears the Abbott���A���logo and the Abbo-Code DI): Bottles
of 100 (NDC 0074-3325-13).<br/>Recommended storage: Store below 86��F (30��C).
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Should overdosage of HYTRIN 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 and renal function should be monitored and supported as needed.
Laboratory data indicate that HYTRIN is highly protein bound; therefore, dialysis
maynot be of benefit.
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TERAZOSIN HYDROCHLORIDE
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HYTRIN (Tablet)
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Benign Prostatic Hyperplasia: The incidence of treatment-emergent adverse events
has been ascertained from clinical trials conducted worldwide. All adverse
events reported during these trials were recorded as adverse reactions. The
incidence rates presented below are based on combined data from six placebo-controlled
trials involving once-a-day administration of terazosin at doses ranging from
1 to 20 mg. Table 1 summarizes those adverse events reported for patients
in these trials when the incidence rate in the terazosin group was at least
1% and was greater than that for the placebo group, or where the reaction
is of clinical interest. Asthenia, postural hypotension, dizziness, somnolence,
nasal congestion/rhinitis, and impotence were the only events that were significantly
(p���0.05) more common in patients receiving terazosin than in patients
receiving placebo. The incidence of urinary tract infection was significantly
lower in the patients receiving terazosin than in patients receiving placebo.
An analysis of the incidence rate of hypotensive adverse events (see PRECAUTIONS) adjusted for the length of drug treatment
has shown that the risk of the events is greatest during the initial seven
days of treatment, but continues at all time intervals. Additional adverse events have been reported,
but these are, in general, not distinguishable from symptoms that might have
occurred in the absence of exposure to terazosin. The safety profile of patients
treated in the long-term open-label study was similar to that observed in
the controlled studies. The adverse events
were usually transient and mild or moderate in intensity, but sometimes were
serious enough to interrupt treatment. In the placebo-controlled clinical
trials, the rates of premature termination due to adverse events were not
statistically different between the placebo and terazosin groups. The adverse
events that were bothersome, as judged by their being reported as reasons
for discontinuation of therapy by at least 0.5% of the terazosin group and
being reported more often than in the placebo group, are shown in Table 2.<br/>Hypertension: The prevalence of adverse reactions has been ascertained
from clinical trials conducted primarily in the United States. All adverse
experiences (events) reported during these trials were recorded as adverse
reactions. The prevalence rates presented below are based on combined data
from fourteen placebo-controlled trials involving once-a-day administration
of terazosin, as monotherapy or in combination with other antihypertensive
agents, at doses ranging from 1 to 40 mg. Table 3 summarizes those adverse
experiences reported for patients in these trials where the prevalence rate
in the terazosin group was at least 5%, where the prevalence rate for the
terazosin group was at least 2% and was greater than the prevalence rate for
the placebo group, or where the reaction is of particular interest. Asthenia,
blurred vision, dizziness, nasal congestion, nausea, peripheral edema, palpitations
and somnolence were the only symptoms that were significantly (p<0.05)
more common in patients receiving terazosin than in patients receiving placebo.
Similar adverse reaction rates were observed in placebo-controlled monotherapy
trials. 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 terazosin. The following additional
adverse reactions were reported by at least 1% of 1987 patients who received
terazosin in controlled or open, short- or long-term clinical trials or have
been reported during marketing experience:<br/>Body as a Whole: chest pain, facial edema, fever, abdominal pain,
neck pain, shoulder pain<br/>Cardiovascular System: arrhythmia, vasodilation<br/>Digestive System: constipation, diarrhea, dry mouth, dyspepsia,
flatulence, vomiting<br/>Metabolic/Nutritional Disorders: gout<br/>Musculoskeletal System: arthralgia, arthritis, joint disorder, myalgia<br/>Nervous System: anxiety, insomnia<br/>Respiratory System: bronchitis, cold symptoms, epistaxis, flu symptoms,
increased cough, pharyngitis, rhinitis<br/>Skin and Appendages: pruritus, rash, sweating<br/>Special Senses: abnormal vision, conjunctivitis, tinnitus<br/>Urogenital System: urinary frequency, urinary incontinence primarily
reported in postmenopausal women, urinary tract infection. The adverse reactions were usually mild
or moderate in intensity but sometimes were serious enough to interrupt treatment.
The adverse reactions that were most bothersome, as judged by their being
reported as reasons for discontinuation of therapy by at least 0.5% of the
terazosin group and being reported more often than in the placebo group, are
shown in Table 4.<br/>Post-marketing Experience: Post-marketing experience indicates that in rare
instances patients may develop allergic reactions, including anaphylaxis,
following administration of terazosin hydrochloride. There have been reports
of priapism and thrombocytopenia during post-marketing surveillance. Atrial
fibrillation has been reported. During cataract surgery,
a variant of small pupil syndrome known as Intraoperative Floppy Iris Syndrome
(IFIS) has been reported in association with alpha-1 blocker therapy (see PRECAUTIONS).
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HYTRIN (terazosin hydrochloride) is indicated for
the treatment of symptomatic benign prostatic hyperplasia (BPH). There is
a rapid response, with approximately 70% of patients experiencing an increase
in urinary flow and improvement in symptoms of BPH when treated with HYTRIN.
The long-term effects of HYTRIN on the incidence of surgery, acute urinary
obstruction or other complications of BPH are yet to be determined. HYTRIN tablets are also indicated for the treatment of hypertension.
HYTRIN tablets can be used alone or in combination with other antihypertensive
agents such as diuretics or beta-adrenergic blocking agents.
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HYTRIN
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