hytrin

DESCRIPTION
HYTRIN (terazosin hydrochloride), an alpha-1-selective adrenoceptor blockingagent, is a quinazoline derivative represented by the following chemical nameand structural formula: (RS)-Piperazine, 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(tetra-hydro-2-furanyl)carbonyl]-,monohydrochloride, dihydrate hytrin.

Terazosin hydrochloride is a white, crystalline substance, freely soluble inwater and isotonic saline and has a molecular weight of 459.93 hytrin. HYTRIN capsules(terazosin hydrochloride capsules) for oral ingestion are supplied in four dosagestrengths containing terazosin hydrochloride equivalent to 1 mg, 2 mg, 5 mg,or 10 mg of terazosin hytrin.

Inactive Ingredients:
1 mg capsules: gelatin, glycerin, iron oxide, methylparaben, mineral oil, polyethyleneglycol, povidone, propylparaben, titanium dioxide, and vanillin hytrin.

2 mg capsules: D&C yellow No hytrin. 10, gelatin, glycerin, methylparaben, mineraloil, polyethylene glycol, povidone, propylparaben, titanium dioxide, and vanillin hytrin.

5 mg capsules: D&C red No hytrin. 28, FD&C red No hytrin. 40, gelatin, glycerin,methylparaben, mineral oil, polyethylene glycol, povidone, propylparaben, titaniumdioxide, and vanillin hytrin.

10 mg capsules: FD&C blue No hytrin. 1, gelatin, glycerin, methylparaben, mineraloil, polyethylene glycol, povidone, propylparaben, titanium dioxide, and vanillin hytrin.

CLINICAL PHARMACOLOGY
Pharmacodynamics:
A hytrin. 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 dynamiccomponent hytrin. The static component is a consequence of an increase in prostatesize hytrin. Over time, the prostate will continue to enlarge hytrin. However, clinical studieshave demonstrated that the size of the prostate does not correlate with theseverity of BPH symptoms or the degree of urinary obstruction hytrin. The dynamic componentis a function of an increase in smooth muscle tone in the prostate and bladderneck, leading to constriction of the bladder outlet hytrin. Smooth muscle tone is mediatedby sympathetic nervous stimulation of alpha-l adrenoceptors, which are abundantin the prostate, prostatic capsule and bladder neck hytrin. The reduction in symptomsand improvement in urine flow rates following administration of terazosin isrelated to relaxation of smooth muscle produced by blockade of alpha-l adrenoceptorsin the bladder neck and prostate hytrin. Because there are relatively few alpha-l adrenoceptorsin the bladder body, terazosin is able to reduce the bladder outlet obstructionwithout affecting bladder contractility hytrin.

Terazosin has been studied in 1222 men with symptomatic BPH hytrin. In three placebo-controlledstudies, symptom evaluation and uroflowmetric measurements were performed approximately24 hours following dosing hytrin. Symptoms were quantified using the Boyarsky Index hytrin. The questionnaire evaluated both obstructive (hesitancy, intermittency, terminaldribbling, impairment of size and force of stream, sensation of incomplete bladderemptying) and irritative (nocturia, daytime frequency, urgency, dysuria) symptomsby rating each of the 9 symptoms from 0-3, for a total score of 27 points hytrin. Resultsfrom these studies indicated that terazosin statistically significantly improvedsymptoms and peak urine flow rates over placebo as follows:

N Symptom Score
(Range 0-27)
Mean
Baseline Mean
Change
(%) N Peak Flow Rate
(mL/sec)
Mean
Baseline Mean
Change
(%)
Study 1 (10 mg) a
Titration to fixed dose (12 wks)
Placebo 55 9.7 -2.3 (24) 54 10.1 +1.0 (10)
Terazosin 54 10.1 -4.5 (45) * 52 8.8 +3.0 (34) *
Study 2 (2, 5, 10, 20 mg) b
Titration to response (24 wks)
Placebo 89 12.5 -3.8 (30) 88 8.8 +1.4 (16)
Terazosin 85 12.2 -5.3 (43) * 84 8.4 +2.9 (35) *
Study 3 (1, 2, 5, 10 mg) c
Titration to response (24 wks)
Placebo 74 10.4 -1.1 (11) 74 8.8 +1.2 (14)
Terazosin 73 10.9 -4.6 (42) * 73 8.6 +2.6 (30) *
a Highest dose 10 mg shown hytrin.
b 23% of patients on 10 mg, 41% of patients on 20 mg hytrin.
c 67% of patients on 10 mg hytrin.
*Significantly (p </= 0.05) more improvement than placebo hytrin.

In all three studies, both symptom scores and peak urine flow rates showed statisticallysignificant improvement from baseline in patients treated with terazosin fromweek 2 (or the first clinic visit) and throughout the study duration hytrin.

Analysis of the effect of terazosin on individual urinary symptoms demonstratedthat compared to placebo, terazosin significantly improved the symptoms of hesitancy,intermittency, impairment in size and force of urinary stream, sensation ofincomplete emptying, terminal dribbling, daytime frequency and nocturia hytrin.

Global assessments of overall urinary function and symptoms were also performedby investigators who were blinded to patient treatment assignment hytrin. In studies1 and 3, patients treated with terazosin had a significantly (p </= 0.001)greater overall improvement compared to placebo treated patients hytrin.

In a short term study (Study 1), patients were randomized to either 2, 5 or10 mg of terazosin or placebo hytrin. Patients randomized to the 10 mg group achieveda statistically significant response in both symptoms and peak flow rate comparedto placebo (Figure 1) hytrin.

+ for baseline values see above table

* p </= 0.05, compared to placebo group

In a long-term, open-label, non-placebo controlled clinical trial, 181 menwere followed for 2 years and 58 of these men were followed for 30 months hytrin. Theeffect of terazosin on urinary symptom scores and peak flow rates was maintainedthroughout the study duration (Figures 2 and 3):

In this long-term trial, both symptom scores and peak urinary flow rates showedstatistically significant improvement suggesting a relaxation of smooth musclecells hytrin.

Although blockade of alpha-1 adrenoceptors also lowers blood pressure in hypertensivepatients with increased peripheral vascular resistance, terazosin treatmentof normotensive men with BPH did not result in a clinically significant bloodpressure lowering effect:

Mean Changes in Blood Pressure from
Baseline to Final Visit in all Double-Blind,
Placebo-Controlled Studies Normotensive
Patients Hypertensive
Patients
DBP </= 90 mm Hg DBP > 90 mm Hg
Mean
Change N Mean
Change
Group N
SBP
(mm Hg) Placebo 293 -0.1 45 -5.8
Terazosin 519 -3.3 * 65 -14.4 *
DBP
(mm Hg) Placebo 293 +0.4 45 -7.1
Terazosin 519 -2.2 * 65 -15.1 *
*p </= 0.05 vs hytrin. placebo

B hytrin. Hypertension
In animals, terazosin causes a decrease in blood pressure by decreasing totalperipheral vascular resistance hytrin. The vasodilatory hypotensive action of terazosinappears to be produced mainly by blockade of alpha-1 adrenoceptors hytrin. Terazosindecreases blood pressure gradually within 15 minutes following oral administration hytrin.

Patients in clinical trials of terazosin were administered once daily (thegreat majority) and twice daily regimens with total doses usually in the rangeof 5-20 mg/day, and had mild (about 77%, diastolic pressure 95-105 mmHg) ormoderate (23%, diastolic pressure 105-115 mmHg) hypertension hytrin. Because terazosin,like all alpha antagonists, can cause unusually large falls in blood pressureafter the first dose or first few doses, the initial dose was 1 mg in virtuallyall trials, with subsequent titration to a specified fixed dose or titrationto some specified blood pressure end point (usually a supine diastolic pressureof 90 mmHg) hytrin.

Blood pressure responses were measured at the end of the dosing interval (usually24 hours) and effects were shown to persist throughout the interval, with theusual supine responses 5-10 mmHg systolic and 3.5-8 mmHg diastolic greater thanplacebo hytrin. The responses in the standing position tended to be somewhat larger,by 1-3 mmHg, although this was not true in all studies hytrin. The magnitude of theblood pressure responses was similar to prazosin and less than hydrochlorothiazide(in a single study of hypertensive patients) hytrin. In measurements 24 hours afterdosing, heart rate was unchanged hytrin.

Limited measurements of peak response (2-3 hours after dosing) during chronicterazosin administration indicate that it is greater than about twice the trough(24 hour) response, suggesting some attenuation of response at 24 hours, presumablydue to a fall in blood terazosin concentrations at the end of the dose interval hytrin. This explanation is not established with certainty, however, and is not consistentwith the similarity of blood pressure response to once daily and twice dailydosing and with the absence of an observed dose-response relationship over arange of 5-20 mg, i.e., if blood concentrations had fallen to the point of providingless than full effect at 24 hours, a shorter dosing interval or larger doseshould have led to increased response hytrin.

Further dose response and dose duration studies are being carried out hytrin. Bloodpressure should be measured at the end of the dose interval; if response isnot satisfactory, patients may be tried on a larger dose or twice daily dosingregimen hytrin. The latter should also be considered if possibly blood pressure-relatedside effects, such as dizziness, palpitations, or orthostatic complaints, areseen within a few hours after dosing hytrin.

The greater blood pressure effect associated with peak plasma concentrations(first few hours after dosing) appears somewhat more position-dependent (greaterin the erect position) than the effect of terazosin at 24 hours and in the erectposition there is also a 6-10 beat per minute increase in heart rate in thefirst few hours after dosing hytrin. During the first 3 hours after dosing 12.5% ofpatients 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 hytrin.

There was a tendency for patients to gain weight during terazosin therapy hytrin. In placebo-controlled monotherapy trials, male and female patients receivingterazosin gained a mean of 1.7 and 2.2 pounds respectively, compared to lossesof 0.2 and 1.2 pounds respectively in the placebo group hytrin. Both differences werestatistically significant hytrin.

During controlled clinical trials, patients receiving terazosin monotherapyhad a small but statistically significant decrease (a 3% fall) compared to placeboin total cholesterol and the combined low-density and very-low-density lipoproteinfractions hytrin. No significant changes were observed in high-density lipoproteinfraction and triglycerides compared to placebo hytrin.

Analysis of clinical laboratory data following administration of terazosinsuggested the possibility of hemodilution based on decreases in hematocrit,hemoglobin, white blood cells, total protein and albumin hytrin. Decreases in hematocritand total protein have been observed with alpha-blockade and are attributedto hemodilution hytrin.

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