HYTRIN

HYTRIN- terazosin hydrochloride capsule, liquid filled
Abbott Laboratories

Description

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.

Image from Drug Label Content
(click image for full-size original)

Terazosin hydrochloride is a white, crystalline substance, freely soluble in water and isotonic saline and has a molecular weight of 459.93. HYTRIN capsules (terazosin hydrochloride capsules) 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.

Inactive Ingredients

1 mg capsules: gelatin, glycerin, iron oxide, methylparaben, mineral oil, polyethylene glycol, povidone, propylparaben, titanium dioxide, and vanillin.

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

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

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

CLINICAL PHARMACOLOGY

Pharmacodynamics

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 bladder neck. 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 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 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:

Symptom Score (Range 0-27) Peak Flow Rate (mL/sec)
N Mean Baseline Mean Change (%) N Mean Baseline Mean Change (%)

a Highest dose 10 mg shown.

b 23% of patients on 10 mg, 41% of patients on 20 mg.

c 67% of patients on 10 mg.

* Significantly (p ≤ 0.05) more improvement than placebo.

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)*

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

Analysis of the effect of terazosin on individual urinary symptoms demonstrated that compared to placebo, terazosin 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 terazosin 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 terazosin 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).

Figure 1. Study 1
Mean Change in Total Symptom Score from Baseline+ Mean Increase in Peak Flow Rate (mL/sec) from Baseline+

+ for baseline values see above table

* p ≤ 0.05, compared to placebo group

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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 terazosin on urinary symptom scores and peak flow rates was maintained throughout the study duration (Figures 2 and 3):

Figure 2. Mean Change in Total Symptom Score from Baseline Long-term, Open-label, Non-placebo Controlled Study (N = 494)

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* p ≤ 0.05 vs. baseline

mean baseline = 10.7

Figure 3. Mean Change in Peak Flow Rate from Baseline Long-term, Open-label, Non-placebo Controlled Study (N = 494)

Image from Drug Label Content
(click image for full-size original)

* 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:

Mean Changes in Blood Pressure from Baseline to Final Visit in all Double-blind, Placebo-controlled Studies
Normotensive Patients DBP ≤ 90 mm Hg Hypertensive Patients DBP > 90 mm Hg
Group N Mean Change N Mean Change

* p ≤ 0.05 vs. placebo

SBP Placebo 293 -0.1 45 -5.8
(mm Hg) Terazosin 519 -3.3* 65 -14.4*
DBP Placebo 293 +0.4 45 -7.1
(mm Hg) Terazosin 519 -2.2* 65 -15.1*

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