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Uroxatral (Alfuzosin Hydrochloride) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Each UROXATRAL (alfuzosin HCl extended-release tablets) tablet contains 10 mg alfuzosin hydrochloride as the active ingredient. Alfuzosin hydrochloride is a white to off-white crystalline powder that melts at approximately 240°C. It is freely soluble in water, sparingly soluble in alcohol, and practically insoluble in dichloromethane.

Alfuzosin hydrochloride is (R,S)-N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl) methylamino] propyl] tetrahydro-2-furancarboxamide hydrochloride. The empirical formula of alfuzosin hydrochloride is C19H27N5O4•HCl. The molecular weight of alfuzosin hydrochloride is 425.9. Its structural formula is:

The tablet also contains the following inactive ingredients: colloidal silicon dioxide (NF), ethylcellulose (NF), hydrogenated castor oil (NF), hydroxypropyl methylcellulose (USP), magnesium stearate (NF), mannitol (USP), microcrystalline cellulose (NF), povidone (USP), and yellow ferric oxide (NF).

CLINICAL PHARMACOLOGY

The symptoms associated with benign prostatic hyperplasia (BPH) such as urinary frequency, nocturia, weak stream, hesitancy and incomplete emptying are related to two components, anatomical (static) and functional (dynamic). The static component is related to the prostate size. Prostate size alone does not correlate with symptom severity. The dynamic component is a function of the smooth muscle tone in the prostate and its capsule, the bladder neck, and the bladder base as well as the prostatic urethra. The smooth muscle tone is regulated by alpha-adrenergic receptors. Alfuzosin exhibits selectivity for alpha1-adrenergic receptors in the lower urinary tract. Blockade of these adrenoreceptors can cause smooth muscle in the bladder neck and prostate to relax, resulting in an improvement in urine flow and a reduction in symptoms of BPH.

UROXATRAL (alfuzosin HCl extended-release) is a selective antagonist of post-synaptic alpha1-adrenoreceptors, which are located in the prostate, bladder base, bladder neck, prostatic capsule, and prostatic urethra.

Pharmacokinetics

The pharmacokinetics of UROXATRAL have been evaluated in adult healthy male volunteers after single and/or multiple administration with daily doses ranging from 7.5 mg to 30 mg, and in patients with BPH at doses from 7.5 mg to 15 mg.

Absorption

The absolute bioavailability of UROXATRAL 10 mg tablets under fed conditions is 49%. Following multiple dosing of 10 mg UROXATRAL under fed conditions, the time to maximum concentration is 8 hours.

Cmax and AUC0-24 are 13.6 (SD = 5.6) ng/mL and 194 (SD = 75) ng·h/mL, respectively. UROXATRAL exhibits linear kinetics following single and multiple dosing up to 30 mg. Steady-state plasma levels are reached with the second dose of UROXATRAL administration. Steady-state alfuzosin plasma concentrations are 1.2- to 1.6-fold higher than those observed after a single administration.

Effect of Food

As illustrated in Figure 1, the extent of absorption is 50% lower under fasting conditions. Therefore, UROXATRAL should be taken immediately following a meal. (See DOSAGE AND ADMINISTRATION.)

Figure 1 – Mean (SEM) Alfuzosin Plasma Concentration-Time Profiles after a Single Administration of UROXATRAL 10 mg tablets to 8 Healthy Middle-Aged Male Volunteers in Fed and Fasted States

Distribution

The volume of distribution following intravenous administration in healthy male middle-aged volunteers was 3.2 L/kg. Results of in vitro studies indicate that alfuzosin is moderately bound to human plasma proteins (82% to 90%), with linear binding over a wide concentration range (5 to 5,000 ng/mL).

Metabolism

Alfuzosin undergoes extensive metabolism by the liver, with only 11% of the administered dose excreted unchanged in the urine. Alfuzosin is metabolized by three metabolic pathways: oxidation, O-demethylation, and N-dealkylation. The metabolites are not pharmacologically active. CYP3A4 is the principal hepatic enzyme isoform involved in its metabolism.

Excretion and Elimination

Following oral administration of 14C-labeled alfuzosin solution, the recovery of radioactivity after 7 days (expressed as a percentage of the administered dose) was 69% in feces and 24% in urine. Following oral administration of UROXATRAL 10 mg tablets, the apparent elimination half-life is 10 hours.

Special Populations

Elderly

In a pharmacokinetic assessment during phase 3 clinical studies in patients with BPH, there was no relationship between peak plasma concentrations of alfuzosin and age. However, trough levels were positively correlated with age. The concentrations in subjects ≥75 years of age were approximately 35% greater than in those below 65 years of age.

Patients with Renal Impairment

The Pharmacokinetic profiles of UROXATRAL 10 mg tablets in subjects with normal renal function (CLCR>80 mL/min), mild impairment (CLCR 60 to 80 mL/min), moderate impairment (CLCR 30 to 59 mL/min), and severe impairment (CLCR <30 mL/min) were compared. These clearances were calculated by the Cockcroft-Gault formula. Relative to subjects with normal renal function, the mean Cmax and AUC values were increased by approximately 50% in patients with mild, moderate, or severe renal impairment. (See PRECAUTIONS, Renal Insufficiency).

Patients with Hepatic Insufficiency

In patients with moderate or severe hepatic insufficiency (Child-Pugh categories B and C), the plasma apparent clearance (CL/F) was reduced to approximately one-third to one-fourth that observed in healthy subjects. This reduction in clearance results in three to four-fold higher plasma concentrations of alfuzosin in these patients compared to healthy subjects. Therefore, UROXATRAL is contraindicated in patients with moderate to severe hepatic impairment (See CONTRAINDICATIONS). The pharmacokinetics of UROXATRAL have not been studied in patients with mild hepatic insufficiency. (See PRECAUTIONS, Hepatic Insufficiency).

Drug-Drug Interactions

Metabolic interactions

CYP3A4 is the principal hepatic enzyme isoform involved in the metabolism of alfuzosin.

Potent CYP3A4 inhibitors

Repeated administration of 400 mg of ketoconazole, a potent inhibitor of CYP3A4, increased alfuzosin Cmax 2.3-fold and AUClast 3.2-fold following a single 10 mg dose of alfuzosin. Therefore, UROXATRAL should not be co-administered with potent inhibitors of CYP3A4 because exposure is increased, (e.g., ketoconazole, itraconazole, or ritonavir). (See CONTRAINDICATIONS).

Moderate CYP3A4 inhibitors

Diltiazem

Repeated co-administration of 240 mg/day of diltiazem, a moderately-potent inhibitor of CYP3A4, with 7.5 mg/day (2.5 mg three times daily) alfuzosin (equivalent to the exposure with UROXATRAL) increased the Cmax and AUC0-24 of alfuzosin 1.5- and 1.3-fold, respectively. Alfuzosin increased the Cmax and AUC0-12 of diltiazem 1.4-fold. Although no changes in blood pressure were observed in this study, diltiazem is an antihypertensive medication and the combination of UROXATRAL and antihypertensive medications has the potential to cause hypotension in some patients. (See WARNINGS).

In human liver microsomes, at concentrations that are achieved at the therapeutic dose, alfuzosin did not inhibit CYP1A2, 2A6, 2C9, 2C19, 2D6 or 3A4 isoenzymes. In primary culture of human hepatocytes, alfuzosin did not induce CYP1A, 2A6 or 3A4 isoenzymes.

Other interactions

Warfarin

Multiple dose administration of an immediate release tablet formulation of alfuzosin 5 mg twice daily for six days to six healthy male volunteers did not affect the pharmacological response to a single 25 mg oral dose of warfarin.

Digoxin

Repeated co-administration of UROXATRAL 10 mg tablets and digoxin 0.25 mg/day for 7 days did not influence the steady-state pharmacokinetics of either drug.

Cimetidine

Repeated administration of 1 g/day cimetidine increased both alfuzosin Cmax and AUC values by 20%.

Atenolol

Single administration of 100 mg atenolol with a single dose of 2.5 mg of an immediate release alfuzosin tablet in eight healthy young male volunteers increased alfuzosin Cmax and AUC values by 28% and 21%, respectively. Alfuzosin increased atenolol Cmax and AUC values by 26% and 14%, respectively. In this study, the combination of alfuzosin with atenolol caused significant reductions in mean blood pressure and in mean heart rate. (See WARNINGS.)

Hydrochlorothiazide

Single administration of 25 mg hydrochlorothiazide did not modify the pharmacokinetic parameters of alfuzosin. There was no evidence of pharmacodynamic interaction between alfuzosin and hydrochlorothiazide in the 8 patients in this study.

Electrophysiology

The effect of 10 mg and 40 mg alfuzosin on QT interval was evaluated in a double-blind, randomized, placebo and active-controlled (moxifloxacin 400 mg), 4-way crossover single dose study in 45 healthy white male subjects aged 19 to 45 years. The QT interval was measured at the time of peak alfuzosin plasma concentrations. The 40 mg dose of alfuzosin was chosen because this dose achieves higher blood levels than those achieved with the co-administration of UROXATRAL and ketoconazole 400 mg. Table 1 summarizes the effect on uncorrected QT and mean corrected QT interval (QTc) with different methods of correction (Fridericia, population-specific, and subject-specific correction methods) at the time of peak alfuzosin plasma concentrations. No single one of these correction methodologies is known to be more valid. The mean change of heart rate associated with a 10 mg dose of alfuzosin in this study was 5.2 beats/minute and 5.8 beats/minute with 40 mg alfuzosin. The change in heart rate with moxifloxacin was 2.8 beats/minute.

Table 1. Mean QT and QTc changes in msec (95% CI) from baseline at Tmax (relative to placebo) with different methodologies to correct for effect of heart rate.
Drug/DoseQTFridericia methodPopulation-specific methodSubject-specific method
Alfuzosin
10 mg
-5.8
(-10.2, -1.4)
4.9
(0.9, 8.8)
1.8
(-1.4, 5.0)
1.8
(-1.3, 5.0)
Alfuzosin
40 mg
-4.2
(-8.5, 0.2)
7.7
(1.9, 13.5)
4.2
(-0.6, 9.0)
4.3
(-0.5, 9.2)
MoxifloxacinActive control 400 mg6.9
(2.3, 11.5)
12.7
(8.6, 16.8)
11.0
(7.0, 15.0)
11.1
(7.2, 15.0)

The QT effect appeared greater for 40 mg compared to 10 mg alfuzosin. The effect of the highest alfuzosin dose (four times the therapeutic dose) studied did not appear as large as that of the active control moxifloxacin at its therapeutic dose. This study, however, was not designed to make direct statistical comparisons between the drugs or the dose levels. There has been no signal of Torsade de Pointes in the extensive post-marketing experience with alfuzosin outside the United States.

A separate post-marketing QT study evaluated the effect of the co-administration of 10 mg alfuzosin with a drug of similar QT effect size. In this study, the mean placebo-substracted QTcF increase of alfuzosin 10 mg alone was 1.9 msec (upperbound 95% CI, 5.5 msec). The concomitant administration of the two drugs showed an increased QT effect when compared with either drug alone. This QTcF increase [5.9 msec (UB 95% CI, 9.4 msec)] was not more than additive. Although this study was not designed to make direct statistical comparisons between drugs, the QT increase with both drugs given together appeared to be lower than the QTcF increase seen with the positive control moxifloxacin 400 mg [10.2 msec (UB 95% CI, 13.8 msec)]. The clinical impact of these QTc changes is unknown.

Clinical Studies

Three randomized placebo-controlled, double-blind, parallel-arm, 12-week studies were conducted with the 10 mg daily dose of alfuzosin. In these three studies, 1,608 patients [mean age 64.2 years, range 49-92 years; Caucasian (96.1%), Black (1.6%), Asian (1.1%), Other (1.2%) were randomized and 473 patients received UROXATRAL 10 mg daily. Table 1 provides the results of the three studies that evaluated the 10 mg dose.

There were two primary efficacy variables in these three studies. The International Prostate Symptom Score (IPSS, or AUA Symptom Score) consists of seven questions that assess the severity of both irritative (frequency, urgency, nocturia) and obstructive (incomplete emptying, stopping and starting, weak stream, and pushing or straining) symptoms, with possible scores ranging from 0 to 35. The second efficacy variable was peak urinary flow rate. The peak flow rate was measured just prior to the next dose in study 2 and on average at 16 hours post-dosing in studies 1 and 3.

There was a statistically significant reduction from baseline to last assessment (Week 12) in the IPSS versus placebo in all three studies, indicating a reduction in symptom severity (Table 2 and Figures 2, 3, and 4).

Table 2 — Mean Change (SD) from Baseline to week 12 in International Prostate Symptom Score in Three Randomized, Controlled, Double Blind Studies
Symptom ScoreStudy 1Study 2Study 3
Placebo (n=167)UROXATRAL 10 mg (n=170)Placebo (n=152)UROXATRAL 10 mg (n=137)Placebo (n=150)UROXATRAL 10 mg (n=151)
Total symptom score
  Baseline18.2 (6.4)18.2 (6.3)17.7 (4.1)17.3 (3.5)17.7 (5.0)18.0 (5.4)
  ChangeDifference between baseline value and last value-1.6 (5.8)-3.6 (4.8)-4.9 (5.9)-6.9 (4.9)-4.6 (5.8)-6.5 (5.2)
  p-value0.0010.0020.007

Figure 2 — Mean Change from Baseline in Total Symptom Score, by Visit: Study 1

Figure 3 — Mean Change from Baseline in Total Symptom Score, by Visit: Study 2

Figure 4 — Mean Change from Baseline in Total Symptom Score, by Visit: Study 3

Peak urinary flow rate was increased statistically significantly from baseline to last assessment (Week 12) versus placebo in studies 1 and 2 (Table 3 and Figures 5, 6, and 7).

Table 3 — Mean (SD) from Baseline in Peak Urine Flow Rate (mL/sec) in Three Randomized, Controlled, Double-Blind Studies
Study 1Study 2Study 3
Placebo (n=167)UROXATRAL 10 mg (n=170)Placebo (n=147)UROXATRAL 10 mg (n=136)Placebo (n=150)UROXATRAL 10 mg (n=136)
Mean Peak flow rate
  Baseline10.2 (4.0)9.9 (3.9)9.2 (2.0)9.4 (1.9)9.3 (2.6)9.5 (3.0)
  ChangeDifference between baseline value and last value0.2 (3.5)1.7 (4.2)1.4 (3.2)2.3 (3.6)0.9 (3.0)1.5 (3.3)
  p-value0.00040.030.22

Figure 5 — Mean Change from Baseline in Peak Urine Flow Rate (mL/s), by Visit: Study 1

Figure 6 — Mean Change from Baseline in Peak Urine Flow Rate (mL/s), by Visit: Study 2

Figure 7 — Mean Change from Baseline in Peak Urine Flow Rate (mL/s), by Visit: Study 3

Mean total IPSS decreased at the first scheduled observation at Day 28 and mean peak flow rate increased starting at the first scheduled observation at Day 14 in studies 2 and 3 and Day 28 in study 1.

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