Alfuzosin Hydrochloride 10 mg Tablet, Extended Release, 30-count — NDC 51655-432-52 (Billing 51655-0432-52)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Alfuzosin is a selective antagonist of post-synaptic alpha 1 -adrenoreceptors, which are located in the prostate, bladder base, bladder neck, prostatic capsule, and prostatic urethra.

12.2Pharmacodynamics Alfuzosin exhibits selectivity for alpha 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. Cardiac 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 coadministration of alfuzosin hydrochloride extended-release tablets and ketoconazole 400 mg. Table 3 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 3 - 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/Dose QT Fridericia method Population- specific method Subject- specific method Alfuzosin 10 mg -5.8 (-10.2, -1.4) 4.9 (0.9, 8.8) 1.8 (-1.4, 5) 1.8 (-1.3, 5) Alfuzosin 40 mg -4.2 (-8.5, 0.2) 7.7 (1.9, 13.5) 4.2 (-0.6, 9) 4.3 (-0.5, 9.2) Moxifloxacin Active control 400 mg 6.9 (2.3, 11.5) 12.7 (8.6, 16.8) 11 (7, 15) 11.1 (7.2, 15) 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 postmarketing experience with alfuzosin outside the United States.

A separate postmarketing QT study evaluated the effect of the coadministration of 10 mg alfuzosin with a drug of similar QT effect size. In this study, the mean placebo-subtracted 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.

12.3Pharmacokinetics The pharmacokinetics of alfuzosin hydrochloride extended-release tablets 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 alfuzosin hydrochloride extended-release 10 mg tablets under fed conditions is 49%. Following multiple dosing of 10 mg alfuzosin hydrochloride extended-release tablets under fed conditions, the time to maximum concentration is 8 hours.

Cmax and AUC0-24 are 13.6 (SD = 5.6… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Alfuzosin is a selective antagonist of post-synaptic alpha 1 -adrenoreceptors, which are located in the prostate, bladder base, bladder neck, prostatic capsule, and prostatic urethra.

12.3Pharmacokinetics The pharmacokinetics of alfuzosin hydrochloride extended-release tablets 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 alfuzosin hydrochloride extended-release 10 mg tablets under fed conditions is 49%. Following multiple dosing of 10 mg alfuzosin hydrochloride extended-release tablets 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. Alfuzosin hydrochloride extended-release tablets exhibits linear kinetics following single and multiple dosing up to 30 mg. Steady-state plasma levels are reached with the second dose of alfuzosin hydrochloride extended-release tablet 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, alfuzosin hydrochloride extended-release tablets should be taken with food and with the same meal each day [see Dosage and Administration ( 2 )] .

Figure 1 – Mean (SEM) Alfuzosin Plasma Concentration-Time Profiles after a Single Administration of Alfuzosin Hydrochloride Extended-Release 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

3.2L/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 ng/mL 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 Following oral administration of 14 C-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 alfuzosin hydrochloride extended-release10 mg tablets, the apparent elimination half-life is 10 hours. Specific Populations Geriatric Use : 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. Renal Impairment : The Pharmacokinetic profiles of alfuzosin hydrochloride extended-release10 mg tablets in subjects with normal renal function (CL CR >80 mL/min), mild impairment (CL CR 60 to 80 mL/min), moderate impairment (CL CR 30 to 59 mL/min), and severe impairment (CL CR <30 mL/min) were compared.

These clearances were calculated by the Cockcroft-Gault formula. Relative to subjects with normal renal function, the mean C max and AUC values were increased by approximately 50% in patients with mild, moderate, or severe renal impairment [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.6 )] . Hepatic Impairment : The pharmacokinetics of alfuzosin hydrochloride extended-release tablets have not been studied in patients with mild hepatic impairment.

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… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Alfuzosin exhibits selectivity for alpha 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. Cardiac 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 coadministration of alfuzosin hydrochloride extended-release tablets and ketoconazole 400 mg. Table 3 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 3 - 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/Dose QT Fridericia method Population- specific method Subject- specific method Alfuzosin 10 mg -5.8 (-10.2, -1.4) 4.9 (0.9, 8.8) 1.8 (-1.4, 5) 1.8 (-1.3, 5) Alfuzosin 40 mg -4.2 (-8.5, 0.2) 7.7 (1.9, 13.5) 4.2 (-0.6, 9) 4.3 (-0.5, 9.2) Moxifloxacin Active control 400 mg 6.9 (2.3, 11.5) 12.7 (8.6, 16.8) 11 (7, 15) 11.1 (7.2, 15) 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 postmarketing experience with alfuzosin outside the United States.

A separate postmarketing QT study evaluated the effect of the coadministration of 10 mg alfuzosin with a drug of similar QT effect size. In this study, the mean placebo-subtracted 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.

14 CLINICAL STUDIES Three randomized placebo-controlled, double-blind, parallel-arm, 12-week trials were conducted with the 10 mg daily dose of alfuzosin. In these three trials, 1,608 patients [mean age 64.2 years, range 49 to 92 years; Caucasian (96.1%), Black (1.6%), Asian (1.1%), Other (1.2%)] were randomized and 473 patients received alfuzosin hydrochloride extended-release 10 mg tablet daily. Table 4 provides the results of the three trials 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 with higher numerical scores on the IPSS total symptom score representing greater severity of symptoms. 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 trials 1 and 3. There was a statistically significant reduction from baseline to last assessment (Week 12) in the IPSS total symptom score versus placebo in all three studies, indicating a reduction in symptom severity (Table 5 and Figures 2, 3, and 4). Table 4 — Mean Change (SD) from Baseline to week 12 in International Prostate Symptom Score in Three Randomized, Controlled, Double Blind Trials Trial 1 Trial 2 Trial 3 Symptom Score Placebo (n = 167) Alfuzosin Hydrochloride Extended-Release Tablets 10 mg (n = 170) Placebo (n = 152) Alfuzosin Hydrochloride Extended-Release Tablets 10 mg (n = 137) Placebo (n = 150) Total symptom score Baseline 18.2 (6.4) 18.2 (6.3) 17.7 (4.1) 17.3 (3.5) 17.7 (5) Change 1 -1.6 (5.8) -3.6 (4.8) -4.9 (5.9) -6.9 (4.9) -4.6 (5.8) p-value 0.001 0.002 0.007 Peak urinary flow rate was increased statistically significantly from baseline to last assessment (Week 12) versus placebo in trials 1 and 2 (Table 5 and Figures 5, 6, and 7).

Table 5 — Mean (SD) Change from Baseline to Week 12 in Peak Urine Flow Rate (mL/sec) in Three Randomized, Controlled, Double-Blind Trials Trial 1 Trial 2 Trial 3 Placebo (n = 167) Alfuzosin Hydrochloride Extended-Release Tablets 10 mg (n = 170) Placebo (n = 147) Alfuzosin Hydrochloride Extended-Release Tablets 10 mg (n = 136) Placebo (n = 150) Alfuzosin Hydrochloride Extended-Release Tablets 10 mg (n = 151) Mean peak flow rate Baseline 10.2 (4) 9.9 (3.9) 9.2 (2) 9.4 (1.9) 9.3 (2.6) 9.5 (3) Change 2 0.2 (3.5) 1.7 (4.2) 1.4 (3.2) 2.3 (3.6) 0.9 (3) 1.5 (3.3) p-value 0.0004 0.03

0.22Mean 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 trials 2 and 3 and Day 28 in trial 1. 1 - Difference between baseline and week 12. 2 - Difference between baseline and week 12 figure-2 figure-3 figure-4 figure-5 figure-6 figure-7

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility There was no evidence of a drug-related increase in the incidence of tumors in mice following dietary administration of 100 mg/kg/day alfuzosin for 98 weeks (13 and 15 times the maximum recommended human dose [MRHD] of 10 mg based on AUC of unbound drug), in females and males, respectively. The highest dose tested in female mice may not have constituted a maximally tolerated dose. Likewise, there was no evidence of a drug-related increase in the incidence of tumors in rats following dietary administration of 100 mg/kg/day alfuzosin for 104 weeks (53 and 37 times the MRHD in females and males, respectively).

Alfuzosin showed no evidence of mutagenic effect in the Ames and mouse lymphoma assays, and was free of any clastogenic effects in the Chinese hamster ovary cell and in vivo mouse micronucleus assays. Alfuzosin treatment did not induce DNA repair in a human cell line. There was no evidence of reproductive organ toxicity when male rats were administered oral doses of several hundred times (250 mg/kg/day for 26 weeks) the MRHD of alfuzosin.

No impairment of fertility was observed following oral (gavage) administration to male rats at doses of up to 125 mg/kg/day for 70 days. Estrous cycling was inhibited in rats and dogs at approximately 12 and 18 times the MRHD respectively (doses of 25 mg/kg and 20 mg/kg, respectively), but did not result in impaired fertility in female rats.