Alfuzosin Hydrochloride (Page 4 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, 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.

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
*
Difference between baseline and week 12.
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) Alfuzosin Hydrochloride Extended-Release Tablets 10 mg (n = 151)
Total symptom score
Baseline 18.2(6.4) 18.2 (6.3) 17.7 (4.1) 17.3 (3.5)17.7(5) 18 (5.4)
Change *-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
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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
*
Difference between baseline and week 12
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
Baseline10.2 (4)9.9 (3.9)9.2 (2)9.4 (1.9)9.3 (2.6)9.5 (3)
Change *0.2 (3.5)1.7 (4.2)1.4 (3.2)2.3 (3.6)0.9 (3)1.5 (3.3)
p-value0.00040.030.22
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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 trials 2 and 3 and Day 28 in trial 1.

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