Glimepiride (Page 5 of 6)

13 NONCLINICAL TOXICOLOGY

1 3 .1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Studies in rats at doses of up to 5000 parts per million (ppm) in complete feed (approximately 340 times the maximum recommended human dose, based on surface area) for 30 months showed no evidence of carcinogenesis. In mice, administration of glimepiride for 24 months resulted in an increase in benign pancreatic adenoma formation that was dose-related and was thought to be the result of chronic pancreatic stimulation.

No adenoma formation in mice was observed at a dose of 320 ppm in complete feed, or 46 to 54 mg/kg body weight/day. This is at least 28 times the maximum human recommended dose of 8 mg once daily based on surface area.

Glimepiride was non-mutagenic in a battery of in vitro and in vivo mutagenicity studies (Ames test, somatic cell mutation, chromosomal aberration, unscheduled DNA synthesis, and mouse micronucleus test).

There was no effect of glimepiride on male mouse fertility in animals exposed up to 2500 mg/kg body weight (>1,500 times the maximum recommended human dose based on surface area). Glimepiride had no effect on the fertility of male and female rats administered up to 4000 mg/kg body weight (approximately 4,000 times the maximum recommended human dose based on surface area).

14 CLINICAL STUDIES

14.1 Monotherapy

A total of 304 patients with type 2 diabetes already treated with sulfonylurea therapy participated in a 14-week, multicenter, randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of glimepiride monotherapy. Patients discontinued their sulfonylurea therapy then entered a 3-week placebo washout period followed by randomization into 1 of 4 treatment groups: placebo (n=74), glimepiride 1 mg (n=78), glimepiride 4 mg (n=76) and glimepiride 8 mg (n=76). All patients randomized to glimepiride started 1 mg daily. Patients randomized to glimepiride 4 mg or 8 mg had blinded, forced titration of the glimepiride dose at weekly intervals, first to 4 mg and then to 8 mg, as long as the dose was tolerated, until the randomized dose was reached. Patients randomized to the 4 mg dose reached the assigned dose at Week 2. Patients randomized to the 8 mg dose reached the assigned dose at Week 3. Once the randomized dose level was reached, patients were to be maintained at that dose until Week 14. Approximately 66% of the placebo-treated patients completed the trial compared to 81% of patients treated with glimepiride 1 mg and 92% of patients treated with glimepiride 4 mg or 8 mg. Compared to placebo, treatment with glimepiride 1 mg, 4 mg and 8 mg daily provided statistically significant improvements in HbA1C compared to placebo (Table 3).

Table 3: 14-week Monotherapy Trial Comparing Glimepiride to Placebo in Patients Previously Treated With Sulfonylurea Therapy a
Placebo (N=74) Glimepiride
1 mg (N=78) 4 mg (N=76) 8 mg (N=76)
HbA 1C (%)
n=59 n=65 n=65 n=68
Baseline (mean) 8.0 7.9 7.9 8.0
Change from Baseline (adjusted mean b) 1.5 0.3 -0.3 -0.4
Difference from Placebo (adjusted mean b) -1.2* (-1.5, -0.8) -1.8* (-2.1, -1.4) -1.8* (-2.2, -1.5)
Mean Baseline Weight
n=67 n=76 n=75 n=73
Baseline (mean) 85.7 84.3 86.1 85.5
Change from Baseline (adjusted mean b) -2.3 -0.2 0.5 1.0
Difference from Placebo (adjusted mean b) 2.0* (1.4, 2.7) 2.8* (2.1, 3.5) 3.2* (2.5, 4.0)
a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value * p ≤0.001

A total of 249 patients who were treatment-naïve or who had received limited treatment with antidiabetic therapy in the past were randomized to receive 22 weeks of treatment with either glimepiride (n=123) or placebo (n=126) in a multicenter, randomized, double-blind, placebo-controlled, dose-titration trial. The starting dose of glimepiride was 1 mg daily and was titrated upward or downward at 2-week intervals to a goal FPG of 90 to 150 mg/dL. Blood glucose levels for both FPG and PPG were analyzed in the laboratory. Following 10 weeks of dose adjustment, patients were maintained at their optimal dose (1, 2, 3, 4, 6 or 8 mg) for the remaining 12 weeks of the trial. Treatment with glimepiride provided statistically significant improvements in HbA1C and FPG compared to placebo (Table 4).

Table 4: 22-Week Monotherapy Trial Comparing Glimepiride to Placebo in Patients Who Were Treatment-Naïve or Who Had No Recent Treatment with Antidiabetic Therapy a
Placebo (N=126) Glimepiride (N=123)

HbA 1C (%)

n=97 n=106
Baseline (mean) 9.1 9.3
Change from Baseline (adjusted mean b) -1.1* -2.2*
Difference from Placebo (adjusted mean b) 95% confidence interval -1.1* (-1.5, -0.8)
Body Weight (kg)
n=122 n=119
Baseline (mean) 86.5 87.1

Change from Baseline (adjusted mean b)

-0.9 1.8
Difference from Placebo (adjusted mean b) 95% confidence interval 2.7 (1.9, 3.6)
a Intent to treat population using last observation on study b Least squares mean adjusted for baseline value * p ≤0.0001

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