GLUCOPHAGE (Page 5 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately 3 times the maximum recommended human daily dose of 2550 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.

There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.

Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately 2 times the maximum recommended human daily dose of 2550 mg based on body surface area comparisons.

14 CLINICAL STUDIES

14.1 GLUCOPHAGE

Adult Clinical StudiesA double-blind, placebo-controlled, multicenter US clinical trial involving obese patients with type 2 diabetes mellitus whose hyperglycemia was not adequately controlled with dietary management alone (baseline fasting plasma glucose [FPG] of approximately 240 mg/dL) was conducted. Patients were treated with GLUCOPHAGE (up to 2550 mg/day) or placebo for 29 weeks. The results are presented in Table 7.

Table 7: Mean Change in Fasting Plasma Glucose and HbA1c at Week 29 Comparing GLUCOPHAGE vs Placebo in Patients with Type 2 Diabetes Mellitus
GLUCOPHAGE (n=141) Placebo (n=145) p-Value
FPG (mg/dL) Baseline Change at FINAL VISIT 241.5 53.0 237.7 6.3 NS* 0.001
Hemoglobin A1c (%) Baseline Change at FINAL VISIT 8.4 1.4 8.2 0.4 NS* 0.001

* Not statistically significant

Mean baseline body weight was 201 lbs and 206 lbs in the GLUCOPHAGE and placebo arms, respectively. Mean change in body weight from baseline to week 29 was -1.4 lbs and -2.4 lbs in the GLUCOPHAGE and placebo arms, respectively.

A 29-week, double-blind, placebo-controlled study of GLUCOPHAGE and glyburide, alone and in combination, was conducted in obese patients with type 2 diabetes mellitus who had failed to achieve adequate glycemic control while on maximum doses of glyburide (baseline FPG of approximately 250 mg/dL). Patients randomized to the combination arm started therapy with GLUCOPHAGE 500 mg and glyburide 20 mg. At the end of each week of the first 4 weeks of the trial, these patients had their dosages of GLUCOPHAGE increased by 500 mg if they had failed to reach target fasting plasma glucose. After week 4, such dosage adjustments were made monthly, although no patient was allowed to exceed GLUCOPHAGE 2500 mg. Patients in the GLUCOPHAGE only arm (metformin plus placebo) discontinued glyburide and followed the same titration schedule. Patients in the glyburide arm continued the same dose of glyburide. At the end of the trial, approximately 70% of the patients in the combination group were taking GLUCOPHAGE 2000 mg/glyburide 20 mg or GLUCOPHAGE 2500 mg/glyburide 20 mg. The results are displayed in Table 8.

Table 8: Mean Change in Fasting Plasma Glucose and HbA1c at Week 29 Comparing GLUCOPHAGE/Glyburide (Comb) vs Glyburide (Glyb) vs GLUCOPHAGE (GLU): in Patients with Type 2 Diabetes Mellitus with Inadequate Glycemic Control on Glyburide
p-Values

Comb

(n=213)

Glyb

(n=209)

GLU

(n=210)

Glyb vs Comb

GLU vs Comb

GLU vs Glyb

Fasting Plasma Glucose (mg/dL)
Baseline Change at FINAL VISIT

250.5

-63.5

247.5

13.7

253.9

-0.9

NS*

0.001

NS*

0.001

NS*

0.025

Hemoglobin A1c (%)
Baseline Change at FINAL VISIT

8.8

-1.7

8.5

0.2

8.9

-0.4

NS*

0.001

NS*

0.001

0.007

0.001

* Not statistically significant

Mean baseline body weight was 202 lbs, 203 lbs, and 204 lbs in the GLUCOPHAGE/glyburide, glyburide, and GLUCOPHAGE arms, respectively. Mean change in body weight from baseline to week 29 was 0.9 lbs, -0.7 lbs, and -8.4 lbs in the GLUCOPHAGE/glyburide, glyburide, and GLUCOPHAGE arms, respectively.

Pediatric Clinical Studies

A double-blind, placebo-controlled study in pediatric patients aged 10 to 16 years with type 2 diabetes mellitus (mean FPG 182.2 mg/dL), treatment with GLUCOPHAGE (up to 2000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks) was conducted. The results are displayed in Table 9.

Table 9: Mean Change in Fasting Plasma Glucose at Week 16 Comparing GLUCOPHAGE vs Placebo in Pediatric Patientsa with Type 2 Diabetes Mellitus
GLUCOPHAGE

Placebo

p-Value
FPG (mg/dL) (n=37)

(n=36)

-
Baseline Change at FINAL VISIT 162.4 42.9 192.3 21.4 <0.001

a Pediatric patients mean age 13.8 years (range 10-16 years)

Mean baseline body weight was 205 lbs and 189 lbs in the GLUCOPHAGE and placebo arms, respectively. Mean change in body weight from baseline to week 16 was -3.3 lbs and -2.0 lbs in the GLUCOPHAGE and placebo arms, respectively.

14.2 GLUCOPHAGE XR

A 24-week, double-blind, placebo-controlled study of GLUCOPHAGE XR, taken once daily with the evening meal, was conducted in patients with type 2 diabetes mellitus who had failed to achieve glycemic control with diet and exercise. Patients entering the study had a mean baseline HbA 1c of 8.0% and a mean baseline FPG of 176 mg/dL. The treatment dose was increased to 1500 mg once daily if at Week 12 HbA 1c was 7.0% but <8.0% (patients with HbA 1c 8.0% were discontinued from the study). At the final visit (24-week), mean HbA 1c had increased 0.2% from baseline in placebo patients and decreased 0.6% with GLUCOPHAGE XR. A 16-week, double-blind, placebo-controlled, dose-response study of GLUCOPHAGE XR, taken once daily with the evening meal or twice daily with meals, was conducted in patients with type 2 diabetes mellitus who had failed to achieve glycemic control with diet and exercise. The results are shown in Table 10.

Table 10: Mean Changes from Baseline* in HbA1c and Fasting Plasma Glucose at Week 16 Comparing GLUCOPHAGE XR vs Placebo in Patients with Type 2 Diabetes Mellitus
GLUCOPHAGE XR

500 mg

Once

Daily

1000 mg

Once

Daily

1500 mg

Once

Daily

2000 mg

Once

Daily

1000 mg

Once

Daily

Placebo

Hemoglobin A1c (%) (n=115) (n=115) (n=111) (n=125) (n=112) (n=111)
Baseline 8.2 8.4 8.3 8.4 8.4 8.4
Change at FINAL VISIT -0.4 -0.6 -0.9 -0.8 -1.1 0.1
p-value a <0.001 <0.001 <0.001 <0.001 <0.001 -
FPG (mg/dL) (n=126) (n=118) (n=120) (n=132) (n=122) (n=113)
Baseline 182.7 183.7 178.9 181.0 181.6 179.6
Change at FINAL VISIT -15.2 -19.3 -28.5 -29.9 -33.6 7.6
p-value a <0.001 <0.001 <0.001 <0.001 <0.001 <0.001

a All comparisons versus Placebo

Mean baseline body weight was 193 lbs, 192 lbs, 188 lbs, 196 lbs, 193 lbs and 194 lbs in the GLUCOPHAGE XR 500 mg , 1000 mg, 1500 mg, and 2000 mg once daily, 1000 mg twice daily and placebo arms, respectively. Mean change in body weight from baseline to week 16 was -1.3 lbs, -1.3 lbs, -0.7 lbs, -1.5 lbs, -2.2 lbs and -1.8 lbs, respectively.

A 24-week, double-blind, randomized study of GLUCOPHAGE XR, taken once daily with the evening meal, and GLUCOPHAGE, taken twice daily (with breakfast and evening meal), was conducted in patients with type 2 diabetes mellitus who had been treated with GLUCOPHAGE 500 mg twice daily for at least 8 weeks prior to study entry. The results are shown in Table 11.

Table 11: Mean Changes from Baseline* in HbA1c and Fasting Plasma Glucose at Week 24 Comparing GLUCOPHAGE XR vs GLUCOPHAGE in Patients with Type 2 Diabetes Mellitus
GLUCOPHAGE 500 mg Twice Daily GLUCOPHAGE XR

1000 mg

Once Daily

1500 mg

Once Daily

Hemoglobin A1c (%) (n=67) (n=72) (n=66)
Baseline 7.06 6.99 7.02
Change at FINAL VISIT 0.14 a 0.27 0.13
(95% CI) (-0.04,0.31) (0.11,0.43) (-0.02,0.28)
FPG (mg/dL) (n=69) (n=72) (n=70)
Baseline 127.2 131.0 131.4
Change at FINAL VISIT 14.0 11.5 7.6
(95% CI) (7.0,21.0) (4.4,18.6) (1.0,14.2)

a n=68

Mean baseline body weight was 210lbs, 203 lbs and 193 lbs in the GLUCOPHAGE 500mg twice daily, and GLUCOPHAGE XR 1000mg and 1500mg once daily arms, respectively. Mean change in body weight from baseline to week 24 was 0.9 lbs, 1.1 lbs and 0.9 lbs, respectively.

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