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.
Adult Clinical Studies A 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 metformin hydrochloride (up to 2550 mg/day) or placebo for 29 weeks. The results are presented in Table 7.
|Metformin Hydrochloride (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 metformin hydrochloride and placebo arms, respectively. Mean change in body weight from baseline to week 29 was -1.4 lbs and -2.4 lbs in the metformin hydrochloride and placebo arms, respectively.A 29-week, double-blind, placebo-controlled study of metformin hydrochloride 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 metformin hydrochloride 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 metformin hydrochloride 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 metformin hydrochloride 2500 mg. Patients in the metformin hydrochloride 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 metformin hydrochloride 2000 mg/glyburide 20 mg or metformin hydrochloride 2500 mg/glyburide 20 mg. The results are displayed in Table 8.
|Comb (n=213)||Glyb (n=209 )||MET (n=210)||p-Values|
|Glyb vs Comb||MET vs Comb||MET 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 metformin hydrochloride /glyburide, glyburide, and metformin hydrochloride 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 metformin hydrochloride /glyburide, glyburide, and metformin hydrochloride 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 metformin hydrochloride (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.
|FPG (mg/dL) Baseline Change at FINAL VISIT||(n=37) 162.4 –42.9||(n=36) 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 metformin hydrochloride and placebo arms, respectively. Mean change in body weight from baseline to week 16 was -3.3 lbs and -2.0 lbs in the metformin hydrochloride and placebo arms, respectively.
|Metformin Hydrochloride Tablets|
|500 mg||Bottles of 100||NDC 24724-014-01||White to off white, round shaped, biconvex, film coated tablets debossed with ‘I45’ on one side and plain on the other side|
|Bottles of 500||NDC 24724-014-50|
|850 mg||Bottles of 100||NDC 24724-015-01||White to off white, capsule shaped, biconvex, film coated tabletsdebossed with ‘I46’ on one side and plain on other side.|
|Bottles of 500||NDC 24724-015-50|
|1000 mg||Bottles of 100||NDC 24724-016-01||white to off white, oval shaped, biconvex, film coated tablets debossedwith ‘I’ and ‘47’ separated by a breakline on one side and the breakline on the other side|
|Bottles of 500||NDC 24724-016-50|
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