Prescription Drug Information: Metformin Hydrochloride (Page 4 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

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 based on body surface area comparisons.

14 CLINICAL STUDIES

14.1 Metformin Hydrochloride Tablets

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 tablets (up to 2550 mg/day) or placebo for 29 weeks. The results are presented in Table 6.

Table 6: Mean Change in Fasting Plasma Glucose and HbA1c at Week 29 Comparing Metformin Hydrochloride Tablets vs Placebo in Patients with Type 2 Diabetes Mellitus

Metformin Hydrochloride Tablets (n=141) Placebo (n=145) p-Value
FPG (mg/dL) Baseline Change at FINAL VISIT 241.5–53.0 237.76.3 NS*0.001
Hemoglobin A1c (%) Baseline Change at FINAL VISIT 8.4–1.4 8.20.4 NS*0.001

*Not statistically significant

Mean baseline body weight was 201 lbs and 206 lbs in the metformin hydrochloride tablets 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 tablets and placebo arms, respectively. A 29-week, double-blind, placebo-controlled study of metformin hydrochloride tablets 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 tablets 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 tablets 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 tablets 2500 mg. Patients in the metformin hydrochloride tablets 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 tablets 2000 mg/glyburide 20 mg or metformin hydrochloride tablets 2500 mg/glyburide 20 mg. The results are displayed in Table 7.Table 7: Mean Change in Fasting Plasma Glucose and HbA1c at Week 29 Comparing Metformin Hydrochloride Tablets /Glyburide (Comb) vs Glyburide (Glyb) vs Metformin Hydrochloride Tablets (GLU): in Patients with Type 2 Diabetes Mellitus with Inadequate Glycemic Control on Glyburide

Comb (n=213) Glyb (n=209) GLU (n=210) p-Values
Glyb vs Comb GLU vs Comb GLU vs Glyb
Fasting Plasma Glucose (mg/dL) Baseline 250.5 247.5 253.9 NS* NS* NS*
Change at FINAL VISIT –63.5 13.7 –0.9 0.001 0.001 0.025
Hemoglobin A1c (%) Baseline 8.8 8.5 8.9 NS* NS* 0.007
Change at FINAL VISIT –1.7 0.2 –0.4 0.001 0.001 0.001

* Not statistically significant

Mean baseline body weight was 202 lbs, 203 lbs, and 204 lbs in the metformin hydrochloride tablets /glyburide, glyburide, and metformin hydrochloride tablets 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 tablets /glyburide, glyburide, and metformin hydrochloride tablets 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 tablets (up to 2000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks) was conducted. The results are displayed in Table 8.Table 8: Mean Change in Fasting Plasma Glucose at Week 16 Comparing Metformin Hydrochloride Tablets vs Placebo in Pediatric Patientsa with Type 2 Diabetes Mellitus

Metformin Hydrochloride Tablets Placebo p-Value
FPG (mg/dL) Baseline Change at FINAL VISIT (n=37) 162.4 –42.9 (n=36) 192.3 21.4 <0.001

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

Mean baseline body weight was 205 lbs and 189 lbs in the metformin hydrochloride tablets 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 tablets and placebo arms, respectively.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Metformin Hydrochloride Tablets, USP:

500 mg Bottles of 30 NDC 25000-134-03

500 mg Bottles of 1000 NDC 25000-134-14

500 mg Bulk (16455 tablets) NDC 25000-134-98

850 mg Bottles of 30 NDC 25000-131-03

850 mg Bottles of 500 NDC 25000-131-12

850 mg Bulk (9680 tablets) NDC 25000-131-98

1000 mg Bottles of 30 NDC 25000-132-03

1000 mg Bottles of 500 NDC 25000-132-12
1000 mg Bulk (8225 tablets) NDC 25000-132-98

Metformin Hydrochloride Tablets, USP 500 mg are white to off-white colored, film coated, round shaped tablet with beveled edges on both side and debossed with ‘134’ on one side and plain on other side.

Metformin Hydrochloride Tablets, USP 850 mg are white to off-white colored, film coated, round shaped tablet with beveled edges on both side and debossed with ‘131’ on one side and plain on other side.

Metformin Hydrochloride Tablets, USP 1000 mg are white to off-white colored, film coated, oval shaped tablet with ‘132’ debossed on one side and breakline on both sides.


16.2 Storage

Store at 20°–25° C (68°–77° F); excursions permitted to 15°–30° C (59°–86° F). [See USP Controlled Room Temperature.]

Dispense in light-resistant containers.

17 PATIENT COUNSELING INFORMATION


Advise the patient to read the FDA-approved patient labeling (Patient Information).
Lactic Acidosis:
Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development. Advise patients to discontinue metformin hydrochloride tablets immediately and to promptly notify their healthcare provider if unexplained hyperventilation, myalgias, malaise, unusual somnolence or other nonspecific symptoms occur. Counsel patients against excessive alcohol intake and inform patients about importance of regular testing of renal function while receiving metformin hydrochloride tablets Instruct patients to inform their doctor that they are taking metformin hydrochloride tablets prior to any surgical or radiological procedure, as temporary discontinuation may be required [see Warnings and Precautions (5.1)]

.
Hypoglycemia
Inform patients that hypoglycemia may occur when metformin hydrochloride tablets is coadministered with oral sulfonylureas and insulin. Explain to patients receiving concomitant therapy the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development [see Warnings and Precautions (5.3)]

.
Vitamin B12 Deficiency:
Inform patients about importance of regular haematological parameters while receiving metformin hydrochloride tablets

[see Warnings and Precautions (5.2)]

.
Females of Reproductive Age:
Inform females that treatment with metformin hydrochloride tablets

may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy [see Use in Specific Populations (8.3)].

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