Prescription Drug Information: Metformin Hydrochloride (Page 4 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 Metformin Hydrochloride

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.

Table 7: Mean Change in Fasting Plasma Glucose and HbA1c at Week 29 Comparing Metformin Hydrochloride vs Placebo in Patients with Type 2 Diabetes Mellitus

Metformin Hydrochloride (n=141) Placebo (n=145) p-Value
FPG (mg/dL) BaselineChange at FINAL VISIT 241.5–53.0 237.76.3 NS*0.001
Hemoglobin A1c (%)BaselineChange 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 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.

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

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 250.5–63.5 247.513.7 253.9–0.9 NS*0.001 NS*0.001 NS*0.025
Hemoglobin A1c (%)Baseline Change at FINAL VISIT 8.8–1.7 8.50.2 8.9–0.4 NS*0.001 NS*0.001 0.0070.001

* 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.

Table 9: 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 Placebo p-Value
FPG (mg/dL) BaselineChange at FINAL VISIT (n=37) 162.4–42.9 (n=36) 192.321.4 <0.001

a Pediatric patients mean age 13.8 years (range 10 to 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.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Metformin Hydrochloride Tablets USP, 500 mg: White, biconvex, circular shaped film coated tablets with ‘A’ debossed on one side and ‘12’ debossed on the other side.

Bottles of 50 NDC 65862-008-50

Bottles of 60 NDC 65862-008-60

Bottles of 90 NDC 65862-008-90

Bottles of 100 NDC 65862-008-01

Bottles of 300 NDC 65862-008-33

Bottles of 500 NDC 65862-008-05

Bottles of 1,000 NDC 65862-008-99

Bottles of 4,500 NDC 65862-008-45

Metformin Hydrochloride Tablets USP, 850 mg: White, biconvex, circular shaped film coated tablets with ‘A’ debossed on one side and ‘13’ debossed on the other side.

Bottles of 50 NDC 65862-009-50

Bottles of 60 NDC 65862-009-60

Bottles of 90 NDC 65862-009-90

Bottles of 100 NDC 65862-009-01

Bottles of 300 NDC 65862-009-33

Bottles of 500 NDC 65862-009-05

Bottles of 1,000 NDC 65862-009-99

Bottles of 2,500 NDC 65862-009-44

Metformin Hydrochloride Tablets USP, 1000 mg: White, biconvex, oval shaped film coated tablets with a score line in between ‘1’ and ‘4’ on one side and ‘A’ debossed on the other side.

Bottles of 50 NDC 65862-010-50

Bottles of 60 NDC 65862-010-60

Bottles of 90 NDC 65862-010-90

Bottles of 100 NDC 65862-010-01

Bottles of 300 NDC 65862-010-33

Bottles of 500 NDC 65862-010-05

Bottles of 1,000 NDC 65862-010-99

Bottles of 2,000 NDC 65862-010-46

16.2 Storage

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 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 are 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 hematological 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)].

Distributed by:

Aurobindo Pharma USA, Inc.

279 Princeton-Hightstown Road

East Windsor, NJ 08520

Manufactured by:

Aurobindo Pharma Limited

Hyderabad-500 038, India

Revised: 07/2018

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