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 1,500 mg/kg/day, respectively. These doses are both approximately 3 times the maximum recommended human daily dose of 2,550 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 2,550 mg based on body surface area comparisons.

14 CLINICAL STUDIES

14.2 Metformin Hydrochloride Extended-Release Tablets

A 24-week, double-blind, placebo-controlled study of metformin hydrochloride extended-release tablets, 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 1,500 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 metformin hydrochloride extended-release tablets.

A 16-week, double-blind, placebo-controlled, dose-response study of metformin hydrochloride extended-release tablets, 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 Metformin Hydrochloride Extended-Release Tablets vs Placebo in Patients with Type 2 Diabetes Mellitus

Metformin Hydrochloride Extended-Release Tablets

Placebo

500 mg

Once

Daily

1,000 mg

Once

Daily

1,500 mg

Once

Daily

2,000 mg

Once

Daily

1,000 mg Twice

Daily

Hemoglobin A 1c (%)

Baseline

Change at FINAL VISIT

p-value a

(n=115)

8.2

–0.4

< 0.001

(n=115)

8.4

–0.6

< 0.001

(n=111)

8.3

–0.9

< 0.001

(n=125)

8.4

–0.8

< 0.001

(n=112)

8.4

–1.1

< 0.001

(n=111)

8.4

0.1

FPG (mg/dL)

Baseline

Change at FINAL VISIT

p-value a

(n=126)

182.7

–15.2

< 0.001

(n=118)

183.7

–19.3

< 0.001

(n=120)

178.9

–28.5

< 0.001

(n=132)

181.0

–29.9

< 0.001

(n=122)

181.6

–33.6

< 0.001

(n=113)

179.6

7.6

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 metformin hydrochloride extended-release tablets 500 mg , 1,000 mg, 1,500 mg, and 2,000 mg once daily, 1,000 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 metformin hydrochloride extended-release tablets, taken once daily with the evening meal, and metformin hydrochloride, taken twice daily (with breakfast and evening meal), was conducted in patients with type 2 diabetes mellitus who had been treated with metformin hydrochloride 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 Metformin Hydrochloride Extended-Release Tablets vs Metformin Hydrochloride Tablets in Patients with Type 2 Diabetes Mellitus

Metformin Hydrochloride Tablets

500 mg

Twice Daily

Metformin Hydrochloride Extended-Release Tablets

1,000 mg

Once Daily

1,500 mg

Once Daily

Hemoglobin A 1c (%)

Baseline

Change at FINAL VISIT

(95% CI)

(n=67)

7.06

0.14 a

(–0.04, 0.31)

(n=72)

6.99

0.27

(0.11, 0.43)

(n=66)

7.02

0.13

(–0.02, 0.28)

FPG (mg/dL)

Baseline

Change at FINAL VISIT

(95% CI)

(n=69)

127.2

14.0

(7.0, 21.0)

(n=72)

131.0

11.5

(4.4, 18.6)

(n=70)

131.4

7.6

(1.0, 14.2)

a n=68

Mean baseline body weight was 210 lbs, 203 lbs and 193 lbs in the metformin hydrochloride tablets 500 mg twice daily, and metformin hydrochloride extended-release tablets 1,000 mg and 1,500 mg 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.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Metformin Hydrochloride Extended-release Tablets USP, 500 mg are white, capsule shaped, biconvex tablets debossed “IP 178” on one side and plain on the other side.

They are available as follows:

Bottles of 90: NDC 42291-610-90

Bottles of 180: NDC 42291-610-18

Bottles of 360: NDC 42291-610-36

Bottles of 1,000: NDC 42291-610-10

Metformin Hydrochloride Extended-release Tablets USP, 750 mg are white, capsule shaped, biconvex tablets debossed “IP 179” on one side and plain on the other side.

They are available as follows:

Bottles of 180: NDC 42291-611-18

Bottles of 90: NDC 42291-611-90

Bottles of 270: NDC 42291-611-27

Bottles of 500: NDC 42291-611-50

16.2 Storage

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

Dispense in light-resistant containers as defined in the USP.

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 extended-release 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 extended-release tablets. Instruct patients to inform their doctor that they are taking metformin hydrochloride extended-release 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 extended-release tablets are co-administered 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 B 12 Deficiency:

Inform patients about importance of regular hematological parameters while receiving metformin hydrochloride extended-release tablets [see Warnings and Precautions (5.2)] .

Females of Reproductive Age:

Inform females that treatment with metformin hydrochloride extended-release tablets may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy [see Use in Specific Populations (8.3)].

Metformin Hydrochloride Extended-Release Tablets Administration Information:

Inform patients that metformin hydrochloride extended-release tablets must be swallowed whole and not crushed, cut, or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.

Manufactured for:
AvKARE, Inc.
Pulaski, TN 38478

Mfg. Rev. 08-2018-03
AV Rev. 09/18 (P)

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