2.1 Adult Dosage

2.3 Recommendations for Use in Renal Impairment

• Assess renal function prior to initiation of metformin hydrochloride extended-release tablets and periodically thereafter.
• Metformin hydrochloride extended-release tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m 2.
• Initiation of metformin hydrochloride extended-release tablets in patients with an eGFR between 30 mL/minute/1.73 m 2and 45 mL/minute/1.73 m 2is not recommended.
• In patients taking metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/min/1.73 m 2, assess the benefit risk of continuing therapy.
• Discontinue metformin hydrochloride extended-release tablets if the patient's eGFR later falls below 30 mL/minute/1.73 m 2[see Warnings and Precautions (5.1)] .

2.4 Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 mL/min/1.73 m 2and 60 mL/min/1.73 m 2; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart metformin hydrochloride extended-release tablets if renal function is stable.

5.1 Lactic Acidosis

There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metforminassociated lactic acidosis was characterized by elevated blood lactate concentrations (> 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels were generally > 5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of metformin hydrochloride extended-release tablets. In metformin hydrochloride extended-release tablets treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.

Educate patients and their families about the symptoms of lactic acidosis and, if these symptoms occur, instruct them to discontinue metformin hydrochloride extended-release tablets and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

• Renal impairment— The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment.
  The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)] :
  • Before initiating metformin hydrochloride extended-release tablets, obtain an estimated glomerular filtration rate (eGFR).
  • Metformin hydrochloride extended-release tablets are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2[see Contraindications (4)] .
  • Initiation of metformin hydrochloride extended-release tablets is not recommended in patients with eGFR between 30 mL/min/1.73 m 2and 45 mL/min/1.73 m 2.
  • Obtain an eGFR at least annually in all patients taking metformin hydrochloride extended-release tablets. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
  • In patients taking metformin hydrochloride extended-release tablets whose eGFR falls below 45 mL/min/1.73 m 2, assess the benefit and risk of continuing therapy.
• Drug interactions— The concomitant use of metformin hydrochloride extended-release tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation. Consider more frequent monitoring of patients.
• Age 65 or greater— The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.
• Radiologic studies with contrast— Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 mL/min/1.73 m 2and 60 mL/min/1.73 m 2; in patients with a history of hepatic impairment, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart metformin hydrochloride extended-release tablets if renal function is stable.
• Surgery and other procedures— Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment. Metformin hydrochloride extended-release tablets should be temporarily discontinued while patients have restricted food and fluid intake.
• Hypoxic states— Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may cause prerenal azotemia. When such an event occurs, discontinue metformin hydrochloride extended-release tablets.
• Excessive alcohol intake— Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving metformin hydrochloride extended-release tablets.
• Hepatic impairment— Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of metformin hydrochloride extended-release tablets in patients with clinical or laboratory evidence of hepatic disease.

5.2 Vitamin B 12Deficiency

In metformin hydrochloride tablets clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12absorption from the B 12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin hydrochloride tablets or vitamin B 12supplementation. Certain individuals (those with inadequate vitamin B 12or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12levels. Measure hematologic parameters on an annual basis and vitamin B 12at 2 to 3 year intervals in patients on metformin hydrochloride extended-release tablets and manage any abnormalities [see Adverse Reactions (6.1)] .

5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. Metformin hydrochloride extended-release tablets may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with metformin hydrochloride extended-release tablets [see Drug Interactions (7)].

5.4 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin hydrochloride extended-release tablets.

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of metformin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin hydrochloride extended-release tablets may result in ovulation in some anovulatory women.

8.4 Pediatric Use

8.5 Geriatric Use

Controlled clinical studies of metformin hydrochloride extended-release tablets did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [see Warnings and Precautions (5.1)] .

8.6 Renal Impairment

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Metformin hydrochloride extended-release tablets are contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m 2[see Dosage and Administration (2.3), Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)] .

8.7 Hepatic Impairment

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Metformin hydrochloride extended-release tablets are not recommended in patients with hepatic impairment. [see Warnings and Precautions (5.1)] .

12.1 Mechanism of Action

Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

12.3 Pharmacokinetics

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 vitrotests: Ames test ( S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivomouse 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.

14.2 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 1cof 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 1cwas ≥ 7.0% but < 8.0% (patients with HbA 1c≥ 8.0% were discontinued from the study). At the final visit (24-week), mean HbA 1chad 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 6.

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 tablets, taken twice daily (with breakfast and evening meal), was conducted in patients with type 2 diabetes mellitus who had been treated with metformin hydrochloride tablets 500 mg twice daily for at least 8 weeks prior to study entry. The results are shown in Table 7.

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.

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 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 B 12Deficiency:

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.