2.1 Recommended Dosage

The starting dose of metformin hydrochloride extended-release tablets in patients who are not currently taking metformin is 500 mg orally, once daily with the evening meal. Increase the dose in 500 mg increments every 1 to 2 weeks if a higher dose of metformin hydrochloride extended-release tablets is needed and there are no gastrointestinal adverse reactions. The dosage of metformin hydrochloride extended-release tablets must be individualized on the basis of both effectiveness and tolerability, while not exceeding the maximum recommended daily dose of 2,000 mg.

2.2 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 m2.

Initiation of metformin hydrochloride extended-release tablets in patients with an eGFR between 30 to 45 mL/minute/1.73 m2 is not recommended.

In patients taking metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/min/1.73 m2, 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 m2 [see Contraindications (4) and Warnings and Precautions (5.1)].

2.3 Switching from Immediate-Release Metformin to Metformin Hydrochloride Extended-Release Tablets

If switching from immediate-release metformin to metformin hydrochloride extended-release tablets, initiate metformin hydrochloride extended-release tablets once daily at the same total dose, up to 2,000 mg once daily.

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 and 60 mL/min/1.73 m2; 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 [See Warnings and Precautions (5.1)].

2.5 Important Administration Instructions

Administer metformin hydrochloride extended-release tablets orally, once daily with the evening meal. Metformin hydrochloride extended-release tablets must be swallowed whole and never split, crushed or chewed. If a dose of metformin hydrochloride extended-release tablets is missed, instruct patients not to take two doses the same day and to resume their usual dose of metformin hydrochloride extended-release tablets with the next schedule dose [See Patient Counseling Information (17)].

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, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (greater than 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate/pyruvate ratio; metformin plasma levels generally greater than 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/minute 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 (2.2), 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/minute/1.73 m2[see Contraindications (4)].
• Initiation of metformin hydrochloride extended-release tablets is not recommended in patients with eGFR between 30 to 45 mL/minute/1.73 m2.
• Obtain an eGFR at least annually in all patients taking metformin hydrochloride extended-release tablets. In patients at increased 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 later falls below 45 mL/min/1.73 m2, 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 [see Drug Interactions (7)]. Therefore, 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 [see Use in Specific Populations (8.5)].

Radiological 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 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re­evaluate 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 also cause prerenal azotemia. When such events occur, discontinue metformin hydrochloride extended-release tablets.

Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients 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 B12 Levels

In controlled, 29-week clinical trials of immediate release metformin, a decrease to subnormal levels of previously normal serum Vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin hydrochloride extended-release tablets or Vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on metformin hydrochloride extended-release tablets and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with inadequate Vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal Vitamin B12 levels. In these patients, routine serum Vitamin B12 measurements at two- to three-year intervals may be useful.

5.3 Hypoglycemia

Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta­adrenergic blocking drugs.

5.4 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin hydrochloride extended-release tablets or any other oral anti-diabetic drug.

6.1 Clinical Trials Experience

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Lactic acidosis [see Warnings and Precautions (5.1)]
• Vitamin B12 Levels [see Warnings and Precautions (5.2)]
• Hypoglycemia [see Warnings and Precautions (5.3)]

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 clinical practice.

In clinical trials conducted in the U.S., over 1000 patients with type 2 diabetes mellitus have been treated with metformin hydrochloride extended-release tablets 1,500 to 2,000 mg/day in active-controlled and placebo-controlled studies with the 500 mg dosage form.

In the 24-week monotherapy trial comparing metformin hydrochloride extended-release tablets to immediate-release metformin, serious adverse reactions were reported in 3.6% (19/528) of the metformin hydrochloride extended-release tablets-treated patients compared to 2.9% (5/174) of the patients treated with immediate-release metformin. In the add-on to sulfonylurea study, patients receiving background glyburide therapy were randomized to receive add-on treatment of either one of three different regimens of metformin hydrochloride extended-release tablets or placebo. In total, 431 patients received metformin hydrochloride extended-release tablets and glyburide and 144 patients received placebo and glyburide. A serious adverse reaction was reported in 2.1% (9/431) of the metformin hydrochloride extended-release tablets and glyburide-treated patients compared to 1.4% (2/144) of the placebo and glyburide-treated patients. When the data from the monotherapy and add-on to sulfonylurea clinical trials were combined, the most frequently (incidence greater than or equal to 0.5 %) reported serious adverse reactions classified by system organ class were gastrointestinal disorders (1.0% of metformin hydrochloride extended-release tablets-treated patients compared to 0% of patients not treated with metformin hydrochloride extended-release tablets) and cardiac disorders (0.4% of metformin hydrochloride extended-release tablets-treated patients compared to 0.5% of patients not treated with metformin hydrochloride extended-release tablets). Only 2 serious adverse reactions (unstable angina [n=2] and pancreatitis [n=2]) were reported in more than one metformin hydrochloride extended-release tablets-treated patient.

Adverse reactions reported in greater than 5% of patients treated with metformin hydrochloride extended-release tablets that were more common in the combined metformin hydrochloride extended-release tablets and glyburide group than in the placebo and glyburide group are shown in Table 1.

In 0.7% of patients treated with metformin hydrochloride extended-release tablets and glyburide, diarrhea was responsible for discontinuation of study medication compared to no patients in the placebo and glyburide group.

* ARs that were more common in the metformin hydrochloride extended-release tablets-treated than in the placebo-treated patients.

Laboratory Tests

Vitamin B12 concentrations

Metformin may lower serum vitamin B12 concentrations. Measurement of hematologic parameters on an annual basis is advised in patients on metformin hydrochloride extended-release tablets and any apparent abnormalities should be appropriately investigated and managed. [See Warnings and Precautions (5.2)]

6.2 Postmarketing Experience

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

Cholestatic, hepatocellular, and mixed hepatocellular liver injury

7.1 Carbonic Anhydrase Inhibitors

Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with metformin hydrochloride extended-release tablets may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.

7.2 Drugs that Reduce Metformin Clearance

Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3)]. Consider the benefits and risks of concomitant use.

7.3 Alcohol

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving metformin hydrochloride extended-release tablets.

7.4 Insulin Secretagogues or Insulin

Co-administration of metformin hydrochloride extended-release tablets with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.

7.5 Drugs Affecting Glycemic Control

Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are administered to a patient receiving metformin hydrochloride extended-release tablets, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin hydrochloride extended-release tablets, the patient should be observed closely for hypoglycemia.

8.1 Pregnancy

Teratogenic Effects: Pregnancy Category B

Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day, which represent 3 and 6 times the maximum recommended human daily dose of 2,000 mg based on body surface area comparison for rats and rabbits, respectively. However, because animal reproduction studies are not always predictive of human response, Metformin HCl should not be used during pregnancy unless clearly needed.

8.2 Labor and Delivery

The safety and effectiveness of metformin hydrochloride extended-release tablets used during labor and delivery has not been evaluated in human studies.

8.3 Nursing Mothers

Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Thus, the potential for hypoglycemia in nursing infants after metformin HCl oral solution may exist.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Metformin hydrochloride extended-release tablets are not recommended in pediatric patients below the age of 18 years.

8.5 Geriatric Use

Clinical studies of metformin hydrochloride extended-release tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and 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) and Dosage and Administration (2.2)]

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 m2. [See Dosage and Administration (2.2), 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 a biguanide that improves glucose tolerance in patients with type 2 diabetes, 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. Metformin does not produce hypoglycemia in patients with type 2 diabetes or in healthy subjects except in special circumstances, [see Warnings and Precautions (5)] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and daylong plasma insulin response may actually decrease.

12.3 Pharmacokinetics

Absorption

Following a single oral dose of 1,000 mg (2x500 mg tablets) metformin hydrochloride extended-release tablets after a meal, the time to reach maximum plasma metformin concentration (Tmax) is achieved at approximately 7 to 8 hours. In both single and multiple-dose studies in healthy subjects, once daily 1,000 mg (2x500 mg tablets) dosing provides equivalent systemic exposure, as measured by area-under-the-curve (AUC), and up to 35% higher Cmax, of metformin relative to the immediate release given as 500 mg twice daily. Metformin hydrochloride extended-release tablets must be administered immediately after a meal to maximize therapeutic benefit.

Single oral doses of metformin hydrochloride extended-release tablets from 500 mg to 2,500 mg resulted in less than proportional increase in both AUC and Cmax. Low-fat and high-fat meals increased the systemic exposure (as measured by AUC) from metformin hydrochloride extended-release tablets by about 38% and 73%, respectively, relative to fasting. Both meals prolonged metformin Tmax by approximately 3 hours but Cmax was not affected.

In a two-way, single-dose crossover study in healthy volunteers, the 1,000 mg tablet was found to be bioequivalent to two 500 mg tablets under fed conditions based on equivalent Cmax and AUCs for the two formulations.

Distribution

The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg immediate release metformin hydrochloride averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally less than 1 mcg/mL. During controlled clinical trials, which served as the basis of approval for metformin, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.

Metabolism

Intravenous single-dose studies in healthy subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans), nor biliary excretion. Metabolism studies with extended-release metformin tablets have not been conducted.

Excretion

Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Special Populations

Renal Impairment: Following a single dose administration of metformin hydrochloride extended-release tablets 500 mg in subjects with mild and moderate renal impairment, the oral and renal clearance of metformin were decreased by 33% and 50% and 16% and 53%, respectively. Metformin peak and systemic exposure was 27% and 61% greater, respectively in subjects with mild renal impairment and 74% and 2.36-fold greater in subjects with moderate renal impairment as compared to healthy subjects. [See Dosage and Administration (2.2), Contraindications (4) and Warnings and Precautions (5.1)]

Hepatic Impairment: No pharmacokinetic studies of metformin hydrochloride extended-release tablets have been conducted in subjects with hepatic impairment. [See Warnings and Precautions (5.1)]

Geriatrics: Limited data from controlled pharmacokinetic studies of metformin hydrochloride in healthy elderly subjects suggest that total plasma clearance of metformin is decreased by 35%, the half-life is prolonged by 64% and Cmax is increased by 76%, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function. [See Warnings and Precautions (5.1) and Dosage and Administration (2)]

Gender: In the pharmacokinetic studies in healthy volunteers, there were no important differences between male and female subjects with respect to metformin AUC and t1/2. However, Cmax for metformin was 40% higher in female subjects as compared to males. The gender differences for Cmax are unlikely to be clinically important. Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin hydrochloride tablets was comparable in males and females.

Race: There were no definitive conclusions on the differences between the races with respect to the pharmacokinetics of metformin because of the imbalance in the respective sizes of the racial groups. However, the data suggest a trend towards higher metformin Cmax and AUC values for metformin are obtained in Asian subjects when compared to Caucasian, Hispanic and Black subjects. The differences between the Asian and Caucasian groups are unlikely to be clinically important. In controlled clinical studies of metformin hydrochloride in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n = 249), blacks (n = 51) and Hispanics (n = 24).

Pediatrics: No pharmacokinetic data from studies of metformin hydrochloride extended-release tablets in pediatric subjects are available.

Drug Interactions: Specific pharmacokinetic drug interaction studies with metformin hydrochloride extended-release tablets have not been performed except for one with glyburide. However, such studies have been performed on metformin.

1. All metformin and coadministered drugs were given as single doses

2. AUC = AUC0–∞

3. Ratio of arithmetic means

4. Metformin hydrochloride extended-release tablets 500 mg

5. At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC0-12h

1. All metformin and coadministered drugs were given as single doses

2. AUC = AUC0–∞

3. Ratio of arithmetic means, p-value of difference <0.05

4. AUC0-24 hr reported

5. Ratio of arithmetic means

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies have been performed in Sprague Dawley rats at doses of 150, 300, and 450 mg/kg/day in males and 150, 450, 900, and 1,200 mg/kg/day in females. These doses are approximately 2, 4, and 8 times in males, and 3, 7, 12, and 16 times in females of the maximum recommended human daily dose of 2,000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female rats. A carcinogenicity study was also performed in Tg.AC transgenic mice at doses up to 2,000 mg applied dermally. No evidence of carcinogenicity was observed in male or female mice.

Genotoxicity assessments in the Ames test, gene mutation test (mouse lymphoma cells), chromosomal aberrations test (human lymphocytes) and in vivo mouse micronucleus tests were negative. Fertility of male or female rats was not affected by metformin when administered at dose up to 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose based on body surface area comparisons.