2.1 Adult Dosage

Metformin Hydrochloride Tablets

• The recommended starting dose of Metformin Hydrochloride Tablets is 500 mg orally twice a day or 850 mg once a day, given with meals.
• Increase the dose in increments of 500 mg weekly or 850 mg every 2 weeks on the basis of glycemic control and tolerability, up to a maximum dose of 2550 mg per day, given in divided doses.
• Doses above 2000 mg may be better tolerated given 3 times a day with meals.

2.2 Pediatric Dosage for Metformin Hydrochloride Tablets

• The recommended starting dose of Metformin Hydrochloride Tablets for pediatric patients 10 years of age and older is 500 mg orally twice a day, given with meals.
• Increase dosage in increments of 500 mg weekly on the basis of glycemic control and tolerability, up to a maximum of 2000 mg per day, given in divided doses twice daily.

2.3 Recommendations for Use in Renal Impairment

• Assess renal function prior to initiation of Metformin Hydrochloride Tablets and periodically thereafter.
• Metformin Hydrochloride Tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m2.
• Initiation of Metformin Hydrochloride Tablets in patients with an eGFR between 30– 45 mL/minute/1.73 m2 is not recommended.
• In patients taking Metformin Hydrochloride Tablets whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit risk of continuing therapy.
• Discontinue Metformin Hydrochloride Tablets if the patient’s eGFR later falls below 30 mL/minute/1.73 m2 [see Warnings and Precautions (5.1)].

2.4 Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue Metformin Hydrochloride 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 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. Metformin associated 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. In Metformin Hydrochloride 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 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, obtain an estimated glomerular filtration rate (eGFR).
  • Metformin Hydrochloride is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see Contraindications (4)].
  • Initiation of Metformin Hydrochloride is not recommended in patients with eGFR between 30-45 mL/min/1.73 m2.
  • Obtain an eGFR at least annually in all patients taking Metformin Hydrochloride. 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 whose eGFR falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy.
• Drug interactions — The concomitant use of Metformin Hydrochloride 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 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. Re-evaluate eGFR 48 hours after the imaging procedure, and restart Metformin Hydrochloride 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 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 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 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 Tablets in patients with clinical or laboratory evidence of hepatic disease.

5.2 Vitamin B12 Deficiency

In Metformin Hydrochloride clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of Metformin Hydrochloride or vitamin B12  supplementation. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 at 2 to 3 year intervals in patients on Metformin Hydrochloride 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 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 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 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.

Metformin Hydrochloride Tablets

In a U.S. clinical trial of Metformin Hydrochloride in patients with type 2 diabetes mellitus, a total of 141 patients received Metformin Hydrochloride up to 2550 mg per day. Adverse reactions reported in greater than 5% of Metformin Hydrochloride treated patients and that were more common than in placebo-treated patients, are listed in Table 1.

Table 1: Adverse Reactions from a Clinical Trial of Metformin Hydrochloride Occurring >5% and More Common than Placebo in Patients with Type 2 Diabetes Mellitus

Diarrhea led to discontinuation of Metformin Hydrochloride in 6% of patients. Additionally, the following adverse reactions were reported in ≥1% to ≤5% of Metformin Hydrochloride treated patients and were more commonly reported with Metformin Hydrochloride than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation.

In Metformin Hydrochloride clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients.

Pediatric Patients

In clinical trials with Metformin Hydrochloride Tablets in pediatric patients with type 2 diabetes mellitus, the profile of adverse reactions was similar to that observed in adults.

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

Risk Summary

Limited data with Metformin Hydrochloride in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy [see Clinical Considerations].

No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2-and 5times, respectively, a 2550 mg clinical dose, based on body surface area [see Data].

The estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes mellitus with an HbA1C >7 and has been reported to be as high as 20–25% in women with a HbA1C >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Poorly-controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.

Data

Human Data

Published data from post-marketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups.

Animal Data

Metformin hydrochloride did not adversely affect development outcomes when administered to pregnant rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 5 times a 2550 mg clinical dose based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

8.2 Lactation

Risk Summary

Limited published studies report that metformin is present in human milk [see Data]. However, there is insufficient information to determine the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Metformin Hydrochloride and any potential adverse effects on the breastfed child from Metformin Hydrochloride or from the underlying maternal condition.

Data

Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants.

8.3 Females and Males of Reproductive Potential

Discuss the potential for unintended pregnancy with premenopausal women as therapy with Metformin Hydrochloride Tablets may result in ovulation in some anovulatory women.

8.4 Pediatric Use

Metformin Hydrochloride Tablets

The safety and effectiveness of Metformin Hydrochloride Tablets for the treatment of type 2 diabetes mellitus have been established in pediatric patients 10 to 16 years old. Safety and effectiveness of Metformin Hydrochloride have not been established in pediatric patients less than 10 years old.

Use of Metformin Hydrochloride Tablets in pediatric patients 10 to 16 years old for the treatment of type 2 diabetes mellitus is supported by evidence from adequate and well-controlled studies of Metformin Hydrochloride Tablets in adults with additional data from a controlled clinical study in pediatric patients 10 to 16 years old with type 2 diabetes mellitus, which demonstrated a similar response in glycemic control to that seen in adults [see Clinical Studies (14.1)]. In this study, adverse reactions were similar to those described in adults. A maximum daily dose of 2000 mg of Metformin Hydrochloride Tablets are recommended. [See Dosage and Administration (2.2)].

8.5 Geriatric Use

Controlled clinical studies of Metformin Hydrochloride 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 is contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2 [see Dosage and Administration (2.3), 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 is 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

Absorption

The absolute bioavailability of a metformin hydrochloride 500 mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin hydrochloride 500 to 1500 mg and 850 to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. At usual clinical doses and dosing schedules of metformin hydrochloride, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 μg/mL.

Effect of food: Food decreases the extent of absorption and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850 mg tablet of Metformin Hydrochloride with food, compared to the same tablet strength administered fasting.

Distribution

The apparent volume of distribution (V/F) of metformin following single oral doses of Metformin Hydrochloride 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time.

Metabolism

Intravenous single-dose studies in normal 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.

Elimination

Renal clearance (see Table 4) 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.

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.

14.1 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 7.

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

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 8.

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

Mean baseline body weight was 202 lbs, 203 lbs, and 204 lbs in the Metformin/glyburide, glyburide, and Metformin 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/glyburide, glyburide, and Metformin 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 9.

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.