Metformin Hydrochloride Prescribing Information
WARNING: LACTIC ACIDOSIS
Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see
- Lactic Acidosis:See boxed warning.
- Vitamin B12Deficiency:Metformin may lower vitamin B12 levels. Measure hematological parameters annually and vitamin B12 at 2 to 3 year intervals and manage any abnormalities.
- Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues:Increased risk of hypoglycemia when used in combination with insulin and/or an insulin secretagogue. Lower dose of insulin or insulin secretagogue may be required
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 tablets. 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 tablet 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 [
- Before initiating metformin hydrochloride tablets, obtain an estimated glomerular filtration rate (eGFR).
- Metformin hydrochloride tablets are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2[seeContraindications (4)].
- Initiation of metformin hydrochloride tablets is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m2.
- Obtain an eGFR at least annually in all patients taking metformin hydrochloride 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 tablets 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 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 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. Re-evaluate eGFR 48 hours after the imaging procedure, and restart metformin hydrochloride 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 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 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.
In metformin hydrochloride tablets clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin hydrochloride tablets or vitamin B12supplementation. Certain individuals (those with inadequate vitamin B12or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12levels. Measure hematologic parameters on an annual basis and vitamin B12at 2 to 3 year intervals in patients on metformin hydrochloride tablets and manage any abnormalities [see
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 tablet
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin hydrochloride tablets.
Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g. carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided [see
- Lactic Acidosis:See boxed warning.
- Vitamin B12Deficiency:Metformin may lower vitamin B12 levels. Measure hematological parameters annually and vitamin B12 at 2 to 3 year intervals and manage any abnormalities.
- Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues:Increased risk of hypoglycemia when used in combination with insulin and/or an insulin secretagogue. Lower dose of insulin or insulin secretagogue may be required
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 tablets. 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 tablet 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 [
- Before initiating metformin hydrochloride tablets, obtain an estimated glomerular filtration rate (eGFR).
- Metformin hydrochloride tablets are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2[seeContraindications (4)].
- Initiation of metformin hydrochloride tablets is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m2.
- Obtain an eGFR at least annually in all patients taking metformin hydrochloride 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 tablets 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 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 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. Re-evaluate eGFR 48 hours after the imaging procedure, and restart metformin hydrochloride 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 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 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.
In metformin hydrochloride tablets clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin hydrochloride tablets or vitamin B12supplementation. Certain individuals (those with inadequate vitamin B12or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12levels. Measure hematologic parameters on an annual basis and vitamin B12at 2 to 3 year intervals in patients on metformin hydrochloride tablets and manage any abnormalities [see
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 tablet
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin hydrochloride tablets.
If metformin-associated lactic acidosis is suspected, immediately discontinue metformin hydrochloride tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [
- Lactic Acidosis:See boxed warning.
- Vitamin B12Deficiency:Metformin may lower vitamin B12 levels. Measure hematological parameters annually and vitamin B12 at 2 to 3 year intervals and manage any abnormalities.
- Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues:Increased risk of hypoglycemia when used in combination with insulin and/or an insulin secretagogue. Lower dose of insulin or insulin secretagogue may be required
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 tablets. 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 tablet 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 [
- Before initiating metformin hydrochloride tablets, obtain an estimated glomerular filtration rate (eGFR).
- Metformin hydrochloride tablets are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2[seeContraindications (4)].
- Initiation of metformin hydrochloride tablets is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m2.
- Obtain an eGFR at least annually in all patients taking metformin hydrochloride 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 tablets 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 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 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. Re-evaluate eGFR 48 hours after the imaging procedure, and restart metformin hydrochloride 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 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 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.
In metformin hydrochloride tablets clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin hydrochloride tablets or vitamin B12supplementation. Certain individuals (those with inadequate vitamin B12or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12levels. Measure hematologic parameters on an annual basis and vitamin B12at 2 to 3 year intervals in patients on metformin hydrochloride tablets and manage any abnormalities [see
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 tablet
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin hydrochloride tablets.
Metformin hydrochloride tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients 10 years of age and older with type 2 diabetes mellitus.
- Starting dose: 500 mg orally twice a day or 850 mg once a day, with meals ()
2.1 Adult DosageMetformin Hydrochloride Tablets- The recommended starting dose of metformin hydrochloride tablets are 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.
- Increase the dose in increments of 500 mg weekly or 850 mg every 2 weeks, up to a maximum dose of 2550 mg per day, given in divided doses ()
2.1 Adult DosageMetformin Hydrochloride Tablets- The recommended starting dose of metformin hydrochloride tablets are 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.
- Doses above 2000 mg may be better tolerated given 3 times a day with meals ()
2.1 Adult DosageMetformin Hydrochloride Tablets- The recommended starting dose of metformin hydrochloride tablets are 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.
- Starting dose: 500 mg orally twice 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.
- Increase dosage in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses twice daily ()
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.
- Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) ()
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 to 45 mL/minute/1.73 m2is 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)].
- Do not use in patients with eGFR below 30 mL/minute/1.73 m
2 ()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 to 45 mL/minute/1.73 m2is 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)].
- Initiation is not recommended in patients with eGFR between 30 to 45 mL/minute/1.73 m
2 ()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 to 45 mL/minute/1.73 m2is 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)].
- Assess risk/benefit of continuing if eGFR falls below 45 mL/minute/1.73 m
2 ()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 to 45 mL/minute/1.73 m2is 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)].
- Discontinue if eGFR falls below 30 mL/minute/1.73 m
2 ()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 to 45 mL/minute/1.73 m2is 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)].
Metformin Hydrochloride Tablets, USP are available as:
• Tablets: 500 mg - White to off-white, round, biconvex, film coated tablets debossed with
G 10 on one side and plain on the other side.
• Tablets: 850 mg - White to off-white, round, biconvex, film coated tablets debossed with
G 11 on one side and plain on the other side.
• Tablets: 1000 mg - White to off-white, oval, biconvex, scored, film coated tablets debossed with
G and12 on either side of the scoreline on one side and plain on the other side.
- Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. ()
8.3 Females and Males of Reproductive PotentialDiscuss the potential for unintended pregnancy with premenopausal women as therapy with metformin hydrochloride tablets may result in ovulation in some anovulatory women.
- Geriatric Use: Assess renal function more frequently. ()
8.5 Geriatric UseControlled 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). - Hepatic Impairment: Avoid use in patients with hepatic impairment. ()
8.7 Hepatic ImpairmentUse of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Metformin hydrochloride tablets are not recommended in patients with hepatic impairment. [
see Warnings and Precautions (5.1)].
Metformin hydrochloride tablets are contraindicated in patients with:
- Severe renal impairment (eGFR below 30 mL/min/1.73 m
2) [].5 WARNINGS AND PRECAUTIONS- Lactic Acidosis:See boxed warning.
- Vitamin B12Deficiency:Metformin may lower vitamin B12 levels. Measure hematological parameters annually and vitamin B12 at 2 to 3 year intervals and manage any abnormalities.
- Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues:Increased risk of hypoglycemia when used in combination with insulin and/or an insulin secretagogue. Lower dose of insulin or insulin secretagogue may be required
5.1 Lactic AcidosisThere 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 tablets. 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 tablet 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 tablets, obtain an estimated glomerular filtration rate (eGFR).
- Metformin hydrochloride tablets are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2[seeContraindications (4)].
- Initiation of metformin hydrochloride tablets is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m2.
- Obtain an eGFR at least annually in all patients taking metformin hydrochloride 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 tablets 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 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 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. Re-evaluate eGFR 48 hours after the imaging procedure, and restart metformin hydrochloride 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 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 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 DeficiencyIn metformin hydrochloride tablets clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin hydrochloride tablets or vitamin B12supplementation. Certain individuals (those with inadequate vitamin B12or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12levels. Measure hematologic parameters on an annual basis and vitamin B12at 2 to 3 year intervals in patients on metformin hydrochloride tablets and manage any abnormalities [see
Adverse Reactions (6.1)].5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin SecretagoguesInsulin 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 tablet
[ see Drug Interactions (7)].5.4 Macrovascular OutcomesThere have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin hydrochloride tablets.
- Hypersensitivity to metformin.
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.