Metformin Hydrochloride Prescribing Information
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 (>5 mmol/Liter), 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 HCl 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 [
• 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
• 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/minute/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
• 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
• 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/minute/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 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.
- 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/1.732is not recommended.
- In patients taking metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/minute/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)].
Metformin hydrochloride extended-release tablets are contraindicated in patients with:
- Severe renal impairment (eGFR below 30 mL/minute/1.73 m2)[seeWarnings and Precautions (5.1)].
- Known hypersensitivity to metformin.
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
• Severe renal impairment: (eGFR below 30 mL/minute/1.73 m2)
• Known hypersensitivity to metformin
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma
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 (>5 mmol/Liter), 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 HCl 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 [
• 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
• 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/minute/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
• 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
• 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/minute/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 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.
Table 2 presents clinically significant drug interactions with metformin hydrochloride extended-release tablets.
Carbonic Anhydrase Inhibitors | |||
Clinical Impact: | Carbonic anhydrase inhibitors 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. | ||
Intervention: | Consider more frequent monitoring of these patients. | ||
Examples: | Topiramate, zonisamide, acetazolamide or dichlorphenamide. | ||
Drugs that Reduce Metformin Hydrochloride Extended-Release Tablets Clearance | |||
Clinical Impact: | 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) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology 12.3)] | ||
Intervention: | Consider the benefits and risks of concomitant use with metformin hydrochloride extended-release tablets. | ||
Examples: | Ranolazine, vandetanib, dolutegravir, and cimetidine. | ||
Alcohol | |||
Clinical Impact: | Alcohol is known to potentiate the effect of metformin on lactate metabolism. | ||
Intervention: | Warn patients against excessive alcohol intake while receiving metformin hydrochloride extended-release tablets. | ||
Insulin Secretagogues or Insulin | |||
Clinical Impact: | Coadministration of metformin hydrochloride extended-release tablets with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia. | ||
Intervention: | Patients receiving an insulin secretagogue or insulin may require lower doses of the insulin secretagogue or insulin. | ||
Drugs Affecting Glycemic Control | |||
Clinical Impact: | Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. | ||
Intervention: | When such drugs are administered to a patient receiving metformin hydrochloride extended-release tablets, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin hydrochloride extended-release tablets, observe the patient closely for hypoglycemia. | ||
Examples: | Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. | ||
- Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring.
- Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin. Consider the benefits and risks of concomitant use.
- Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake.
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 (>5 mmol/Liter), 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 HCl 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 [
• 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
• 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/minute/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
• 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
• 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/minute/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 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.
Metformin hydrochloride extended-release tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
• Starting dose: 500 mg orally once daily with the evening meal (
- The recommended starting dose of metformin hydrochloride extended-release tablets are 500 mg orally once daily with the evening meal.
- Increase the dose in increments of 500 mg every 1 to 2 weeks on the basis of glycemic control and tolerability, up to a maximum of 2,000 mg once daily with the evening meal.
- Patients receiving metformin hydrochloride (HCl) may be switched to metformin hydrochloride extended-release tablets once daily at the same total daily dose, up to 2,000 mg once daily.
- Swallow metformin hydrochloride extended-release tablets whole and never crush, cut or chew.
- If a dose of metformin hydrochloride extended-release tablets are 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.
• Increase the dose in increments of 500 mg every 1 to 2 weeks, up to a maximum of 2,000 mg once daily with the evening meal. (
- The recommended starting dose of metformin hydrochloride extended-release tablets are 500 mg orally once daily with the evening meal.
- Increase the dose in increments of 500 mg every 1 to 2 weeks on the basis of glycemic control and tolerability, up to a maximum of 2,000 mg once daily with the evening meal.
- Patients receiving metformin hydrochloride (HCl) may be switched to metformin hydrochloride extended-release tablets once daily at the same total daily dose, up to 2,000 mg once daily.
- Swallow metformin hydrochloride extended-release tablets whole and never crush, cut or chew.
- If a dose of metformin hydrochloride extended-release tablets are 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.
• Patients receiving metformin hydrochloride (HCl) tablets may be switched to metformin hydrochloride extended-release tablets once daily at the same total daily dose, up to 2,000 mg once daily. (
- The recommended starting dose of metformin hydrochloride extended-release tablets are 500 mg orally once daily with the evening meal.
- Increase the dose in increments of 500 mg every 1 to 2 weeks on the basis of glycemic control and tolerability, up to a maximum of 2,000 mg once daily with the evening meal.
- Patients receiving metformin hydrochloride (HCl) may be switched to metformin hydrochloride extended-release tablets once daily at the same total daily dose, up to 2,000 mg once daily.
- Swallow metformin hydrochloride extended-release tablets whole and never crush, cut or chew.
- If a dose of metformin hydrochloride extended-release tablets are 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.
• Swallow metformin hydrochloride extended-release tablets whole and never crush, cut or chew. (
- The recommended starting dose of metformin hydrochloride extended-release tablets are 500 mg orally once daily with the evening meal.
- Increase the dose in increments of 500 mg every 1 to 2 weeks on the basis of glycemic control and tolerability, up to a maximum of 2,000 mg once daily with the evening meal.
- Patients receiving metformin hydrochloride (HCl) may be switched to metformin hydrochloride extended-release tablets once daily at the same total daily dose, up to 2,000 mg once daily.
- Swallow metformin hydrochloride extended-release tablets whole and never crush, cut or chew.
- If a dose of metformin hydrochloride extended-release tablets are 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.
• Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR). (
- 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/1.732is not recommended.
- In patients taking metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/minute/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)].
o Do not use in patients with eGFR below 30 mL/minute/1.73 m
2
o Initiation is not recommended in patients with eGFR between 30 to 45 mL/minute/1.73 m
2.
o Assess risk/benefit of continuing metformin hydrochloride extended-release tablets if eGFR falls below 45 mL/minute/1.73 m
2.
o Discontinue if eGFR falls below 30 mL/minute/1.73 m
2.
• Metformin hydrochloride extended-release tablets may need to be discontinued at time of, or prior to, 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/minute/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
Metformin hydrochloride extended-release USP tablets are available as:
- Extended-release tablets:500 mg White to off white coated, oval shaped tablets debossed with "G41" on one side and Plain on other side.
- Extended-release tablets:1,000 mg White to off white coated, oval shaped tablets debossed with
"G42" on one side and Plain on 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 extended-release tablets may result in ovulation in some anovulatory women.
- Geriatric Use: Assess renal function more frequently. ( )
8.5 Geriatric UseClinical 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. 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 Dosage and Administration (2.2)and 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 extended-release tablets are not recommended in patients with hepatic impairment.
[see Warnings and Precautions (5.1).]
Metformin hydrochloride extended-release tablets are contraindicated in patients with:
- Severe renal impairment (eGFR below 30 mL/minute/1.73 m
2)[see5.1 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, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), 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 HCl 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 (2.1)and 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/minute/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
[seeDrug 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
[seeUse 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/minute/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 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.
]. - Known hypersensitivity to metformin.
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.