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 evidenceof ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL (see PRECAUTIONS).
Risk factors for metformin associated lactic acidosis include renal impairment, concamitent 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 DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, AND PRECAUTIONS).
If metformin associated lactic acidosis is suspected, immediately discontinue metformin hydrochloride extend release tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended (see PRECAUTIONS).
* Lactic acidosis -There have been post marketing 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 or
metformin hydrochloride extend release tablets. In metformin hydrochloride extend release tablets treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt
hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable with a clearance of up to 170 mL/min under good
hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.
Educate patients and their families about the symptoms of lactic acidosis and, if these symptoms occur, instruct them to discontinue metformin hydrochloride extend 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 post marketing 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, CLINICAL PHARMACOLOGY):
o Before initiating metformin hydrochloride extend release tablets, obtain an estimated glomerular filtration rate (eGFR)
o Metformin hydrochloride extend release tablets is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 (see CONTRAINDICATIONS).
o Initiation of metformin hydrochloride extend release tablets is not recommended in patients with eGFR between 30-45 mL/min/1.73 m2.
o Obtain an eGFR at least annually in all patients taking metformin hydrochloride extend release tablets. In patients at risk for the development of renal impairment (e.g., the
elderly), renal function should be assessed more frequently.
o In patients taking metformin hydrochloride extend release 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 extend release tablets with specific drugs may increase the risk of metformin-associated lactic acidosis:
those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation. Consider more frequent
monitoring of patients.
* Age 65 or greater -- The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal,
or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.
* Radiologic studies with contrast -- Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the
occurrence of lactic acidosis. Stop metformin hydrochloride extended release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR
between 30 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 extended release tablets if renal function is stable.
* Surgery and other procedures -- withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment.
Metformin hydrochloride extended-release tablets should be temporarily discontinued while patients have restricted food and fluid intake.
* Hypoxic states -- several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when
accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been
associated with lactic acidosis and may cause prerenal azotemia. When such an event occurs, discontinue metformin hydrochloride extended release tablets.
* Excessive alcohol intake -- Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake,
acute or chronic, 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.
Vitamin B12 levels -- In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on metformin hydrochloride extended-release tablets and any apparent abnormalities should be appropriately investigated and managed (see P R ECAUTIONS: Laboratory Tests).
Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at 2- to 3- year intervals may be useful.
Change in clinical status of patients with previously controlled type 2 diabetes -- A patient with type 2 diabetes previously well controlled on metformin hydrochloride extended-release tablets who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, metformin hydrochloride extended-release tablets must be stopped immediately and other appropriate corrective measures initiated (see also WARNINGS).
Hypoglycemia -- Hypoglycemia does not occur in patients receiving metformin hydrochloride extended-release tablets alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol.
Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs.
Macrovascular Outcomes -- There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin hydrochloride extended-release tablets or any other anti-diabetic drug.