RiteMED Metformin Extended-Release Tablet 1 g Special Precautions

Lactic Acidosis: Lactic acidosis is a rare, but serious, metabolic complication that occurs due to metformin accumulation during treatment. When it occurs, it is fatal in approximately 50% of cases. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 mcg/mL are generally found.
If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of the drug. In metformin-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin 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.
The risk factors for the development of metformin-associated lactic acidosis and the recommendations to reduce and manage metformin-associated lactic acidosis include the following: Renal Impairment: Metformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function.
Before initiating metformin therapy, obtain the patient's eGFR. The eGFR should be determined at least annually in all patients taking metformin. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently (e.g., every 3 to 6 months).
Initiating metformin therapy in patients with eGFR between 30 to 45 mL/min/1.73 m² is not recommended. In patients taking metformin whose eGFR falls below 45 mL/min/1.73 m², the benefits and risks of continuing treatment should be assessed. Discontinue metformin if the patient's eGFR later falls below 30 mL/min/1.73 m². Metformin is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m².
Drug Interactions: The concomitant use of metformin 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.
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. Discontinue metformin 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 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 should be temporarily discontinued while patients have restricted food and fluid intake.
Hypoxic States: Several of the post marketing 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. Promptly discontinue metformin when such events occur.
Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism. Excessive alcohol intake on an acute or chronic basis should be avoided in patients receiving metformin.
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. Avoid use of metformin in patients with clinical or laboratory evidence of hepatic disease.
Macrovascular Outcomes: Macrovascular risk reduction with the use of metformin or any antidiabetic drug has not been established in clinical studies.
Vitamin B₁₂ Levels: Evaluate hematologic parameters prior to initiation of metformin therapy and at least annually. Impairment of vitamin B₁₂ absorption has been reported in some patients, and long-term treatment with metformin has been associated with reductions in vitamin B₁₂ serum levels. Periodic measurements of serum vitamin B₁₂ levels should be performed in patients on long-term treatment with metformin, particularly in patients with anemia or neuropathy.
Hypoglycemia: Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol.
Elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemia. It may be difficult to recognize hypoglycemic states in the elderly, and in people who are taking beta-adrenergic blocking drugs.
Maintaining Adequate Glycemic Control during Periods of Stress: Temporary discontinuation of metformin and administration of insulin may be necessary in periods of stress such as fever, trauma, infection, or surgery to maintain adequate glucose control. Metformin may be reinstituted after the acute episode is resolved.
Hypothyroidism: Metformin induces a reduction in thyrotropin [thyroid stimulating hormone (TSH)] levels in patients with treated or untreated hypothyroidism. Regular monitoring of TSH levels is recommended in patients with hypothyroidism.
Other Precautions: Increased incidence of benign stromal uterine polyps was observed in female rats treated with 900 mg/kg/day of metformin HCl in long-term carcinogenicity studies
Effects on Ability to Drive and Use Machines: Patients should be warned about driving a vehicle or operating machinery under conditions where risk of hypoglycemia is present.
Use in Children: The use of metformin HCl immediate-release tablet has been established in pediatric patients 10 to 16 years old with type 2 diabetes. The safety and efficacy of metformin HCI extended-release tablet have not been established in these patients.
Use in the Elderly: Aging is associated with reduced renal function and metformin is known to be substantially excreted in the kidney. The risk of serious adverse reactions to metformin is greater in patients with reduced/impaired renal function especially in the elderly. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, dose of elderly patients should not be titrated to the maximum dose. Metformin treatment should not be initiated in patients ≥80 years old unless creatinine clearance demonstrates that renal function is not reduced.
Age 65 years or older: 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.