Amaryl M Warnings

For Glimepiride: In exceptional stress-situations (e.g., trauma, surgery, febrile infections) blood glucose regulation may deteriorate, and a temporary change to insulin may be necessary to maintain good metabolic control.
For Metformin: Lactic acidosis: Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with this drug. When it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia.
Lactic acidosis is characterized by elevated blood lactate levels (>5mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5μ g/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patients-years, with approximately 0.015 fatal cases/1000 patients-years). Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal multiple concomitant medical/surgical problems and multiple concomitant medications.
The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin and by use of the minimum effective dose of metformin. In addition, this drug should be withheld in the presence of any condition associated with hypoxemia or dehydration.
Because impaired hepatic function may significantly limit the ability to clear lactate, this drug should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking this drug, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, this drug should be temporarily discontinued prior to any intravascular radio-contrast study and for any surgical procedure. The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur.
Serum electrolytes, ketones, blood glucose, blood pH, lactate levels, and blood metformin levels may be useful. Once a patient is stabilized on any dose level of this drug, gastrointestinal symptoms, which are common during initiation of therapy with metformin, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
Levels of fasting venous plasma lactate above the upper limit of normal but less than 5mmol/L in patients taking this drug do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling. Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketouria and ketonemia).
Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking this drug, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery.
Administration of iodinated contrast agent: Radiologic studies involving the use of intravascular iodinated contrast materials (e.g., intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with contrast materials): Intravascular contrast studies iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving this drug (see Contraindications). Therefore, in patients in whom any such study is planned, this drug should be discontinued at the time of or prior to the procedure, and withheld for 48hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal. See Contraindications and Interactions.
Surgery: This drug therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.
Increased risk of cardiovascular mortality: The administration of oral hypoglycemic drug has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP) to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes.
UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 g per day) or phenformin (100 mg/day) had a rate of cardiovascular mortality 2.5 times that of patients treated with diet alone and it resulted in discontinuation of the use of tolbutamide or phenformin. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and benefits of glimepiride and of alternative modes of therapy. Although only one drug in the sulfonylurea class (tolbutamide) and one drug in the biguanide class (phenformin), it is prudent from a safety standpoint to consider that this warning may also apply to other hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.