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Before initiation of GLUCOPHAGE or GLUCOPHAGE XR therapy and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and GLUCOPHAGE or GLUCOPHAGE XR discontinued if evidence of renal impairment is present. Use of concomitant medications that may affect renal function or metformin disposition Concomitant medication( s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion (see PRECAUTIONS: Drug Interactions), should be used with caution. Text Continues Below
Radiologic studies involving the use of intravascular iodinated contrast materials (for exam-ple, intravenous urogram, intravenous cholangiography, angiography, and computed tomog-raphy (CT) scans with intravascular contrast materials) Ñ Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin (see CONTRAINDICATIONS). Therefore, in patients in whom any such study is planned, GLUCOPHAGE or GLUCOPHAGE XR should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal. Hypoxic states Cardiovascular collapse (shock) from whatever cause, acute congestive heart fail-ure, acute myocardial infarction and other conditions characterized by hypoxemia have been associ-ated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on GLUCOPHAGE or GLUCOPHAGE XR therapy, the drug should be promptly discontinued. Lactic Acidosis
Lactic acidosis is a rare, but serious, metabolic complication that can occur due to met-formin accumulation during treatment with GLUCOPHAGE or GLUCOPHAGE XR; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in asso-ciation with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is char-acterized 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 µg/ mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/ 1000 patient-years, with approximately 0.015 fatal cases/ 1000 patient-years). Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypo-perfusion, often in the setting of multiple concomitant medical/ surgical problems and mul-tiple concomitant medications. Patients with congestive heart failure requiring pharmaco-logic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. 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 GLUCOPHAGE or GLUCOPHAGE XR and by use of the minimum effective dose of GLUCOPHAGE or GLUCOPHAGE XR. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. GLUCOPHAGE or GLUCOPHAGE XR treatment should not be initiated in patients 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, GLUCOPHAGE and GLUCOPHAGE XR should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, GLUCOPHAGE and GLUCOPHAGE XR 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 GLUCOPHAGE or GLUCOPHAGE XR, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addi-tion, GLUCOPHAGE and GLUCOPHAGE XR should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see also PRECAUTIONS). 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 (see also PRECAU-TIONS). GLUCOPHAGE and GLUCOPHAGE XR should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose and, if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of GLUCOPHAGE or GLUCOPHAGE XR, gastrointestinal symptoms, which are common during initiation of therapy, 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 5 mmol/ L in patients taking GLUCOPHAGE or GLUCOPHAGE XR do not necessarily indi-cate 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. (See also PRECAUTIONS.) Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria 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 GLUCOPHAGE or GLUCOPHAGE XR, 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 aci-dosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery. (See also CONTRAINDICATIONS and PRECAUTIONS.) Table 8. Summary of Mean Percent Changes from Baseline* in Major Lipid Variables at Final Visit (16-week study)
GLUCOPHAGE XR
500 mg 1000 mg 1500 mg 2000 mg 1000 mg Once Once Once Once Twice Daily Daily Daily Daily Daily Placebo
Total Cholesterol (mg/ dL) (n= 120) (n= 113) (n= 110) (n= 126) (n= 117) (n= 110) Baseline 210.3 218.1 214.6 204.4 208.2 208.6 Mean % change at 1.0% 1.7% 0.7% -1.6% -2.6% 2.6% FINAL VISIT Total Triglycerides (mg/ dL) (n= 120) (n= 113) (n= 110) (n= 126) (n= 117) (n= 110) Baseline 220.2 211.9 198.0 194.2 179.0 211.7 Mean % change at 14.5% 9.4% 15.1% 14.9% 9.4% 10.9%
FINAL VISIT LDL-Cholesterol (mg/ dL) (n= 119) (n= 113) (n= 109) (n= 126) (n= 117) (n= 107) Baseline 131.0 134.9 135.8 125.8 131.4 131.9 Mean % change at -1.4% -1.6% -3.5% -3.3% -5.5% 3.2%
FINAL VISIT HDL-Cholesterol (mg/ dL) (n= 120) (n= 108) (n= 108) (n= 125) (n= 117) (n= 108) Baseline 40.8 41.6 40.6 40.2 42.4 39.4 Mean % change at 6.2% 8.6% 5.5% 6.1% 7.1% 5.8%
FINAL VISIT Table 9. Summary of Mean Percent Changes from Baseline* in Major Lipid Variables at Final Visit (24-week study)
GLUCOPHAGE GLUCOPHAGE XR
500 mg Twice Daily 1000 mg Once Daily 1500 mg Once Daily
Total Cholesterol (mg/ dL) (n= 68) (n= 70) (n= 66) Baseline 199.0 201.9 201.6 Mean % change at 0.1% 1.3% 0.1%
FINAL VISIT Total Triglycerides (mg/ dL) (n= 68) (n= 70) (n= 66) Baseline 178.0 169.2 206.8 Mean % change at 6.3% 25.3% 33.4%
FINAL VISIT LDL-Cholesterol (mg/ dL) (n= 68) (n= 70) (n= 66) Baseline 122.1 126.2 115.7 Mean % change at -1.3% -3.3% -3.7%
FINAL VISIT HDL-Cholesterol (mg/ dL) (n= 68) (n= 70) (n= 65) Baseline 41.9 41.7 44.6 Mean % change at 4.8% 1.0% -2.1%
FINAL VISIT Table 10. GLUCOPHAGE vs Placebo (Pediatrics a ) Summary of Mean Changes from Baseline* in
Plasma Glucose and Body Weight at Final Visit
GLUCOPHAGE Placebo p-Value
FPG (mg/ dL) (n= 37) (n= 36) Baseline 162.4 192.3 Change at FINAL VISIT -42.9 21.4 < 0.001
Body Weight (lbs) (n= 39) (n= 38) Baseline 205.3 189.0 Change at FINAL VISIT -3.3 -2.0 NS** Surgical procedures Ñ GLUCOPHAGE or GLUCOPHAGE XR therapy should be temporarily sus-pended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal. 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 GLUCOPHAGE or GLUCOPHAGE XR. Impaired hepatic function Ñ Since impaired hepatic function has been associated with some cases of lactic acidosis, GLUCOPHAGE and GLUCOPHAGE XR should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Vitamin B 12 levels In controlled clinical trials of GLUCOPHAGE of 29 weeks duration, a decrease to subnormal levels of previously normal serum Vitamin B 12 levels, without clinical man-ifestations, was observed in approximately 7% of patients. Such decrease, possibly due to inter-ference with B 12 absorption from the B 12 -intrinsic factor complex, is, however, very rarely associ-ated with anemia and appears to be rapidly reversible with discontinuation of GLUCOPHAGE or Vitamin B 12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on GLUCOPHAGE or GLUCOPHAGE XR and any apparent abnormalities should be appropriately investigated and managed (see PRECAUTIONS: Laboratory Tests). Certain individuals (those with inadequate Vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal Vitamin B 12 levels. In these patients, routine serum Vitamin B 12 measurements at two-to three-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 GLUCOPHAGE or GLUCOPHAGE XR who devel-ops 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, GLUCOPHAGE or GLUCOPHAGE XR must be stopped immediately and other appropriate corrective measures initiated (see also WARNINGS). Hypoglycemia Hypoglycemia does not occur in patients receiving GLUCOPHAGE or GLUCOPHAGE XR 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 con-comitant 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. Loss of control of blood glucose When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold GLUCOPHAGE or GLUCOPHAGE XR and tem-porarily administer insulin. GLUCOPHAGE or GLUCOPHAGE XR may be reinstituted after the acute episode is resolved. The effectiveness of oral antidiabetic drugs in lowering blood glucose to a targeted level decreas-es in many patients over a period of time. This phenomenon, which may be due to progression of the underlying disease or to diminished responsiveness to the drug, is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective during initial therapy. Should secondary failure occur with either GLUCOPHAGE or GLUCOPHAGE XR or sulfonylurea monotherapy, combined therapy with GLUCOPHAGE or GLUCOPHAGE XR and sulfonylurea may result in a response. Should secondary failure occur with combined GLUCOPHAGE/ sulfonylurea therapy or GLUCOPHAGE XR/ sulfonylurea therapy, it may be necessary to consider therapeutic alternatives including initiation of insulin therapy. Laboratory Tests Response to all diabetic therapies should be monitored by periodic measurements of fasting blood glucose and glycosylated hemoglobin levels, with a goal of decreasing these levels toward the nor-mal range. During initial dose titration, fasting glucose can be used to determine the therapeutic response. Thereafter, both glucose and glycosylated hemoglobin should be monitored. Measurements of glycosylated hemoglobin may be especially useful for evaluating long-term con-trol (see also DOSAGE AND ADMINISTRATION). Initial and periodic monitoring of hematologic parameters (e. g., hemoglobin/ hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with GLUCOPHAGE therapy, if this is sus-pected, Vitamin B 12 deficiency should be excluded. Specific Patient Populations GLUCOPHAGE or GLUCOPHAGE XR are not recommended for use in pregnancy. GLUCOPHAGE is not recommended in patients below the age of 10 years. GLUCOPHAGE XR is not recommend-ed in pediatric patients (below the age of 17 years). The initial and maintenance dosing of GLUCOPHAGE or GLUCOPHAGE XR should be conserva-tive in patients with advanced age, due to the potential for decreased renal function in this popu-lation. Any dosage adjustment should be based on a careful assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of GLUCOPHAGE or GLUCOPHAGE XR. Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly. (See WARNINGS.) Page: << Prev | 1 | 2 | 3 | 4 | 5
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