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General: Glucovance: Hypoglycemia: Glucovance is capable of producing hypoglycemia or hypoglycemic symptoms, therefore, proper patient selection, dosing, and instructions are important to avoid potential hypoglycemic episodes. The risk of hypoglycemia is increased when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents or ethanol. Renal or hepatic insufficiency may cause elevated drug levels of both glibenclamide and metformin hydrochloride and the hepatic insufficiency may also diminish gluconeogenic capacity, both of which, increase the risk of hypoglycemic reactions. 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 β-adrenergic blocking drugs.
Metformin hydrochloride: Monitoring of Renal Function: 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. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive Glucovance. In patients with advanced age, Glucovance should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those ≥80 years, renal function should be monitored regularly and, generally, Glucovance should not be titrated to the maximum dose. Before initiation of Glucovance 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 Glucovance 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 eg, cationic drugs that are eliminated by renal tubular secretion, should be used with caution.
Radiologic studies involving the use of intravascular iodinated contrast materials (eg, IV urogram, IV cholangiography, angiography and computed tomography (CT) scans with intravascular contrast materials): 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. Therefore, in patients in whom any such study is planned, Glucovance should be temporarily discontinued at the time of or prior to the procedure and withheld for 48 hrs 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 failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on Glucovance therapy, Glucovance should be promptly discontinued.
Surgical Procedures: Glucovance therapy should be temporarily suspended 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 Glucovance. Due to its effect on the gluconeogenic capacity of the liver, alcohol may also increase the risk of hypoglycemia.
Impaired Hepatic Function: Since impaired hepatic function has been associated with some cases of lactic acidosis, Glucovance should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
Vitamin B12 Levels: In controlled clinical trials with metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B12 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 and any apparent abnormalities should be appropriately investigated and managed.
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 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, Glucovance must be stopped immediately and other appropriate corrective measures initiated.
Carcinogenicity, Mutagenicity & Impairment of Fertility: No animal studies have been conducted with the combined products in Glucovance. The following data are based on findings in studies performed with the individual products.
Glibenclamide: Studies in rats with glibenclamide alone at doses up to 300 mg/kg daily (approximately 145 times the maximum recommended human daily dose of 20 mg for the glibenclamide component of Glucovance based on body surface area comparisons) for 18 months revealed no carcinogenic effects. In a 2-year oncogenicity study of glibenclamide in mice, there was no evidence of treatment-related tumors.
There was no evidence of mutagenic potential of glibenclamide alone in the following in vitro tests: Salmonella microsome test (Ames test) and in the DNA damage/alkaline elution assay.
Metformin hydrochloride: Long-term carcinogenicity studies were performed with metformin alone in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg daily and 1500 mg/kg daily, respectively. These doses are both approximately 4 times the maximum recommended human daily dose of 2000 mg of the metformin component of Glucovance based on body surface area comparisons. No evidence of carcinogenicity with metformin alone was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin alone in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day of metformin alone.
There was no evidence of a mutagenic potential of metformin alone in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.
Fertility of male or female rats was unaffected by metformin alone when administered at doses as high as 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose of the metformin component of Glucovance based on body surface area comparisons.
Use in pregnancy: Teratogenic Effects: Pregnancy Category B: Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Most experts recommend that insulin be used during pregnancy to maintain blood glucose as close to normal as possible. Because animal reproduction studies are not always predictive of human response, Glucovance should not be used during pregnancy unless clearly needed.
There are no adequate and well-controlled studies in pregnant women with Glucovance or its individual components. No animal studies have been conducted with the combined products in Glucovance. The following data are based on findings in studies performed with the individual products.
Glibenclamide: Reproduction studies were performed in rats and rabbits at doses up to 500 times the maximum recommended human daily dose of 20 mg of the glibenclamide component of Glucovance based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to glibenclamide.
Metformin hydrochloride: Metformin alone was not teratogenic in rats or rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 6 times the maximum recommended human daily dose of 2000 mg of the metformin component of Glucovance based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.
Nonteratogenic Effects: Prolonged severe hypoglycemia (4-10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. It is not recommended that Glucovance be used during pregnancy. However, if it is used, Glucovance should be discontinued at least 2 weeks before the expected delivery date.
Use in lactation: Although it is not known whether glibenclamide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk. Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue Glucovance, taking into account the importance of the drug to the mother. If Glucovance is discontinued and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.
Use in children: Safety and effectiveness of Glucovance in pediatric patients have not been established.
Use in the elderly: Of the 642 patients who received Glucovance in double-blind clinical studies, 23.8% were ≥65 years while 2.8% were ≥75 years. Of the 1302 patients who received Glucovance in open-label clinical studies, 20.7% were ≥65 years while 2.5% were ≥75 years. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Metformin hydrochloride is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, Glucovance should only be used in patients with normal renal function. Because aging is associated with reduced renal function, Glucovance should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of Glucovance.
