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Hepatic effects When a thiazolidinedione is used in combination with GLUCOVANCE, periodic monitoring of liver function tests should be performed in compliance with the labeled recommendations for the thiazolidinedione. Information for Patients Text Continues Below
GLUCOVANCE Patients should be informed of the potential risks and benefits of GLUCOVANCE and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose, glycosylated hemoglobin, renal function, and hematologic parameters. The risks of lactic acidosis associated with metformin therapy, its symptoms, and conditions that predispose to its development, as noted in the WARNINGS and PRECAUTIONS sections, should be explained to patients. Patients should be advised to discontinue GLUCOVANCE (Glyburide and Metformin HCl Tablets) immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of GLUCOVANCE, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease. The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving GLUCOVANCE.
(See Patient Information Printed Below.) Laboratory Tests Periodic fasting blood glucose and glycosylated hemoglobin (HbA 1c ) measurements should be per-formed to monitor therapeutic response. 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 metformin therapy, if this is suspected, Vitamin B 12 deficiency should be excluded. Lactic Acidosis: Lactic acidosis is a rare, but serious, metabolic complication that can occur due to met-formin accumulation during treatment with GLUCOVANCE; 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 signifi-cant
tissue hypoperfusion and hypoxemia. 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 g/ 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 hypoperfusion,
often in the setting of multiple concomitant medical/ surgical problems and multiple con-comitant medications. Patients with congestive heart failure requiring pharmacologic 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 metformin and by use of the minimum effective dose of met-formin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. GLUCOVANCE 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, GLUCOVANCE should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significant-ly limit the ability to clear lactate, GLUCOVANCE 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 GLUCOVANCE, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, GLUCOVANCE 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 PRECAUTIONS). GLUCOVANCE should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glu-cose, 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 GLUCOVANCE, 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 5 mmol/ L in patients taking GLUCOVANCE 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. (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 GLUCOVANCE, the drug should be discontinued immedi-ately and general supportive measures promptly instituted. Because metformin hydrochlo-ride 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. (See also CONTRAINDICATIONS and PRECAUTIONS.) Glyburide The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including non-steroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta-adrenergic blocking agents. When such drugs are administered to a patient receiving GLUCOVANCE, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving GLUCOVANCE, the patient should be observed closely for loss of blood glucose control. A possible interaction between glyburide and ciprofloxacin, a fluoroquinolone antibiotic, has been reported, resulting in a potentiation of the hypoglycemic action of glyburide. The mechanism for this interaction is not known. A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topi-cal, or vaginal preparations of miconazole is not known. Metformin Hydrochloride ____Furosemide A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the metformin plasma and blood C max by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the C max and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of met-formin and furosemide when co-administered chronically. ____ Nifedipine A single-dose, metformin-nifedipine drug interaction study in normal healthy vol-unteers demonstrated that co-administration of nifedipine increased plasma metformin C max and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. T max and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine. ____ Cationic drugs Cationic drugs (e. g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single-and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimina-tion half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of GLUCOVANCE and/ or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system. ____ Other In healthy volunteers, the pharmacokinetics of metformin and propranolol and met-formin and ibuprofen were not affected when co-administered in single-dose interaction studies. Carcinogenesis, Mutagenesis, Impairment of Fertility No animal studies have been conducted with the combined products in GLUCOVANCE. The fol-lowing data are based on findings in studies performed with the individual products. Glyburide Studies in rats with glyburide alone at doses up to 300 mg/ kg/ day (approximately 45 times the max-imum recommended human daily dose of 20 mg for the glyburide component of GLUCOVANCE based on body surface area comparisons) for 18 months revealed no carcinogenic effects. In a two-year oncogenicity study of glyburide in mice, there was no evidence of treatment-related tumors. There was no evidence of mutagenic potential of glyburide alone in the following in vitro tests: Salmonella microsome test (Ames test) and in the DNA damage/ alkaline elution assay. Metformin Hydrochloride Longterm 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/ day and 1500 mg/ kg/ day, respectively. These doses are both approximately four times the maximum recommended human daily dose of 2000 mg of the metformin component of GLUCOVANCE (Glyburide and Metformin HCl Tablets) 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 aberra-tions 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 three times the maximum recommended human daily dose of the metformin component of GLUCOVANCE based on body surface area comparisons.
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. (See below.) 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. Glyburide 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 glyburide component of GLUCOVANCE based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to glyburide. 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 two and six 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 to 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 two weeks before the expected delivery date. (See Pregnancy; Teratogenic Effects: Pregnancy Category B.) Nursing Mothers Although it is not known whether glyburide 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. Pediatric Use Safety and effectiveness of GLUCOVANCE in pediatric patients have not been established. Geriatric Use Of the 642 patients who received GLUCOVANCE in double-blind clinical studies, 23.8% were 65 and older while 2.8% were 75 and older. Of the 1302 patients who received GLUCOVANCE in open-label clinical studies, 20.7% were 65 and older while 2.5% were 75 and older. 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 (see CONTRAINDICA-TIONS, WARNINGS, and CLINICAL PHARMACOLOGY: Pharmacokinetics). 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 mon-itoring
of renal function. Generally, elderly patients should not be titrated to the maximum dose of GLUCOVANCE (see also WARNINGS and DOSAGE AND ADMINISTRATION). Page: << Prev | 1 | 2 | 3 | 4 | 5
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