PRECAUTIONS General Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Glyburide and Metformin Hydrochloride or any other anti-diabetic drug. Glyburide and Metformin Hydrochloride The glyburide component of glyburide and metformin HCl tablets is not bioequivalent to Micronase ® . In addition, it has been reported that bioavailability studies have demonstrated that micronized glyburide tablets 3 mg provide serum glyburide concentration that are not bioequivalent to those from nonmicronized glyburide tablets 5 mg. Therefore, patients should be retitrated when transferred from micronized glyburide tablets or other oral hypoglycemic agents. Hypoglycemia Glyburide and Metformin Hydrochloride 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 glyburide 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 beta-adrenergic blocking drugs. Glyburide Hemolytic anemia Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because Glyburide and Metformin Hydrochloride belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered. In postmarketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency. 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 Glyburide and Metformin Hydrochloride. In patients with advanced age, Glyburide and Metformin Hydrochloride 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 of age, renal function should be monitored regularly and, generally, Glyburide and Metformin Hydrochloride should not be titrated to the maximum dose (see WARNINGS and DOSAGE AND ADMINISTRATION). Before initiation of Glyburide and Metformin Hydrochloride 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 Glyburide and Metformin Hydrochloride 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. Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous 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 (see CONTRAINDICATIONS). Therefore, in patients in whom any such study is planned, Glyburide and Metformin Hydrochloride 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 reevaluated 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 Glyburide and Metformin Hydrochloride therapy, the drug should be promptly discontinued. Surgical procedures Glyburide and Metformin Hydrochloride 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 Glyburide and Metformin Hydrochloride. 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, Glyburide and Metformin Hydrochloride should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Vitamin B 12 levels In controlled clinical trials with metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum Vitamin B 12, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12 absorption from the B 12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or Vitamin B 12 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 (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 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, Glyburide and Metformin Hydrochloride must be stopped immediately and other appropriate corrective measures initiated (see also WARNINGS). Addition of Thiazolidinediones to Glyburide and Metformin Hydrochloride Therapy Hypoglycemia Patients receiving Glyburide and Metformin Hydrochloride in combination with a thiazolidinedione may be at risk for hypoglycemia. Weight gain Weight gain was seen with the addition of rosiglitazone to Glyburide and Metformin Hydrochloride, similar to that reported for thiazolidinedione therapy alone. Hepatic effects When a thiazolidinedione is used in combination with Glyburide and Metformin Hydrochloride, periodic monitoring of liver function tests should be performed in compliance with the labeled recommendations for the thiazolidinedione. Information for Patients Glyburide and Metformin Hydrochloride Patients should be informed of the potential risks and benefits of Glyburide and Metformin Hydrochloride 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 Glyburide and Metformin Hydrochloride 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 Glyburide and Metformin Hydrochloride, 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 Glyburide and Metformin Hydrochloride. (See Patient Information Printed Below.) Laboratory Tests Periodic fasting blood glucose (FBG) and HbA 1c measurements should be performed to monitor therapeutic response. Initial and periodic monitoring of hematologic parameters (eg, 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. Drug Interactions Glyburide and Metformin Hydrochloride Certain drugs tend to produce hyperglycemia and may lead to loss of blood glucose control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving Glyburide and Metformin Hydrochloride, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving Glyburide and Metformin Hydrochloride, the patient should be observed closely for hypoglycemia. Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid as compared to sulfonylureas, which are extensively bound to serum proteins. Glyburide The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including nonsteroidal 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 Glyburide and Metformin Hydrochloride, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving Glyburide and Metformin Hydrochloride, 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, topical, 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 metformin and furosemide when co-administered chronically. Nifedipine A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers 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 (eg, 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 elimination 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 Glyburide and Metformin Hydrochloride 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 metformin 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 Glyburide and Metformin Hydrochloride. The following 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 145 times the maximum recommended human daily [MRHD] dose of 20 mg for the glyburide component of Glyburide and Metformin Hydrochloride 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 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/day and 1500 mg/kg/day, respectively. These doses are both approximately four times the MRHD dose of 2000 mg of the metformin component of Glyburide and Metformin Hydrochloride 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 three times the MRHD dose of the metformin component of Glyburide and Metformin Hydrochloride 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, Glyburide and Metformin Hydrochloride should not be used during pregnancy unless clearly needed. (See below.) There are no adequate and well-controlled studies in pregnant women with Glyburide and Metformin Hydrochloride or its individual components. No animal studies have been conducted with the combined products in Glyburide and Metformin Hydrochloride. 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 MRHD dose of 20 mg of the glyburide component of Glyburide and Metformin Hydrochloride 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 Glyburide and Metformin Hydrochloride 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 Glyburide and Metformin Hydrochloride be used during pregnancy. However, if it is used, Glyburide and Metformin Hydrochloride 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 Glyburide and Metformin Hydrochloride, taking into account the importance of the drug to the mother. If Glyburide and Metformin Hydrochloride is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered. Pediatric Use The safety and efficacy of Glyburide and Metformin Hydrochloride was evaluated in an active-controlled, double-blind, 26-week randomized trial involving a total of 167 pediatric patients (ranging from 9 to 16 years of age) with type 2 diabetes. Glyburide and Metformin Hydrochloride was not shown statistically to be superior to either metformin or glyburide with respect to reducing HbA 1c from baseline (see Table 5). No unexpected safety findings were associated with Glyburide and Metformin Hydrochloride in this trial. Table 5: HbA 1c (Percent) Change From Baseline at 26 Weeks: Pediatric Study Glyburide and Metformin Glyburide Metformin Hydrochloride 2.5 mg 500 mg 1.25 mg/250 mg Tablets Tablets Tablets Mean Final Dose 6.5 mg 1500 mg 3.1 mg/623 mg Hemoglobin A 1c N=49 N=54 N=57 Baseline Mean (%) 7.70 7.99 7.85 Mean Change from Baseline -0.96 -0.48 -0.80 Difference from Metformin -0.32 Difference from Glyburide +0.16 Geriatric Use Of the 642 patients who received Glyburide and Metformin Hydrochloride in double-blind clinical studies, 23.8% were 65 and older while 2.8% were 75 and older. Of the 1302 patients who received Glyburide and Metformin Hydrochloride 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, Glyburide and Metformin Hydrochloride should only be used in patients with normal renal function (see CONTRAINDICATIONS, WARNINGS, and CLINICAL PHARMACOLOGY: Pharmacokinetics). Because aging is associated with reduced renal function, Glyburide and Metformin Hydrochloride 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 Glyburide and Metformin Hydrochloride (see also WARNINGS and DOSAGE AND ADMINISTRATION).