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Glucovance

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Glucovance

WARNINGS

Metformin Hydrochloride

Lactic acidosis

Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with GLUCOVANCE (glyburide and metformin) (Glyburide and Metformin HC1) Tablets; 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 ( > 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). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. 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 concomitant 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 metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. GLUCOVANCE (glyburide and metformin) 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 (glyburide and metformin) 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, GLUCOVANCE (glyburide and metformin) 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 (glyburide and metformin) , since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, GLUCOVANCE (glyburide and metformin) 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 (glyburide and metformin) 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 GLUCOVANCE (glyburide and metformin) , 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 (glyburide and metformin) 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 (glyburide and metformin) , 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. (See also CONTRAINDICATIONS and PRECAUTIONS.)

Special Warning on Increased Risk of Cardiovascular Mortality

The administration of oral hypoglycemic drugs 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), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to 1 of 4 treatment groups (Diabetes 19 (Suppl. 2):747-830,1970).

UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 g per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone.

A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. 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 glyburide and of alternative modes of therapy.

Although only 1 drug in the sulfonylurea class (tolbutamide) was included in this study, 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.

PRECAUTIONS

General

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macro vascular risk reduction with GLUCOVANCE (glyburide and metformin) or any other antidiabetic drug.

Glucovance (glyburide and metformin)

Hypoglycemia

GLUCOVANCE (glyburide and metformin) 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 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 GLUCOVANCE (glyburide and metformin) 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 GLUCOVANCE (glyburide and metformin) . In patients with advanced age, GLUCOVANCE (glyburide and metformin) 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, GLUCOVANCE (glyburide and metformin) should not be titrated to the maximum dose (see WARNINGS and DOSAGE AND ADMINISTRATION). Before initiation of GLUCOVANCE (glyburide and metformin) 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 (glyburide and metformin) 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, GLUCOVANCE (glyburide and metformin) 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 GLUCOVANCE (glyburide and metformin) therapy, the drug should be promptly discontinued.

Surgical procedures

GLUCOVANCE (glyburide and metformin) 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 (glyburide and metformin) . 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 (glyburide and metformin) 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 (see PRECAUTIONS: Laboratory Tests).

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 (glyburide and metformin) must be stopped immediately and other appropriate corrective measures initiated (see also WARNINGS).

Addition of Thiazolidinediones to GLUCOVANCE (glyburide and metformin) Therapy

Hypoglycemia

Patients receiving GLUCOVANCE (glyburide and metformin) in combination with a thiazolidinedione may be at risk for hypoglycemia.

Weight gain

Weight gain was seen with the addition of rosiglitazone to GLUCOVANCE (glyburide and metformin) , similar to that reported for thiazolidinedione therapy alone.

Hepatic effects

When a thiazolidinedione is used in combination with GLUCOVANCE (glyburide and metformin) , periodic monitoring of liver function tests should be performed in compliance with the labeled recommendations for the thiazolidinedione.

Information for Patients

Glucovance (glyburide and metformin)

Patients should be informed of the potential risks and benefits of GLUCOVANCE (glyburide and metformin) and alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions; a regular exercise program; and 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) immediately and 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 (glyburide and metformin) , 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.)

Laboratory Tests

Periodic fasting blood glucose (FBG) and HbAic 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 812 deficiency should be excluded.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal studies have been conducted with the combined products in GLUCOVANCE (glyburide and metformin) . 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 GLUCOVANCE (glyburide and metformin) based on body surface area comparisons) for 18 months revealed no carcinogenic effects. In a 2-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 4 times the MRHD dose of 2000 mg of the metformin component of GLUCOVANCE (glyburide and metformin) 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 MRHD dose of the metformin component of GLUCOVANCE (glyburide and metformin) 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 (glyburide and metformin) should not be used during pregnancy unless clearly needed. (See below.)

There are no adequate and well-controlled studies in pregnant women with GLUCOVANCE (glyburide and metformin) or its individual components. No animal studies have been conducted with the combined products in GLUCOVANCE (glyburide and metformin) . 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 GLUCOVANCE (glyburide and metformin) 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 2 and 6 times the MRHD dose of 2000 mg of the metformin component of GLUCOVANCE (glyburide and metformin) 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 (glyburide and metformin) be used during pregnancy. However, if it is used, GLUCOVANCE (glyburide and metformin) should be discontinued at least 2 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 (glyburide and metformin) , taking into account the importance of the drug to the mother. If GLUCOVANCE (glyburide and metformin) is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

Pediatric Use

The safety and efficacy of GLUCOVANCE (glyburide and metformin) were evaluated in an active-controlled, double-blind, 26-week randomized trial involving a total of 167 pediatric patients (ranging from 9-16 years of age) with type 2 diabetes. GLUCOVANCE (glyburide and metformin) was not shown statistically to be superior to either metformin or glyburide with respect to reducing HbAic from baseline (see Table 5). No unexpected safety findings were associated with GLUCOVANCE (glyburide and metformin) in this trial.

Table 5: HbA1c (Percent) Change From Baseline at 26 Weeks: Pediatric Study

  Glyburide
2.5 mg tablets
Metformin
500 mg tablets
GLUCOVANCE
1.25 mg/250 mg tablets
Mean Final Dose 6.5 mg 1500 mg 3.1 mg/623mg
Hemoglobin A1c 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 Difference from Glyburide     -0.32
+0.16

Geriatric Use

Of the 642 patients who received GLUCOVANCE (glyburide and metformin) 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 (glyburide and metformin) 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 (glyburide and metformin) should only be used in patients with normal renal function (see CONTRAINDICATIONS, WARNINGS, and CLINICAL PHARMACOLOGY: Pharmacokinctics). Because aging is associated with reduced renal function, GLUCOVANCE (glyburide and metformin) 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 (see also WARNINGS and DOSAGE AND ADMINISTRATION).

Last reviewed on RxList: 1/11/2011
This monograph has been modified to include the generic and brand name in many instances.

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