GLUCOVANCE® (Glyburide and Metformin HCl Tablets) contains two oral antihyperglycemic drugs used in the management of type 2 diabetes, glyburide and metformin hydrochloride.
Glyburide is an oral antihyperglycemic drug of the sulfonylurea class. The chemical name for glyburide is 1-[[p-[2-(5-chloro-o-anisamido)ethyl]phenyl]sulfonyl]-3-cyclo-hexylurea. Glyburide is a white to off-white crystalline compound with a molecular formula of C23H28ClN3O5S and a molecular weight of 494.01. The glyburide used in GLUCOVANCE has a particle size distribution of 25% undersize value not more than 6 µm, 50% undersize value not more than 7-10 µm, and 75% undersize value not more than 21 µm. The structural formula is represented below.
Metformin hydrochloride is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide monohydrochloride) is not chemically or pharmacologically related to sulfonylureas, thiazolidinediones, or α-glucosidase inhibitors. It is a white to off-white crystalline compound with a molecular formula of C4H12ClN5 (monohydrochloride) and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula is as shown:
GLUCOVANCE is available for oral administration in tablets containing 1.25 mg glyburide with 250 mg metformin hydrochloride, 2.5 mg glyburide with 500 mg metformin hydrochloride, and 5 mg glyburide with 500 mg metformin hydrochloride. In addition, each tablet contains the following inactive ingredients: microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate. The tablets are film coated, which provides color differentiation.
GLUCOVANCE combines glyburide and metformin hydrochloride, two antihyperglycemic agents with complementary mechanisms of action, to improve glycemic control in patients with type 2 diabetes.
GLUCOVANCE is indicated as initial therapy, as an adjunct to diet and exercise, to improve glycemic control in patients with type 2 diabetes whose hyperglycemia cannot be satisfactorily managed with diet and exercise alone.
GLUCOVANCE is indicated as second-line therapy when diet, exercise, and initial treatment with a sulfonylurea or metformin do not result in adequate glycemic control in patients with type 2 diabetes. For patients requiring additional therapy, a thiazolidinedione may be added to GLUCOVANCE to achieve additional glycemic control.
GLUCOVANCE (Glyburide and Metformin HCl Tablets) is contraindicated in patients with:
GLUCOVANCE should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function. (See also PRECAUTIONS.)
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 one of four 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 2-1/2 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 one 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.
Periodic fasting blood glucose and glycosylated hemoglobin (HbA1c) measurements should be performed 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 B12 deficiency should be excluded.
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.
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.
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.
The safety and efficacy of GLUCOVANCE were 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. GLUCOVANCE was not shown statistically to be superior to either metformin or glyburide with respect to reducing HbA1c from baseline (see Table 5). No unexpected safety findings were associated with GLUCOVANCE in this trial.
1.25 mg/250 mg
|Mean Final Dose||6.5 mg||1500 mg||3.1 mg/623 mg|
|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|
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 CONTRAINDICATIONS, 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 monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of GLUCOVANCE (see also WARNINGS and DOSAGE AND ADMINISTRATION).
In double-blind clinical trials involving GLUCOVANCE as initial therapy or as second-line therapy, a total of 642 patients received GLUCOVANCE, 312 received metformin therapy, 324 received glyburide therapy, and 161 received placebo. The percent of patients reporting events and types of adverse events reported in clinical trials of GLUCOVANCE (all strengths) as initial therapy and second-line therapy are uled in Table 6.
|Number (%) of Patients|
|Upper respiratory infection||22 (13.7)||57 (17.6)||51 (16.3)||111 (17.3)|
|Diarrhea||9 (5.6)||20 (6.2)||64 (20.5)||109 (17.0)|
|Headache||17 (10.6)||37 (11.4)||29 (9.3)||57 (8.9)|
|Nausea/vomiting||10 (6.2)||17 (5.2)||38 (12.2)||49 (7.6)|
|Abdominal pain||6 (3.7)||10 (3.1)||25 (8.0)||44 (6.9)|
|Dizziness||7 (4.3)||18 (5.6)||12 (3.8)||35 (5.5)|
In a controlled clinical trial of rosiglitazone versus placebo in patients treated with GLUCOVANCE (n=365), 181 patients received GLUCOVANCE with rosiglitazone and 184 received GLUCOVANCE with placebo.
Edema was reported in 7.7% (14/181) of patients treated with rosiglitazone compared to 2.2% (4/184) of patients treated with placebo. A mean weight gain of 3 kg was observed in rosiglitazone-treated patients.
Disulfiram-like reactions have very rarely been reported in patients treated with glyburide tablets.
In controlled clinical trials of GLUCOVANCE there were no hypoglycemic episodes requiring medical intervention and/or pharmacologic therapy; all events were managed by the patients. The incidence of reported symptoms of hypoglycemia (such as dizziness, shakiness, sweating, and hunger), in the initial therapy trial of GLUCOVANCE are summarized in Table 7. The frequency of hypoglycemic symptoms in patients treated with GLUCOVANCE 1.25 mg/250 mg was highest in patients with a baseline HbA1c<7%, lower in those with a baseline HbA1c of between 7% and 8%, and was comparable to placebo and metformin in those with a baseline HbA1c>8%. For patients with a baseline HbA1c between 8% and 11% treated with GLUCOVANCE 2.5 mg/500 mg as initial therapy, the frequency of hypoglycemic symptoms was 30 to 35%. As second-line therapy in patients inadequately controlled on sulfonylurea alone, approximately 6.8% of all patients treated with GLUCOVANCE experienced hypoglycemic symptoms. When rosiglitazone was added to GLUCOVANCE therapy, 22% of patients reported one or more fingerstick glucose measurements ≤50 mg/dL compared to 3.3% of placebo-treated patients. All hypoglycemic events were managed by the patients and only one patient discontinued for hypoglycemia. (See PRECAUTIONS: General:Addition of Thiazolidinediones to GLUCOVANCE Therapy.)
The incidence of GI side effects (diarrhea, nausea/vomiting, and abdominal pain) in the initial therapy trial are summarized in Table 7. Across all GLUCOVANCE trials, GI symptoms were the most common adverse events with GLUCOVANCE and were more frequent at higher dose levels. In controlled trials, <2% of patients discontinued GLUCOVANCE therapy due to GI adverse events.
1.25 mg/250 mg
2.5 mg/500 mg
|Mean Final Dose||0 mg||5.3 mg||1317 mg||2.78 mg/557 mg||4.1 mg/824 mg|
Number (%) of patients|
with symptoms of
|5 (3.1)||34 (21.3)||5 (3.1)||18 (11.4)||61 (37.7)|
Number (%) of patients |
|39 (24.2)||38 (23.8)||69 (43.3)||50 (31.6)||62 (38.3)|
Overdosage of sulfonylureas, including glyburide tablets, can produce hypoglycemia. Mild hypoglycemic symptoms, without loss of consciousness or neurological findings, should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours, since hypoglycemia may recur after apparent clinical recovery.
Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see WARNINGS). Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.
Dosage of GLUCOVANCE must be individualized on the basis of both effectiveness and tolerance while not exceeding the maximum recommended daily dose of 20 mg glyburide/2000 mg metformin. GLUCOVANCE should be given with meals and should be initiated at a low dose, with gradual dose escalation as described below, in order to avoid hypoglycemia (largely due to glyburide), to reduce GI side effects (largely due to metformin), and to permit determination of the minimum effective dose for adequate control of blood glucose for the individual patient.
With initial treatment and during dose titration, appropriate blood glucose monitoring should be used to determine the therapeutic response to GLUCOVANCE and to identify the minimum effective dose for the patient. Thereafter, HbA1c should be measured at intervals of approximately 3 months to assess the effectiveness of therapy. The therapeutic goal in all patients with type 2 diabetes is to decrease FPG, PPG, and HbA1c to normal or as near normal as possible. Ideally, the response to therapy should be evaluated using HbA1c (glycosylated hemoglobin), which is a better indicator of long-term glycemic control than FPG alone.
No studies have been performed specifically examining the safety and efficacy of switching to GLUCOVANCE therapy in patients taking concomitant glyburide (or other sulfonylurea) plus metformin. Changes in glycemic control may occur in such patients, with either hyperglycemia or hypoglycemia possible. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring.
Recommended starting dose: 1.25 mg/250 mg once or twice daily with meals.
For patients with type 2 diabetes whose hyperglycemia cannot be satisfactorily managed with diet and exercise alone, the recommended starting dose of GLUCOVANCE is 1.25 mg/250 mg once a day with a meal. As initial therapy in patients with baseline HbA1c>9% or an FPG >200 mg/dL, a starting dose of GLUCOVANCE 1.25 mg/250 mg twice daily with the morning and evening meals may be used. Dosage increases should be made in increments of 1.25 mg/250 mg per day every two weeks up to the minimum effective dose necessary to achieve adequate control of blood glucose. In clinical trials of GLUCOVANCE as initial therapy, there was no experience with total daily doses greater than 10 mg/2000 mg per day. GLUCOVANCE 5 mg/500 mg should not be used as initial therapy due to an increased risk of hypoglycemia.
Recommended starting dose: 2.5 mg/500 mg or 5 mg/500 mg twice daily with meals.
For patients not adequately controlled on either glyburide (or another sulfonylurea) or metformin alone, the recommended starting dose of GLUCOVANCE is 2.5 mg/500 mg or 5 mg/500 mg twice daily with the morning and evening meals. In order to avoid hypoglycemia, the starting dose of GLUCOVANCE should not exceed the daily doses of glyburide or metformin already being taken. The daily dose should be titrated in increments of no more than 5 mg/500 mg up to the minimum effective dose to achieve adequate control of blood glucose or to a maximum dose of 20 mg/2000 mg per day.
For patients previously treated with combination therapy of glyburide (or another sulfonylurea) plus metformin, if switched to GLUCOVANCE, the starting dose should not exceed the daily dose of glyburide (or equivalent dose of another sulfonylurea) and metformin already being taken. Patients should be monitored closely for signs and symptoms of hypoglycemia following such a switch and the dose of GLUCOVANCE should be titrated as described above to achieve adequate control of blood glucose.
For patients not adequately controlled on GLUCOVANCE, a thiazolidinedione can be added to GLUCOVANCE therapy. When a thiazolidinedione is added to GLUCOVANCE therapy, the current dose of GLUCOVANCE can be continued and the thiazolidinedione initiated at its recommended starting dose. For patients needing additional glycemic control, the dose of the thiazolidinedione can be increased based on its recommended titration schedule. The increased glycemic control attainable with GLUCOVANCE plus a thiazolidinedione may increase the potential for hypoglycemia at any time of day. In patients who develop hypoglycemia when receiving GLUCOVANCE and a thiazolidinedione, consideration should be given to reducing the dose of the glyburide component of GLUCOVANCE. As clinically warranted, adjustment of the dosages of the other components of the antidiabetic regimen should also be considered.
GLUCOVANCE is not recommended for use during pregnancy. The initial and maintenance dosing of GLUCOVANCE should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment requires a careful assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of GLUCOVANCE to avoid the risk of hypoglycemia. Monitoring of renal function is necessary to aid in prevention of metformin-associated lactic acidosis, particularly in the elderly. (See WARNINGS.)
GLUCOVANCE® (Glyburide and Metformin HCl Tablets)
GLUCOVANCE 1.25 mg/250 mg tablet is a pale yellow, capsule-shaped, bevel-edged, biconvex, film-coated tablet with "BMS" debossed on one side and "6072" debossed on the opposite side.
GLUCOVANCE 2.5 mg/500 mg tablet is a pale orange, capsule-shaped, bevel-edged, biconvex, film-coated tablet with "BMS" debossed on one side and "6073" debossed on the opposite side.
GLUCOVANCE 5 mg/500 mg tablet is a yellow, capsule-shaped, bevel-edged, biconvex, film-coated tablet with "BMS" debossed on one side and "6074" debossed on the opposite side.
|GLUCOVANCE||NDC 0087-xxxx-xx for unit of use|
Store at temperatures up to 25° C (77° F). [See USP Controlled Room Temperature.]
Dispense in light-resistant containers.
GLUCOVANCE® is a registered trademark of Merck Santé S.A.S., an associate of Merck KGaA of Darmstadt, Germany. Licensed to Bristol-Myers Squibb Company.
GLUCOPHAGE® is a registered trademark of Merck Santé S.A.S., an associate of Merck KGaA of Darmstadt, Germany. Licensed to Bristol-Myers Squibb Company.
Micronase® is a registered trademark of Pharmacia & Upjohn Company.
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
Revised June 2006