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Glucovance

Generic Name: glyburide and metformin hydrochloride
Dosage Form: tablet, film coated

Medically reviewed on Nov 1, 2018

WARNING: LACTIC ACIDOSIS

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions (5.1)].
Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided [see Dosage and Administration (2.3), Contraindications (4) and Warnings and Precautions (5.1)].
If metformin-associated lactic acidosis is suspected, immediately discontinue Glucovance and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)].

Indications and Usage for Glucovance

See also: Basaglar

Glucovance is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Glucovance Dosage and Administration

General Considerations

  • For patients not adequately controlled on diet and exercise, the recommended starting dose is 1.25 mg glyburide and 250mg metformin, once or 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.
  • For patients previously treated with a combination therapy of glyburide (or another sulfonylurea) and metformin, the starting dose of Glucovance should not exceed the daily dose (or equivalent dose of another sulfonylurea) and metformin already being taken.
  • Glucovance should be given in divided doses with meals and should be initiated at a low dose, with gradual dose escalation on the basis of glycemic control, in order to avoid hypoglycemia (largely due to glyburide) and reduce GI side effects (largely due to metformin) up to a maximum dose of 20 mg glyburide/2000 mg metformin per day.

Patients Receiving Colesevelam

  • When colesevelam is coadministered with glyburide, maximum plasma concentration and total exposure to glyburide is reduced. Therefore, Glucovance should be administered at least 4 hours prior to colesevelam [see Drug Interactions (7)].

Recommendations for Use in Renal Impairment

  • Assess renal function prior to initiation of Glucovance and periodically thereafter.
  • Glucovance is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m2.
  • Initiation of Glucovance in patients with an eGFR between 30 – 45 mL/minute/1.73 m2 is not recommended.
  • In patients taking Glucovance whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit risk of continuing therapy.
  • Discontinue Glucovance if the patient’s eGFR later falls below 30 mL/minute/1.73 m2, [see Warnings and Precautions (5.1)].

Discontinuation for Iodinated Contrast Imaging Prcedures

  • Discontinue Glucovance at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast.
  • Re-evaluate eGFR 48 hours after the imaging procedure; restart Glucovance if renal function is stable.

Dosage Forms and Strengths

Glucovance is available as:

  • Tablets glyburide 2.5 mg/metformin 500 mg: pale orange, capsule-shaped, bevel-edged, biconvex, film-coated tablet with "BMS" debossed on one side and "6073" debossed on the opposite side.
  • Tablets glyburide 5 mg/ metformin 500 mg: yellow, capsule-shaped, bevel-edged, biconvex, film-coated tablet with "BMS" debossed on one side and "6074" debossed on the opposite side.

Contraindications

Glucovance is contraindicated in patients with:

  • Severe renal impairment (eGFR below 30 mL/min/1.73m2) [see Warnings and Precautions (5.1)].
  • Hypersensitivity to metformin or glyburide.
  • Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
  • Concomitant administration of bosentan [see Drug Interactions (7)].

Warnings and Precautions

Lactic Acidosis

There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels were generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of Glucovance. In Glucovance treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.

Educate patients and their families about the symptoms of lactic acidosis and, if these symptoms occur, instruct them to discontinue Glucovance and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

  • Renal Impairment—The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment.The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)]:
  • Before initiating Glucovance, obtain an estimated glomerular filtration rate (eGFR).
  • Glucovance is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see CONTRAINDICATIONS (4)].
  • Initiation of Glucovance is not recommended in patients with eGFR between 30-45 mL/min/1.73 m2.
  • Obtain an eGFR at least annually in all patient taking Glucovance. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
  • In patients taking Glucovance whose eGFR falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy. 
  • Drug interactions—The concomitant use of Glucovance with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation. Consider more frequent monitoring of patients.
  • Age 65 or Greater—The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.
  • Radiologic studies with contrast—Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop Glucovance at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism or heart failure, or in patients who will be administered intra-arterial iodinated contrast. Reevaluate eGFR 48 hours after the imaging procedure, and restart Glucovance if renal function is stable.
  • Surgery and other procedures—Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment. Glucovance should be temporarily discontinued while patients have restricted food and fluid intake.
  • Hypoxic states—Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may cause prerenal azotemia. When such an event occurs, discontinue Glucovance.
  • Excessive Alcohol intake—Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake, acute or chronic, while receiving Glucovance.
  • Hepatic impairment—Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of Glucovance in patients with clinical or laboratory evidence of hepatic disease.

Hypoglycemia

All sulfonylurea-containing products, including Glucovance, are 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, 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.

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.

Hemolytic Anemia

Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because Glucovance contains a sulfonylurea agent (glyburide), 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.

Vitamin B12 Deficiency

In metformin clinical trials of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 at 2 to 3 year intervals in patients on Glucovance and manage any abnormalities (see Adverse Reactions (6.1) ).

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Glucovance.

Adverse Reactions

The following adverse reactions are also discussed elsewhere in the labeling:

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
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 listed in Table 1.

Table 1: Most Common Clinical Adverse Events (>5%) in Double-Blind Clinical Studies of Glucovance Used as Initial or Second-Line Therapy
                                                                                          Number (%) of Patients

Adverse Event                                  Placebo                          Glyburide                              Metformin                     Glucovance

                                                            N=161                             N=324                                 N=312                           N=642
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)

Disulfiram-like reactions have very rarely been reported in patients treated with glyburide tablets.

Hypoglycemia

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 2. 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.

Gastrointestinal Reactions

The incidence of gastrointestinal (GI) side effects (diarrhea, nausea/vomiting, and abdominal pain) in the Glucovance initial therapy trial are summarized in Table 2. 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.

Table 2: Treatment Emergent Symptoms of Hypoglycemia or Gastrointestinal Adverse Events in a Placebo- and Active-Controlled Trial of Glucovance as Initial Therapy
Variable      

 Placebo

N=161

Glyburide

Tablets

N=160

Metformin

Tablets

N=159

Glucovance

1.25 mg/250 mg

N=158

 Glucovance

 2.5 mg/500   mg

N=162

 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 hypoglycemia

 5 (3.1)  34 (21.3)  5 (3.1)  18 (11.4)  61 (37.7)

 Number (%) of patients

with gastrointestinal

adverse events

 39 (24.2)  38 (23.8)  69 (43.3)  50 (31.6)  62 (38.3)            

Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.

Cholestatic jaundice and hepatitis may occur rarely with glyburide, which may progress to liver failure. Glucovance should be discontinued if this occurs. Liver function abnormalities, including isolated transaminase elevations, have been reported.

Dermatologic Reactions

Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in 1.5% of glyburide-treated patients. These may be transient and may disappear despite continued use; if skin reactions persist, Glucovance should be discontinued.

Postmarketing Adverse Reactions

The following adverse reactions have been identified during post-approval use of Glucovance. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Allergic: Angioedema, arthralgia, myalgia, and vasculitis have been reported.

Dermatologic: Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas.

Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, which occasionally may present as purpura, hemolytic anemia, aplastic anemia, and pancytopenia, have been reported with sulfonylureas.

Metabolic: Hepatic porphyria reactions have been reported with sulfonylureas; however, these have not been reported with glyburide. Disulfiram-like reactions have been reported very rarely with glyburide. Cases of hyponatremia have been reported with glyburide and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone.

Other Reactions: Changes in accommodation and/or blurred vision have been reported with glyburide and other sulfonylureas. These are thought to be related to fluctuation in glucose levels.

Drug Interactions

Table 3 presents clinically significant drug interactions with Glucovance.

 Table 3: Clinically Significant Drug Interactions with Glucovance
 Carbonic Anhydrase Inhibitors
 Clinical Impact:  Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with Glucovance may increase the risk for lactic acidosis.
 Intervention:  Consider more frequent monitoring of these patients.
 Examples:  Topiramate, zonisamide, acetazolamide and dichlorphenamide.
 Drugs that Reduce Metformin Clearance
Clinical Impact:  Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3)].
Intervention:  Consider the benefits and risks of concomitant use with Glucovance.
 Examples:  Ranolazine, vandetanib, dolutegravir, and cimetidine.
 Alcohol
Clinical Impact:  Alcohol is known to potentiate the effect of metformin on lactate metabolism.
 Intervention:  Warn patients against excessive alcohol intake while receiving Glucovance.
 Drugs that potentiate the hypoglycemic action of sulfonylureas
 Clinical Impact:  Certain drugs may potentiate the hypoglycemic action of sulfonylureas
 Intervention:  Closely observe patient for hypoglycemia during co-administration and for loss of glycemic control when withdrawing these agents.
 Examples:  Nonsteroidal anti-inflammatory agents and other highly protein-boind drugs, salicylcates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, beta-adrenergic blocking agents; potentially with ciprofloxacin, micronazole.
 Bosentan
Clinical Impact:  Increased risk of liver enzyme elevations was observed.
 Intervention:  Concomitant administration is contraindicated.
Concomitant administration with colesevalam
Clinical Impact:  Concomitant administration may led to reduced glyburide absorption (AUC and Cmax: -32% and -47%, respectively).
 Intervention: Glucovance should be administered at least 4 hours prior to colesevelam.
Drugs Reducing Glycemic Control
 Clinical Impact:  Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control.
Intervention:  When such drugs are administered to a patient receiving Glucovance observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving Glucovance, observe the patient closely for hypoglycemia.
 Examples:  Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid.

USE IN SPECIFIC POPULATIONS

Pregnancy

Risk Summary

There are no adequate and well-controlled studies in pregnant women with Glucovance. No animal studies have been conducted with the combined products in Glucovance.
The estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes mellitus with an HbA1c >7 and has been reported to be as high as 20–25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Glyburide
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.

Metformin

Limited data with metformin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy [see Clinical Considerations].

No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- and 4-times, respectively, a 2000 mg clinical dose, based on body surface area [see Data].

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Poorly-controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.

Data

Human Data

Published data from post-marketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups.

Animal Data

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 based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to glyburide.

Metformin did not adversely affect development outcomes when administered to pregnant rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 4 times a 2000 mg clinical dose based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

Lactation

Risk Summary

Limited published studies report that metformin is present in human milk [see Data]. However, there is insufficient information to determine the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Glucovance and any potential adverse effects on the breastfed child from Glucovance or from the underlying maternal condition.

Limited published data indicate that the levels of glyburide in human milk are negligible [see Data]. However, there is insufficient information to determine the effects of glyburide on the breastfed infant and no available information on the effects of glyburide on milk production. 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.

Data

Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants. Published clinical lactation studies report that glyburide is negligible in human milk (< 80 mcg/L).

Females and Males of Reproductive Potential

Discuss the potential for unintended pregnancy with premenopausal women as therapy with Glucovance may result in ovulation in some anovulatory women.

Pediatric Use

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 9-16 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 4). No unexpected safety findings were associated with Glucovance in this trial.

    Table 4: 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/623 mg
 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  -0.32
 Difference from Glyburide  +0.16

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.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [see Dosage and Administration (2) and Warnings and Precautions (5.1)].

Renal Impairment

There is no information on the pharmacokinetics of glyburide in patients with renal insufficiency.

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment.

Glucovance is contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2 [see Dosage and Administration (2.3), Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.2)].

Hepatic Impairment

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Glucovance is not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1)].

Cholestatic jaundice and hepatitis may occur rarely with glyburide which may progress to liver failure; Glucovance should be discontinued if this occurs.

Overdosage

Glyburide

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.

Metformin

Overdose of metformin has occurred, including ingestion of amounts greater than 50 g. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see Warnings and Precautions (5.1]). 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.

Glucovance Description

Glucovance® (Glyburide and Metformin HCl) Tablets for oral use contain 2 oral antihyperglycemic drugs used in the management of type 2 diabetes, glyburide and metformin.

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 to 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 (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 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 is 6.68. The structural formula is as shown:

Glucovance is available for oral administration in tablets containing:

  • 2.5 mg glyburide with 500 mg metformin hydrochloride;
  • 5 mg glyburide with 500 mg metformin hydrochloride.

Each tablet contains the inactive ingredients: microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate. The tablets are film coated, which provides color differentiation.

Glucovance - Clinical Pharmacology

Mechanism of Action

Glucovance combines glyburide and metformin hydrochloride, 2 antihyperglycemic agents with complementary mechanisms of action, to improve glycemic control in patients with type 2 diabetes.

Glyburide appears to lower blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which glyburide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in patients with type 2 diabetes, the blood glucose-lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs.

Metformin is an antihyperglycemic agent that improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

Pharmacokinetics

Absorption

Glucovance

In bioavailability studies of Glucovance 2.5 mg/500 mg and 5 mg/500 mg, the mean area under the plasma concentration versus time curve (AUC) for the glyburide component was 18% and 7%, respectively, greater than that of standard particle-size glyburide coadministered with metformin. The glyburide component of Glucovance, therefore, is not bioequivalent to standard particle-size glyburide. The metformin component of Glucovance is bioequivalent to metformin coadministered with glyburide.
Following administration of a single Glucovance 5 mg/500 mg tablet with either a 20% glucose solution or a 20% glucose solution with food, there was no effect of food on the Cmax and a relatively small effect of food on the AUC of the glyburide component. The Tmax for the glyburide component was shortened from 7.5 hours to 2.75 hours with food compared to the same tablet strength administered fasting with a 20% glucose solution. The clinical significance of an earlier Tmax for glyburide after food is not known. The effect of food on the pharmacokinetics of the metformin component was indeterminate.

Glyburide

Single-dose studies with standard particle-size glyburide tablets in normal subjects demonstrate significant absorption of glyburide within 1 hour, peak drug levels at about 4 hours, and low but detectable levels at 24 hours. Mean serum levels of glyburide, as reflected by areas under the serum concentration-time curve, increase in proportion to corresponding increases in dose. Bioequivalence has not been established between Glucovance and single-ingredient standard particle-size glyburide products.

Metformin

The absolute bioavailability of a 500 mg metformin tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin tablets of 500 mg and 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination.
Effect of food: Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.

Distribution

Glyburide

Sulfonylurea drugs are extensively bound to serum proteins. Displacement from protein binding sites by other drugs may lead to enhanced hypoglycemic action. In vitro, the protein binding exhibited by glyburide is predominantly non-ionic, whereas that of other sulfonylureas (chlorpropamide, tolbutamide, tolazamide) is predominantly ionic. Acidic drugs, such as phenylbutazone, warfarin, and salicylates, displace the ionic-binding sulfonylureas from serum proteins to a far greater extent than the non-ionic binding glyburide. It has not been shown that this difference in protein binding results in fewer drug-drug interactions with glyburide tablets in clinical use.

Metformin

The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg averaged 654±358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin, steady-state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 µg/mL. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 µg/mL, even at maximum doses.

Metabolism and Elimination

Glyburide

The decrease of glyburide in the serum of normal healthy individuals is biphasic; the terminal half-life is about 10 hours. The major metabolite of glyburide is the 4-trans-hydroxy derivative. A second metabolite, the 3-cis-hydroxy derivative, also occurs. These metabolites probably contribute no significant hypoglycemic action in humans since they are only weakly active (1/400 and 1/40 as active, respectively, as glyburide) in rabbits. Glyburide is excreted as metabolites in the bile and urine, approximately 50% by each route. This dual excretory pathway is qualitatively different from that of other sulfonylureas, which are excreted primarily in the urine.

Metformin

Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance (see Table 45) is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Specific Populations

Patients With Type 2 Diabetes

Multiple-dose studies with glyburide in patients with type 2 diabetes demonstrate drug level concentration-time curves similar to single-dose studies, indicating no buildup of drug in tissue depots.

In the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see Table 5), nor is there any accumulation of metformin in either group at usual clinical doses.

Hepatic Impairment

No pharmacokinetic studies have been conducted in patients with hepatic insufficiency for either glyburide or metformin [see Warnings and Precautions (8.7)].

Renal Impairment

No information is available on the pharmacokinetics of glyburide in patients with renal insufficiency.
In patients with decreased renal function the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased (Table 5); [see Dosage and Administration (2), Contraindications (4), and Warnings and Precautions (5.1)].

Geriatrics

There is no information on the pharmacokinetics of glyburide in elderly patients.

Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance is decreased, the half-life is prolonged, and Cmax is increased, when compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (Table; 5); [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].

 Table 5: Select Mean (±SD) Metformin Pharmacokinetic Parameters Following
Single or Multiple Oral Doses of Metformin

 Subject Groups: Metformin Dosea
(number of subjects)
 Cmaxb
(µg/mL)           
 Tmaxc
(hrs)
 Renal Clearance
(mL/min)
Healthy, nondiabetic adults:
 500 mg SDd (24)  1.03 (±0.33)  2.75 (±0.81)     600 (±132)
 850 mg SD (74)e  1.60 (±0.38)  2.64 (±0.82)      552 (±139)
 850 mg t.i.d. for 19 doesesf (9) 2.01 (±0.42)  1.79 (±0.94)      642 (±173)
 Adults with type 2 diabetes:
 850 mg SD (23)  1.48 (±0.5)  3.32 (±1.08)       491 (±138)
 850 mg t.i.d. for 19 doesef (9)  1.90 (±0.62)  2.01 (±1.22)        550 (±160)
Elderlyg, healthy nondiabetic adults:
 850 mg SD (12)  2.45 (±0.70)  2.71 (±1.05)        412 (±98)
 Renal-impaired adults: 850 mg SD
 Mild (CLcrh 61-90 mL/min) (5)  1.86 (±0.52)  3.20 (±0.45)        384 (±122)
 Moderate (CLcr 31-60 mL/min) (4)  4.12 (±1.83)  3.75 (±0.50)        108 (±57)
 Severe (CLcr 10-30 mL/min) (6)  3.93 (±0.92)  4.01 (±1.10)        130 (±90)
 a All doses given fasting except the first 18 doses of the multiple-dose studies
b Peak plasma concentration
 c Time to peak plasma concentration
e Combined results (average means) of 5 studies: mean age 32 years (range 23-59 years)
 f Kinetic study done following dose 19, given fasting
 g Elderly subjects, mean age 71 years (range 65-81 years)
 h CLcr=creatinine clearance normalized to body surface area of 1.73 m2

Pediatrics

After administration of a single oral GLUCOPHAGE® (metformin hydrochloride) 500 mg tablet with food, geometric mean metformin Cmax and AUC differed <5% between pediatric type 2 diabetic patients (12-16 years of age) and gender- and weight-matched healthy adults (20-45 years of age), all with normal renal function.

After administration of a single oral Glucovance tablet with food, dose-normalized geometric mean glyburide Cmax and AUC in pediatric patients with type 2 diabetes (11-16 years of age, n=28, mean body weight of 97 kg) differed <6% from historical values in healthy adults.

Gender

There is no information on the effect of gender on the pharmacokinetics of glyburide.

Metformin pharmacokinetic parameters did not differ significantly in subjects with or without type 2 diabetes when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.

Race

No information is available on race differences in the pharmacokinetics of glyburide.
No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, 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.

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 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

Long-term carcinogenicity studies have been performed 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 maximum recommendation human daily dose (MRHD) of 2000 mg on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.

There was no evidence of a mutagenic potential of metformin 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 when administered at doses as high as 600 mg/kg/day, which is approximately 3 times the MRHD of 2000 mg based on body surface area comparisons.

Clinical Studies

Patients with Inadequate Glycemic Control on Diet and Exercise Alone

In a 20-week, double-blind, placebo-controlled, multicenter U.S. clinical trial, involving 806 drug-naive patients with type 2 diabetes, whose hyperglycemia was not adequately controlled with dietary management alone (baseline fasting plasma glucose [FPG] below 240 mg/dL, baseline hemoglobin A1c [HbA1c] between 7% and 11%), were randomized to receive initial therapy with placebo, 2.5 mg glyburide, 500 mg metformin, Glucovance 1.25 mg/250 mg, or Glucovance 2.5 mg/500 mg. After 4 weeks, the dose was progressively increased to a maximum of 4 tablets daily as needed to reach a target FPG of 126 mg/dL. Trial data at 20 weeks are summarized in Table 6.

 Table 6: Placebo- and Active-Controlled Trial of Glucovance in Patients with Inadequate Glycemic Control on Diet and Exercise Alone: Summary of Trial Data at 20 Weeks
Placebo

 Glyburide

2.5 mg

tablets

Metformin

500 mg

tablets

Glucovance

1.25 MG/250 mg

tablets

Glucovance

2.5 mg/500 mg

tablets

Mean Final Dose  0 mg  5.3 mg  1317 mg  2.78 mg/557 mg  4.1 mg/824 mg
 Hemoglobin A1c  N=147  N=142     N=141  N=149  N=152
 Baseline Mean (%)  8.14  8.14  8.23  8.22  8.20
 Mean Change from Baseline  -0.21  -1.24  -1.03  -1.48  -1.53
 Difference from Placebo  -1.02  -0.82  -1.26a  -1.31a
 Difference from Glyburide  -2.4b  -0.29a
 Difference from Metformin  -0.44b  -0.49b
Fasting Plasma Glucose N=159  N=158  N=156  N=153 ​N=154
 Baseline Mean FPG (mg/dL)  177.2  178.9  175.1  178  176.6
 Mean Change from Baseline  4.6  -35.7  -21.2  -41.5  -40.1
 Difference from Placebo  -40.3  -25.8  -46.1a  -44.7a
 Difference from Glyburide  -5.8c  -4.5c
 Difference from Metformin  -20.3c  -18.9c
 Final HbA1c Distribution (%)  N-147  N=142  N=141  N=149  N=152
 <7%  19.7%  59.9%  50.4%  66.4%  71.7%
 ≥7% and <8%  37.4%  26.1%  29.8%  25.5%  19.1%
 ≥8%  42.9%  14.1%  19.9%  8.1%  9.2%
a p<0.001
b p<0.05
c p=NS

Treatment with Glucovance resulted in significantly greater reduction in HbA1c1c and postprandial plasma glucose (PPG) compared to glyburide, metformin, or placebo. Also, Glucovance therapy resulted in greater reduction in FPG compared to glyburide, metformin, or placebo, but the differences from glyburide and metformin did not reach statistical significance.

Glucovance treatment was associated with a lower weight gain compared to an equivalent dose of glyburide alone (+1.4 kg vs. +1.7 kg) whereas patients on metformin and placebo lost weight (-0.6 kg and 0.7 kg, respectively).

The double-blind, placebo-controlled trial described above restricted enrollment to patients with HbA1c <11% or FPG <240 mg/dL. Screened patients ineligible for the first trial because of HbA1c and/or FPG exceeding these limits were treated directly with Glucovance 2.5 mg/500 mg in an open-label, uncontrolled protocol. In this second study, 3 out of 173 patients (1.7%) discontinued because of inadequate therapeutic response. Across the group of 144 patients who completed 26 weeks of treatment, mean HbA1c was reduced from a baseline of 10.6% to 7.1%. The mean baseline FPG was 283 mg/dL and reduced to 164 and 161 mg/dL after 2 and 26 weeks, respectively. The mean final titrated dose of Glucovance was 7.85 mg/1569 mg (equivalent to approximately 3 Glucovance 2.5 mg/500 mg tablets per day).

Patients with Inadequate Glycemic Control on Sulfonylurea Alone

In a 16-week, double-blind, active-controlled U.S. clinical trial, a total of 639 patients with type 2 diabetes not adequately controlled (mean baseline HbA1c 9.5%, mean baseline FPG 213 mg/dL) while being treated with at least one-half the maximum dose of a sulfonylurea (e.g., glyburide 10 mg, glipizide 20 mg) were randomized to receive glyburide (fixed dose, 20 mg), metformin (500 mg), Glucovance 2.5 mg/500 mg, or Glucovance 5 mg/500 mg. The doses of metformin and Glucovance were titrated to a maximum of 4 tablets daily as needed to achieve FPG <140 mg/dL. Trial data at 16 weeks are summarized in Table 7.

 Table 7: Glucovance in Patients with Inadequate Glycemic Control on Sulfonylurea Alone: Summary of Trial Data at 16 Weeks    

Glyburide

5 mg

tablets

 Metformin

500 mg

tablets

Glucovance

2.5 mg/500 mg

tablets

Glucovance

5 mg/500 mg

tablets

Mean Final Dose 20 mg  1840 mg  8.8 mg/1760 mg  17 mg/1740 mg
Hemoglobin A1c N=158  N=142  N=154  N=159
Baseline Mean (%)  9.63  9.51  9.43  9.44
 Final Mean  9.61  9.82  7.92  7.91
 Difference from Glyburide  -1.69a  -1.70a
 Difference from Metformin -1.90a  -1.91a
 Fasting Plasma Glucose  N=163  N=152  N=160  N=160
 Baseline Mean (mg/dL)  218.4  213.4  212.2  210.2
 Final Mean  221.0  233.8  169.6  161.1
 Difference from Glyburide  -51.3a  -59.9a
 Difference from Metformin  -64.2a  -72.7a
 Final HbA1c Distribution (%) N=158  N=142  N=154  N=159
 <7%  2.5%  2.8%  24.7%  22.6%
 ≥7% and <8%  9.5%  11.3%  33.1%  37.1%
 ≥8%  88%  85.9%  42.2%  40.3%
a p<0.001

After 16 weeks, there was no significant change in the mean HbA1c in patients randomized to glyburide or metformin therapy. Treatment with Glucovance at doses up to 20 mg/2000 mg per day resulted in significant lowering of HbA1c, FPG, and PPG from baseline compared to glyburide or metformin alone.
Weight gain due to glyburide was comparable in all three exposed groups.

How Supplied/Storage and Handling

How Supplied

Table 8 Glucovance® (Glyburide and Metformin HCl) Tablets Available Strenghts, Units, and Appearance

Glucovance Tablets

Glyburide

(mg)

Metformin

hydrocloride

(mg)

 2.5  500

 Bottles

of 100

 NDC 0087-

6073.11

 pale orange, capsule-shaped, bevel-edged, biconvex, film-coated tablet with "BMS" debossed on one side and "6073" debossed on the opposite side
 5  500

 Bottles

of 100

 NDC 0087-

6074.11

 yellow, capsule-shaped, bevel-edged, biconvex, film-coated tablet with "BMS" debossed on one side and "6074" debossed on the opposite side.

Storage

Store at temperatures up to 25°C (77°F). [See USP Controlled Room Temperature]
Dispense in light-resistant containers.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Explain to patients the potential risks and benefits of Glucovance and alternative modes of therapy. Explain to patients the importance of adherence to dietary instructions; a regular exercise program; and regular testing of blood glucose, HbA1c, renal function, and hematologic parameters.

Lactic Acidosis:

Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development. Advise patients to discontinue Glucovance immediately and to promptly notify their healthcare provider practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Counsel patients against excessive alcohol intake and inform patients about importance of regular testing of renal function while receiving Glucovance.

Instruct patients to inform their doctor that they are taking Glucovance prior to any surgical or radiological procedure, as temporary discontinuation of Glucovance may be required until renal function has been confirmed to be normal [see Warnings and Precautions (5.1)].

Hypoglycemia:

Inform patients that hypoglycemia may occur when taking Glucovance. Explain to patients the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development [see Warnings and Precautions (5.2)].

Cardiovascular Mortality:

Inform patients that 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. Patients should be informed of the potential risks and benefits of glyburide and of alternative modes of therapy [see Warnings and Precautions (5.3)].

Hemolytic anemia:

Inform patients that they are at increased risk of hemolytic anemia if they have G6PD deficiency and are treated with sulfonylurea [see Warnings and Precautions (5.4)].

Vitamin B12 Deficiency:

Inform patients about importance of regular hematological testing while receiving Glucovance [see Warnings and Precautions (5.5)].

Females of Reproductive Age:

Inform females that treatment with Glucovance may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy [see Use in Specific Populations (8.3)].


Distributed by:
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA

Glucovance® and GLUCOPHAGE® are registered trademarks of Merck Santé S.A.S., a subsidiary of Merck KGaA of Darmstadt, Germany. Licensed to Bristol-Myers Squibb Company.

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PATIENT INFORMATION
Glucovance® [GLOO-KŌ-VANZ]
(GLYBURIDE AND METFORMIN HYDROCHLORIDE) TABLETS

Read the Patient Information that comes with Glucovance before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or treatment.

What is the most important information I should know about Glucovance?

Serious side effects can happen in people taking Glucovance, including:

Lactic Acidosis. Metformin hydrochloride, a medicine in Glucovance, can cause a rare, but serious, side effect called lactic acidosis (a build-up of lactic acid in the blood) that can cause death. Lactic acidosis is a medical emergency and must be treated in a hospital.

Hemolytic Anemia: Glyburide, a medicine in Glucovance where treatment of patients who have a condition known as glucose-6-phosphate dehydrogenase (G6PD) deficiency and who take Glucovance may develop hemolytic anemia (fast breakdown of red blood cells). G6PD deficiency usually runs in families. Tell your doctor if you or any members of your family have been diagnosed with G6PD deficiency before you start taking Glucovance.

Stop taking Glucovance and call your healthcare provider right away if you get any of the following symptoms of lactic acidosis:

  •  feel very weak and tired.
  • have unusual (not normal) muscle pain.
  • have trouble breathing.
  • have unusual sleepiness or sleep longer than usual.
  • have unexplained stomach or intestinal problems with nausea and vomiting, or diarrhea.
  • feel cold, especially in your arms and legs.
  • feel dizzy or lightheaded.
  • have a slow or irregular heartbeat.

You have a higher chance of getting lactic acidosis if you:

  • have kidney problems. People whose kidneys are not working properly should not take Glucovance.
  • have liver problems.
  • drink a lot of alcohol (very often or short-term “binge” drinking).
  • get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever, vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise and do not drink enough fluids.
  • have certain x-ray tests with injectable dyes or contrast agents.
  • have surgery.
  • have a heart attack, severe infection, or stroke.

What is Glucovance?

  • Glucovance is a prescription medicine that contains glyburide (sulfonylurea) and metformin hydrochloride. Glucovance is used with diet and exercise to help control high blood sugar (hyperglycemia) in adults with type 2 diabetes. Also known as non-insulin-dependant diabetes mellitus.
  • Glucovance is not for people with type 1 diabetes.
  • Glucovance is not for people with diabetic ketoacidosis (increased ketones in your blood or urine).

Glyburide lowers blood sugar primarily by causing more of the body’s own insulin to be released, and metformin lowers blood sugar, in part. These medicines help control your blood sugar in a number of ways. These include helping your body respond better to the insulin it makes naturally decreasing the amount of sugar your liver makes, and decreasing the amount of sugar your intestines absorb. Glucovance does not cause your body to make more insulin. Together, they are efficient in helping you to achieve better glucose control.

Do not take Glucovance if you:

  • have kidney problems.
  • have liver problems.
  • are allergic to either glyburide or metformin hydrochloride in Glucovance or any of the ingredients in Glucovance.
  • See the end of this leaflet for a complete list of ingredients in Glucovance.are going to get an injection of dye or contrast agents for an x-ray procedure or if you are going to have surgery and not able to eat or drink much. In these situations, Glucovance will need to be stopped for a short time. Talk to your healthcare provider about when you should stop Glucovance and when you should start Glucovance again. See “What is the most important information I should know about Glucovance?”
  • have acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.
  • take bosentan.

What should I tell my healthcare provider before taking Glucovance?
Before taking Glucovance tell your healthcare provider if you:

  • have type 1 diabetes. Glucovance should not be used to treat people with type 1 diabetes.
  • have a history or risk for diabetic ketoacidosis (high levels of certain acids, known as ketones, in the blood or urine). Glucovance should not be used for the treatment of diabetic ketoacidosis.
  • are taking insulin.
  • have kidney problems.
  • have liver problems.
  • have heart problems, including congestive heart failure.
  • drink alcohol very often, or drink a lot of alcohol in short-term “binge” drinking.
  • have any other medical conditions.
  • are pregnant or plan to become pregnant. It is not known if Glucovance will harm your unborn baby. If you are pregnant, talk with your healthcare provider about the best way to control your blood sugar while you are pregnant.
  • are breast-feeding or plan to breast-feed. It is not known if Glucovance passes into your breast milk. Talk with your healthcare provider about the best way to feed your baby while you take Glucovance.

Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

  • Glucovance may interfere with the way other medicines work, and other medicines may interfere with how Glucovance works.

Can Glucovance be used in children?

Glucovance has not been studied in children.

How should I take Glucovance?

  • Take Glucovance exactly as your healthcare provider tells you.
  • Glucovance should be taken with meals to help lessen an upset stomach side effect and avoid hypoglycemia.
  • Swallow Glucovance whole.
  • When your body is under some types of stress, such as fever, trauma (such as a car accident), infection, or surgery, the amount of diabetes medicine that you need may change. Tell your healthcare provider right away if you have any of these problems.
  • Your healthcare provider should do blood tests to check how well your kidneys are working before and during your treatment with Glucovance.
  • Your healthcare provider will check your diabetes with regular blood tests, including your blood sugar levels and your hemoglobin A1c.
  • Follow your healthcare provider’s instructions for treating blood sugar that is too low (hypoglycemia). Talk to your healthcare provider if low blood sugar is a problem for you. See “What are the side effects of Glucovance?”
  • Check your blood sugar as your healthcare provider tells you to.
  • Stay on your prescribed diet and exercise program while taking Glucovance.
  • If you miss a dose of Glucovance, take your next dose as prescribed unless your healthcare provider tells you differently. Do not take an extra dose the next day.
  • If you take too much Glucovance, call your healthcare provider, local Poison Control Center, or go to the nearest hospital emergency room right away.

What should I avoid while taking Glucovance?
Do not drink a lot of alcoholic drinks while taking Glucovance. This means you should not binge drink for short periods, and you should not drink a lot of alcohol on a regular basis. Alcohol can increase the chance of getting lactic acidosis.

What are the side effects of Glucovance?

Most common side effects that Glucovance can cause are:
If the side effects below occur, they usually occur during the first few weeks of therapy with Glucovance, Taking Glucovance with meals can help reduce these side effects.

  • diarrhea
  • nausea
  • upset stomach

Less frequently, symptoms of hypoglycemia (low blood sugar), such as:

  • lightheadedness
  • dizziness, shakiness
  • hunger may occur

The risk of hypoglycemic symptoms increases when meals are skipped, too much alcohol is consumed, or heavy exercise occurs without enough food. Following the advice of your doctor can help you to avoid these symptoms.

Serious side effects that Glucovance can cause are:

Lactic acidosis. Metformin, an active ingredient in Glucovance, can cause a rare but serious condition called lactic acidosis (a buildup of an acid in the blood) that can cause death. Lactic acidosis is a medical emergency and must be treated in the hospital.

Call your doctor right away if you have any of the following symptoms, which could be signs of lactic acidosis:

  • you feel cold in your hands or feet.
  • you feel dizzy or lightheaded.
  • you have a slow or irregular heartbeat.
  • you feel very weak or tired.
  • you have trouble breathing.
  • you feel sleepy or drowsy.
  • you have stomach pains, nausea or vomiting.

Most people who have had lactic acidosis with metformin have other things that, combined with the metformin, led to the lactic acidosis. Tell your doctor if you have any of the following, because you have a higher chance for getting lactic acidosis with Glucovance if you:

  • have severe kidney problems, or your kidneys are affected by certain x-ray tests that use injectable dye.
  • have liver problems.
  • drink alcohol very often, or drink a lot of alcohol in short-term "binge" drinking.
  • get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever, vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise and do not drink enough fluids.
  • have surgery.
  • have a heart attack, severe infection, or stroke.

Hemolytic Anemia: People who have a condition known as glucose-6-phosphate dehydrogenase (G6PD) deficiency and who take Glucovance may develop hemolytic anemia (fast breakdown of red blood cells). G6PD deficiency usually runs in families. Tell your doctor if you or any members of your family have been diagnosed with G6PD deficiency before you start taking Glucovance.

How should I store Glucovance?

Store Glucovance at temperatures up to 25°C (77°F).

Keep Glucovance and all medicines out of the reach of children.

General information about the use of Glucovance

If you have questions or problems, talk with your doctor or other healthcare provider. You can ask your doctor or pharmacist for the information about Glucovance that is written for healthcare professionals. Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use Glucovance for a condition for which it was not prescribed. Do not share your medicine with other people.

What are the ingredients of Glucovance?

Active ingredients of Glucovance: glyburide and metformin hydrochloride.
Inactive ingredients in each tablet of Glucovance: microcrystalline cellulose, povidone, croscarmellose sodium, and magnesium stearate.

What is type 2 diabetes?
Type 2 diabetes is a condition in which your body does not make enough insulin, and the insulin that your body produces does not work as well as it should. Your body can also make too much sugar. When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems.

The main goal of treating diabetes is to lower your blood sugar to a normal level.

High blood sugar can be lowered by diet and exercise, and by certain medicines when necessary.

Talk to your healthcare provider about how to prevent, recognize, and take care of low blood sugar (hypoglycemia), high blood sugar (hyperglycemia), and problems you have because of your diabetes.

Glucovance® is a registered trademark of Merck Santé S.A.S., a subsidiary of Merck KGaA of Darmstadt, Germany. Licensed to Bristol-Myers Squibb Company.

Other brands listed are the trademarks of their respective owners.

Distributed by:
Bristol-Myers Squibb Company
Princeton, NJ 08543 USA
[print code TBD]
Rev [XXX 201X

100 Tablets
NDC 0087-6073-11
Glucovance®
(Glyburide and Metformin HCl) Tablets
2.5 mg/500 mg
Rx only
Bristol-Myers Squibb

100 Tablets
NDC 0087-6074-11
Glucovance®
(Glyburide and Metformin HCl) Tablets
5 mg/500 mg
Rx only
Bristol-Myers Squibb

Glucovance 
glyburide and metformin hydrochloride tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0087-6073
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
glyburide (glyburide) glyburide 2.5 mg
metformin hydrochloride (metformin) metformin hydrochloride 500 mg
Inactive Ingredients
Ingredient Name Strength
cellulose, microcrystalline  
POVIDONES  
croscarmellose sodium  
magnesium stearate  
Product Characteristics
Color ORANGE (PALE ORANGE) Score no score
Shape OVAL (CAPSULE-SHAPED) Size 16mm
Flavor Imprint Code BMS;6073
Contains     
Packaging
# Item Code Package Description
1 NDC:0087-6073-11 100 TABLET, FILM COATED in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA021178 12/15/2008 10/31/2018
Glucovance 
glyburide and metformin hydrochloride tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0087-6074
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
glyburide (glyburide) glyburide 5 mg
metformin hydrochloride (metformin) metformin hydrochloride 500 mg
Inactive Ingredients
Ingredient Name Strength
cellulose, microcrystalline  
POVIDONES  
croscarmellose sodium  
magnesium stearate  
Product Characteristics
Color YELLOW Score no score
Shape OVAL (CAPSULE-SHAPED) Size 16mm
Flavor Imprint Code BMS;6074
Contains     
Packaging
# Item Code Package Description
1 NDC:0087-6074-11 100 TABLET, FILM COATED in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA021178 12/15/2008 02/28/2019
Labeler - Bristol-Myers Squibb Company (102826703)
 
Bristol-Myers Squibb Company
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