Glyburide And Metformin Hydrochloride

Q: What should I know before taking Glyburide And Metformin Hydrochloride?

5 WARNINGS AND PRECAUTIONS Lactic Acidosis: See boxed warning. (5.1) Hypoglycemia: May be severe. Ensure proper patient selection, dosing, and instructions, particularly in at-risk populations (e.g., elderly, renally impaired) and when used with other anti-diabetic medications. (5.2) Potential Increased Risk of Cardiovascular Mortality with Sulfonylureas: Inform patient of risks, benefits and treatment alternatives. (5.3) Hemolytic anemia: Can occur if glucose 6-phosphate dehydrogenase (G6PD) de

Q: Is Glyburide And Metformin Hydrochloride available over the counter?

Glyburide And Metformin Hydrochloride is a prescription medication. You will need a valid prescription from a licensed healthcare provider.

Prescription

Brand names: glyburide and metformin hydrochloride

Dosage Form

Tablet

Route

ORAL

Manufacturer

Zydus Pharmaceuticals USA Inc.

About This Medication

11 DESCRIPTION Glyburide and metformin hydrochloride tablets, USP for oral use contain glyburide, USP and metformin hydrochloride, USP. Glyburide, USP is a sulfonylurea and its chemical name is 1-[[ p -[2-(5-chloro- o- anisamido) ethyl]phenyl]sulfonyl]-3-cyclo-hexylurea. Glyburide, USP is a white or almost white, crystalline powder with a molecular formula of C 23 H 28 ClN 3 O 5 S and a molecular weight of 494. The glyburide used in glyburide and metformin hydrochloride tablets, USP has a particle size at least 20% are less than 2 micron, at least 80% are less than 10 micron and 100% are less than 40 micron. The structural formula is represented below. Metformin hydrochloride, USP is a biguanide in hydrochloride salt form and its chemical name is N,N-dimethylimidodicarbonimidic diamide monohydrochloride. It is a white crystals with a molecular formula of C 4 H 12 ClN 5 (monohydrochloride) and a molecular weight of 165.62. Metformin hydrochloride, USP is freely soluble in water, slightly soluble in ethanol (95%), practically insoluble in acetone and in methylene chloride. The structural formula is as shown: Glyburide and metformin hydrochloride tablets, USP are available in film coated tablets containing: 1.25 mg glyburide, USP and 250 mg metformin hydrochloride, USP (equivalent to 194.97 mg metformin); 2.5 mg glyburide, USP and 500 mg metformin hydrochloride, USP (equivalent to 389.93 mg metformin); 5 mg glyburide, USP and 500 mg metformin hydrochloride, USP (equivalent to 389.93 mg metformin). Each tablet contains the following inactive ingredients: calcium carbonate, croscarmellose sodium, magnesium stearate, microcrystalline cellulose and povidone. Additionally, 1.25 mg/250 mg tablets contain opadry II white 33F28398 which contains hypromellose, lactose monohydrate, polyethylene glycol, talc and titanium dioxide. Additionally, 2.5 mg/500 mg tablets contain opadry II orange 31F530003 which contains FD&C blue #2 aluminum lake, FD&C yellow #5 aluminum lake, FD&C yellow #6 aluminum lake, hypromellose, lactose monohydrate, polyethylene glycol and titanium dioxide. Additionally, 5 mg/500 mg tablets contain opadry II green 31F510000 which contains iron oxide black, iron oxide red, iron oxide yellow, hypromellose, lactose monohydrate, polyethylene glycol and titanium dioxide. Image Image

Active Ingredients

Ingredient	Strength
Glyburide	-
Metformin Hydrochloride	-

Indications & Usage

1 INDICATIONS AND USAGE Glyburide and metformin hydrochloride tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Glyburide and metformin hydrochloride tablets are a combination of glyburide, a sulfonylurea, and metformin hydrochloride (HCl), a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. (1)

How It Works

12.1 Mechanism of Action Glyburide primarily lowers blood glucose by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. Sulfonylureas bind to the sulfonylurea receptor in the pancreatic beta-cell plasma membrane, leading to closure of the ATP-sensitive potassium channel, thereby stimulating the release of insulin. 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 daylong plasma insulin response may decrease.

Dosage & Administration

2 DOSAGE AND ADMINISTRATION Adult Dosage: Give glyburide and metformin hydrochloride tablets in divided doses, twice daily, with meals. (2.1) For patients not treated with either glyburide (or another sulfonylurea) or metformin HCl, initiate treatment with another formulation with a dose of 1.25 mg glyburide and 250 mg metformin HCl orally, once or twice daily with meals. (2.1) For patients not adequately controlled on either glyburide (or another sulfonylurea) or metformin HCl alone, the recommended starting dose is 2.5 mg/500 mg or 5 mg/500 mg orally twice daily with meals. (2.1) For patients previously treated with a combination therapy of glyburide (or another sulfonylurea) and metformin HCl, the starting dose should not exceed the daily dose of glyburide (or equivalent dose of another sulfonylurea) and metformin HCl already being taken. (2.1) Increase the dose gradually on the basis of glycemic control and tolerability, up to a maximum to a maximum dose of 20 mg glyburide/2,000 mg metformin HCl daily. (2.1) Renal Impairment: Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) (2.4) Do not use in patients with eGFR below 30 mL/minute/1.73 m 2 (2.4) Initiation is not recommended in patients with eGFR between 30 to 45 mL/minute/1.73 m 2 (2.4) Assess risk/benefit if eGFR falls below 45 mL/minute/1.73 m 2 (2.4) Discontinue if eGFR falls below 30 mL/minute/1.73 m 2 (2.4) Discontinuation for Iodinated Contrast Imaging Procedures: Glyburide and metformin hydrochloride tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures (2.5) 2.1 Dosage Give glyburide and metformin hydrochloride tablets in divided doses, twice daily, with meals. For patients not treated with either glyburide (or another sulfonylurea) or metformin hydrochloride (HCl), initiate treatment with another formulation of glyburide and metformin HCl at a starting dose of 1.25 mg glyburide and 250 mg metformin HCl orally, once or twice daily with meals. For patients not adequately controlled on either glyburide (or another sulfonylurea) or metformin HCl alone, the recommended starting dose of glyburide and metformin hydrochloride tablets is 2.5 mg/500 mg or 5 mg/500 mg orally twice daily with meals. For patients previously treated with a combination therapy of glyburide (or another sulfonylurea) and metformin HCl, the starting dose of glyburide and metformin hydrochloride tablets should not exceed the daily dose of glyburide (or equivalent dose of another sulfonylurea) and metformin HCl already being taken. Increase the dose gradually on the basis of glycemic control and tolerability, up to a maximum to a maximum dose of 20 mg glyburide/2,000 mg metformin HCl daily. 2.2 Patients Receiving Colesevelam Administer glyburide and metformin hydrochloride tablets at least 4 hours prior to colesevelam for patients taking both drugs concomitantly [see Drug Interactions (7) ]. 2.3 Recommendations for Use in Renal Impairment Assess renal function prior to initiation of glyburide and metformin hydrochloride tablets and periodically thereafter. Glyburide and metformin hydrochloride tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m 2 . Initiation of glyburide and metformin hydrochloride tablets in patients with an eGFR between 30 to 45 mL/minute/1.73 m 2 is not recommended. In patients taking glyburide and metformin hydrochloride tablets whose eGFR later falls below 45 mL/min/1.73 m 2 , assess the benefit risk of continuing therapy. Discontinue glyburide and metformin hydrochloride tablets if the patient's eGFR later falls below 30 mL/minute/1.73 m 2 [see Warnings and Precautions (5.1) ]. 2.4 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue glyburide and metformin hydrochloride tablets 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 m 2 ; 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 glyburide and metformin hydrochloride tablets if renal function is stable.

Side Effects Overview

6 ADVERSE REACTIONS The following adverse reactions are also discussed elsewhere in the labeling: Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1) ] Hypoglycemia [see Warnings and Precautions (5.2) ] Cardiovascular mortality [see Warnings and Precautions (5.3) ] Hemolytic anemia [see Warnings and Precautions (5.4 )] Vitamin B 12 Deficiency [ see Warnings and Precautions (5.5) ] Most common (>5%) adverse reactions to glyburide and metformin hydrochloride tablets diarrhea, headache, nausea/vomiting, abdominal pain, and dizziness. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In double-blind clinical studies with glyburide and metformin hydrochloride as initial therapy or as second-line therapy of 20 and 14 weeks, respectively (see section 14), a total of 642 patients received glyburide and metformin hydrochloride, 312 received metformin HCl, 324 received glyburide, and 161 received placebo. Adverse reactions are listed in Table 1. Table 1: Adverse Reactions Occurring >5% in Double-Blind Clinical Studies of Glyburide and Metformin Hydrochloride Used as Initial (20 Weeks) or Second-Line (14 Weeks) Therapy Number (%) of Patients Adverse Reaction Placebo N=161 Glyburide N=324 Metformin HCl N=312 Glyburide and Metformin Hydrochloride N=642 Diarrhea 6% 6% 21% 17% Headache 11% 11% 9% 9% Nausea/vomiting 6% 5% 12% 8% Abdominal pain 4% 3% 8% 7% Dizziness 4% 6% 4% 6% Hypoglycemia The incidence of reported symptoms of hypoglycemia (such as dizziness, shakiness, sweating, and hunger), in the initial therapy study of glyburide and metformin hydrochloride are summarized in Table 2. For patients with a baseline HbA1c between 8% and 11% treated with glyburide and metformin hydrochloride 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 glyburide and metformin hydrochloride experienced hypoglycemic symptoms. Gastrointestinal Reactions The incidence of gastrointestinal (GI) side effects (diarrhea, nausea/vomiting, and abdominal pain) in the glyburide and metformin hydrochloride initial therapy study are summarized in Table 2. Across all glyburide and metformin hydrochloride studies, GI symptoms were the most common adverse events with glyburide and metformin hydrochloride and were more frequent at higher dose levels. In controlled studies, <2% of patients discontinued glyburide and metformin hydrochloride therapy due to GI adverse events. Table 2: Hypoglycemia or Gastrointestinal Adverse Reactions in a Placebo and Active-Controlled Study of Glyburide and Metformin Hydrochloride as Initial Therapy (20 Weeks) Variable Placebo N=161 Glyburide Tablets N=160 Metformin HCl Tablets N=159 Glyburide and Metformin Hydrochloride 1.25 mg/250 mg Tablets N=158 Glyburide and Metformin Hydrochloride 2.5 mg/500 mg Tablets N=162 Number (%) of patients with symptoms of hypoglycemia 3% 21% 3% 11% 38% Number (%) of patients with gastrointestinal adverse events 24% 24% 43% 32% 38% 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. 6.2 Postmarketing Adverse Reactions The following adverse reactions have been identified during post-approval use of glyburide and metformin hydrochloride. 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. Hepatic: 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. Liver function abnormalities, including isolated transaminase elevations, have been reported. 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.

Warnings & Precautions

5 WARNINGS AND PRECAUTIONS Lactic Acidosis: See boxed warning. (5.1) Hypoglycemia: May be severe. Ensure proper patient selection, dosing, and instructions, particularly in at-risk populations (e.g., elderly, renally impaired) and when used with other anti-diabetic medications. (5.2) Potential Increased Risk of Cardiovascular Mortality with Sulfonylureas: Inform patient of risks, benefits and treatment alternatives. (5.3) Hemolytic anemia: Can occur if glucose 6-phosphate dehydrogenase (G6PD) deficient. Consider a non-sulfonylurea alternative. (5.4) Vitamin B 12 Deficiency: Metformin may lower vitamin B 12 levels. Measure hematological parameters annually and vitamin B 12 at 2 to 3 year intervals and manage any abnormalities. (5.5) 5.1 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 glyburide and metformin hydrochloride. In glyburide and metformin hydrochloride treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin HCl 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 glyburide and metformin hydrochloride tablets 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 glyburide and metformin hydrochloride, obtain an estimated glomerular filtration rate (eGFR). Glyburide and metformin hydrochloride is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2 [see CONTRAINDICATIONS (4)]. Initiation of glyburide and metformin hydrochloride is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m 2 . Obtain an eGFR at least annually in all patient taking glyburide and metformin hydrochloride. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. In patients taking glyburide and metformin hydrochloride whose eGFR falls below 45 mL/min/ 1.73 m 2 , assess the benefit and risk of continuing therapy. Drug interactions— The concomitant use of glyburide and metformin hydrochloride 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 [ see Drug Interactions (7) ] . 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 glyburide and metformin hydrochloride 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 m 2 ; 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 glyburide and metformin hydrochloride 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. Glyburide and metformin hydrochloride 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 glyburide and metformin hydrochloride. 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 glyburide and metformin hydrochloride. 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 glyburide and metformin hydrochloride in patients with clinical or laboratory evidence of hepatic disease. 5.2 Hypoglycemia All sulfonylurea drugs, including glyburide and metformin hydrochloride, are capable of producing severe hypoglycemia [see Adverse Reactions (6) ]. Concomitant use of glyburide and metformin hydrochloride with other anti-diabetic medication can increase the risk of hypoglycemia. A lower dose of glyburide and metformin hydrochloride may be required to minimize the risk of hypoglycemia when combining it with other anti-diabetic medications. Educate patients to recognize and manage hypoglycemia. When initiating and increasing glyburide and metformin hydrochloride in patients who may be predisposed to hypoglycemia (e.g., the elderly, patients with renal impairment, patients on other anti-diabetic medications) start with a lower dose. Debilitated or malnourished patients, and those with adrenal, pituitary, or hepatic impairment are particularly susceptible to the hypoglycemic action of anti-diabetic medications. Hypoglycemia is also more likely to occur when caloric intake is deficient, after severe or prolonged exercise, or when alcohol is ingested. The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. Early warning symptoms of hypoglycemia may be different or less pronounced in patients with autonomic neuropathy, the elderly, and in patients who are taking beta-adrenergic blocking medications or other sympatholytic agents. These situations may result in severe hypoglycemia before the patient is aware of the hypoglycemia. These impairments may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Severe hypoglycemia can lead to unconsciousness or convulsions and may result in temporary or permanent impairment of brain function or death. 5.3 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 study designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with type 2 diabetes mellitus. The study involved 823 patients who were randomly assigned to 1 of 4 treatment groups. UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams 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 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. 5.4 Hemolytic Anemia Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents, including glyburide and metformin hydrochloride, can lead to hemolytic anemia. Avoid use of glyburide and metformin hydrochloride in patients with G6PD deficiency. In postmarketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency. 5.5 Vitamin B12 Deficiency In clinical studies of 29-week duration with metformin HCl tablets, a decrease to subnormal levels of previously normal serum vitamin B 12 levels, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation. Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. Measure hematologic parameters on an annual basis and vitamin B 12 at 2 to 3 year intervals in patients on glyburide and metformin hydrochloride and manage any abnormalities [see Adverse Reactions (6.1) ]. 5.6 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with glyburide and metformin hydrochloride.

Contraindications

4 CONTRAINDICATIONS Glyburide and metformin hydrochloride tablets are contraindicated in patients with: Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) [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) ]. Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) (4, 5.1) Hypersensitivity to metformin or glyburide. (4) Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. (4) Concomitant administration of bosentan. (4, 7)

Pharmacokinetics

12.3 Pharmacokinetics Absorption Glyburide and Metformin Hydrochloride In bioavailability studies of glyburide and metformin hydrochloride 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 pharmacokinetics of metformin HCl component of glyburide and metformin hydrochloride was consistent with that of metformin HCl coadministered with glyburide. Effect of food : Following administration of a single glyburide and metformin hydrochloride 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 C max and a relatively small effect of food on the AUC of the glyburide component. The T max 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 effect of food on the pharmacokinetics of the metformin component of glyburide and metformin hydrochloride was indeterminate. However, food is known to decrease the extent of and slightly delay the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (C max ), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (T max ) 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. 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 glyburide and metformin hydrochloride 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 1,500 mg, and 850 mg to 2,550 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. 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 mcg/mL. 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. 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 4) 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 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 4); [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 C max 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 4); [see Dosage and Administration (2.3) and Warnings and Precautions (5.1) ] . Table 4: Select Mean (±SD) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin HCl Subject Groups: Metformin HCl Dose a (number of subjects) C max b ( mcg/mL) T max c ( hrs) Renal Clearance (mL/min) Healthy, nondiabetic adults: 500 mg SD d (24) 850 mg SD (74) e 850 mg t.i.d. for 19 doses f (9) 1.03 (±0.33) 1.60 (±0.38) 2.01 (±0.42) 2.75 (±0.81) 2.64 (±0.82) 1.79 (±0.94) 600 (±132) 552 (±139) 642 (±173) Adults with type 2 diabetes: 850 mg SD (23) 850 mg t.i.d. for 19 doses f (9) 1.48 (±0.5) 1.90 (±0.62) 3.32 (±1.08) 2.01 (±1.22) 491 (±138) 550 (±160) Elderly g , healthy nondiabetic adults: 850 mg SD (12) 2.45 (±0.70) 2.71 (±1.05) 412 (±98) Renal-impaired adults: 850 mg SD Mild (CL cr h 61 to 90 mL/min) (5) Moderate (CL cr 31 to 60 mL/min) (4) Severe (CL cr 10 to 30 mL/min) (6) 1.86 (±0.52) 4.12 (±1.83) 3.93 (±0.92) 3.20 (±0.45) 3.75 (±0.50) 4.01 (±1.10) 384 (±122) 108 (±57) 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 d SD=single dose e Combined results (average means) of 5 studies: mean age 32 years (range 23 to 59 years) f Kinetic study done following dose 19, given fasting g Elderly subjects, mean age 71 years (range 65 to 81 years) h CL cr =creatinine clearance normalized to body surface area of 1.73m 2 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). 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.

Frequently Asked Questions

1 INDICATIONS AND USAGE Glyburide and metformin hydrochloride tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Glyburide and metformin hydrochloride tablets are a combination of glyburide, a sulfonylurea, and metformin hydrochloride (HCl), a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. (1)

2 DOSAGE AND ADMINISTRATION Adult Dosage: Give glyburide and metformin hydrochloride tablets in divided doses, twice daily, with meals. (2.1) For patients not treated with either glyburide (or another sulfonylurea) or metformin HCl, initiate treatment with another formulation with a dose of 1.25 mg glyburide and 250 mg metformin HCl orally, once or twice daily with meals. (2.1) For patients not adequately controlled on either glyburide (or another sulfonylurea) or metformin HCl alone, the recommended starting dose is 2.5 mg/500 …

5 WARNINGS AND PRECAUTIONS Lactic Acidosis: See boxed warning. (5.1) Hypoglycemia: May be severe. Ensure proper patient selection, dosing, and instructions, particularly in at-risk populations (e.g., elderly, renally impaired) and when used with other anti-diabetic medications. (5.2) Potential Increased Risk of Cardiovascular Mortality with Sulfonylureas: Inform patient of risks, benefits and treatment alternatives. (5.3) Hemolytic anemia: Can occur if glucose 6-phosphate dehydrogenase (G6PD) deficient. Consider a non-sulfonylurea alternative. (5.4) Vitamin B 12 Deficiency: Metformin may lower vitamin B 12 levels. …

4 CONTRAINDICATIONS Glyburide and metformin hydrochloride tablets are contraindicated in patients with: Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) [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) ]. Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) (4, 5.1) Hypersensitivity to metformin or glyburide. (4) Acute or chronic metabolic acidosis, including diabetic ketoacidosis, …

Glyburide And Metformin Hydrochloride is a prescription medication. You will need a valid prescription from a licensed healthcare provider.

Similar Tablet Products

Tafenoquine Succinate

Topiramate

Polyethylene Glycol 3350

Adenosinum Ciclophosphoricum - Melatonin …

Demeclocycline

Nicotine Polacrilex

Browse all Tablet products →

References & Data Sources

• DailyMed — Glyburide And Metformin Hydrochloride drug label (National Library of Medicine)
• openFDA — Glyburide And Metformin Hydrochloride label data (U.S. Food & Drug Administration)
• RxNorm — RXCUI 861743 (NLM Normalized Drug Names)
• NDC Directory — Glyburide And Metformin Hydrochloride (FDA National Drug Code)

Medical Disclaimer

The information on this page is intended for educational purposes only and should not be used as a substitute for professional medical advice, diagnosis, or treatment.

Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition or medication.

Data sources: DailyMed (NLM), openFDA, MFDS