Glyburide and Metformin Hydrochloride
Tablet, Film Coated · Oral
Uses
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)
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 250mg 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/2000 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 250mg 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/2000 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.
Dosage forms and strengths
Glyburide and metformin hydrochloride tablets, USP are available as: 1.25 mg/250 mg Tablets: Yellow, capsule shaped, biconvex, film-coated tablet with ‘A’ debossed on one side and ‘46’ on the other side. 2.5 mg/500 mg Tablets: Light pink, capsule shaped, biconvex, film-coated tablet with ‘A’ debossed on one side and ‘47’ on the other side. 5 mg/500 mg Tablets: Yellow, capsule shaped, biconvex, film-coated tablet with ‘A’ debossed on one side and ‘48’ on the other side Tablets: 1.25 mg glyburide and 250 mg metformin HCl (3) Tablets: 2.5 mg glyburide and 500 mg metformin HCl (3) Tablets: 5 mg glyburide and 500 mg metformin HCl (3)
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)
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 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.
Side effects
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 diarrhea, headache, nausea/vomiting, abdominal pain, and dizziness. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharma Holdings, Inc. at 1-844-874-7464 or FDA at 1-800-FDA-1088 or 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 Adverse Reaction Number (%) of Patients 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.
Drug interactions
Table 3 presents clinically significant drug interactions with glyburide and metformin hydrochloride. Table 3: Clinically Significant Drug Interactions with Glyburide and Metformin Hydrochloride 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 glyburide and metformin hydrochloride 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 glyburide and metformin hydrochloride. 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 glyburide and metformin hydrochloride. Drugs that potentiate the hypoglycemic action of glyburide and metformin hydrochloride Clinical Impact: Certain drugs may potentiate the hypoglycemic action of sulfonylureas, one of the components of glyburide and metformin hydrochloride. 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. Colesevalam Clinical Impact: Concomitant administration may led to reduced glyburide absorption (AUC and Cmax: -32% and -47%, respectively). Intervention: Glyburide and metformin hydrochloride 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 glyburide and metformin hydrochloride observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving glyburide and metformin hydrochloride, 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. Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring. (7) Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin. Consider the benefits and risks of concomitant use. (7) Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake. (7) The hypoglycemic action of glyburide and metformin hydrochloride may be potentiated by certain drugs. (7) Concomitant administration of colesevalam may led to reduced glyburide absorption. (7)
Use in specific populations
Pregnancy: Glyburide and metformin hydrochloride should be discontinued at least two weeks before expected delivery. (8.1) Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. (8.3) Geriatric Use: Assess renal function more frequently. (8.5) Hepatic Impairment: Avoid use in patients with hepatic impairment. (8.7) 8.1 Pregnancy Risk Summary Available data from a small number of published studies and postmarketing experience with glyburide use in pregnancy over decades have not identified any drug associated risks for major birth defects, miscarriage, or adverse maternal outcomes. However, sulfonylureas (including glyburide) cross the placenta and have been associated with neonatal adverse reactions such as hypoglycemia. Therefore, glyburide and metformin hydrochloride should be discontinued at least two weeks before expected delivery [see Clinical Considerations ]. 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 evidence of harm to the fetus was observed when doses up to 500 times the maximum recommended human dose of 20 mg of glyburide, based on body surface area, were administered to rats and rabbits in reproduction studies. 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 3- and 6- times, respectively, a 2000 mg clinical dose, based on body surface area [see Data ]. The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes mellitus with an HbA1c >7 and has been reported to be as high as 20 to 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 to 4% and 15 to 20%, respectively. 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, and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Fetal/Neonatal Adverse Reactions Neonates of women with gestational diabetes who are treated with sulfonylureas during pregnancy may be at increased risk for neonatal intensive care admission and may develop respiratory distress, hypoglycemia, birth injury, and be large for gestational age. Prolonged severe hypoglycemia, lasting 4 to 10 days, has been reported in neonates born to mothers receiving a sulfonylurea at the time of delivery and has been reported with the use of agents with a prolonged half-life. Observe newborns for symptoms of hypoglycemia and respiratory distress and manage accordingly. Dose adjustments during pregnancy and the postpartum period Due to reports of prolonged severe hypoglycemia in neonates born to mothers receiving a sulfonylurea at the time of delivery, glyburide and metformin hydrochloride should be discontinued at least two weeks before expected delivery [see Fetal/Neonatal Adverse Reactions ]. 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 maximum recommended human dose of 20 mg of glyburide based on body surface area comparisons and revealed no evidence of harm to the fetus. 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 3 and 6 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. 8.2 Lactation Risk Summary Breastfed infants of lactating women using glyburide and metformin hydrochloride should be monitored for symptoms of hypoglycemia [see Clinical Considerations ]. Although glyburide was negligible in human milk in one small clinical lactation study; this result is not conclusive because of the limitations of the assay used in the study. There are no data on the effects of glyburide on milk production. 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 glyburide and metformin hydrochloride and any potential adverse effects on the breastfed child from glyburide and metformin hydrochloride or from the underlying maternal condition. Clinical Considerations Monitoring for adverse reactions Monitor breastfed infants for signs of hypoglycemia (e.g., jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, seizures).
Pregnancy
8.1 Pregnancy Risk Summary Available data from a small number of published studies and postmarketing experience with glyburide use in pregnancy over decades have not identified any drug associated risks for major birth defects, miscarriage, or adverse maternal outcomes. However, sulfonylureas (including glyburide) cross the placenta and have been associated with neonatal adverse reactions such as hypoglycemia. Therefore, glyburide and metformin hydrochloride should be discontinued at least two weeks before expected delivery [see Clinical Considerations ]. 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 evidence of harm to the fetus was observed when doses up to 500 times the maximum recommended human dose of 20 mg of glyburide, based on body surface area, were administered to rats and rabbits in reproduction studies. 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 3- and 6- times, respectively, a 2000 mg clinical dose, based on body surface area [see Data ]. The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes mellitus with an HbA1c >7 and has been reported to be as high as 20 to 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 to 4% and 15 to 20%, respectively. 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, and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Fetal/Neonatal Adverse Reactions Neonates of women with gestational diabetes who are treated with sulfonylureas during pregnancy may be at increased risk for neonatal intensive care admission and may develop respiratory distress, hypoglycemia, birth injury, and be large for gestational age. Prolonged severe hypoglycemia, lasting 4 to 10 days, has been reported in neonates born to mothers receiving a sulfonylurea at the time of delivery and has been reported with the use of agents with a prolonged half-life. Observe newborns for symptoms of hypoglycemia and respiratory distress and manage accordingly. Dose adjustments during pregnancy and the postpartum period Due to reports of prolonged severe hypoglycemia in neonates born to mothers receiving a sulfonylurea at the time of delivery, glyburide and metformin hydrochloride should be discontinued at least two weeks before expected delivery [see Fetal/Neonatal Adverse Reactions ]. 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 maximum recommended human dose of 20 mg of glyburide based on body surface area comparisons and revealed no evidence of harm to the fetus. 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 3 and 6 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.
Pediatric use
8.4 Pediatric Use Safety and effectiveness of glyburide and metformin hydrochloride have not been established in pediatric patients.
Geriatric use
8.5 Geriatric Use Of the 642 patients who received glyburide and metformin hydrochloride in double-blind clinical studies, 23.8% were 65 and older while 2.8% were 75 and older. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients are particularly susceptible to the hypoglycemic action of anti-diabetic agents. Hypoglycemia may be difficult to recognize in these patients. 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 hypoglycemia and lactic acidosis. Assess renal function more frequently in elderly patients [see Dosage and Administration (2) and Warnings and Precautions (5.1) ].
Overdosage
Glyburide Overdosage of sulfonylureas, including glyburide tablets, can produce hypoglycemia. Mild hypoglycemic symptoms, without loss of consciousness or neurological findings, should be treated with oral glucose. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment are medical emergencies requiring immediate treatment. The patient should be treated with glucagon or intravenous glucose. Patients should be closely monitored for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery. Clearance of glyburide from plasma may be prolonged in persons with liver disease. Because of the extensive protein binding of glyburide, dialysis is unlikely to be of benefit. 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.
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 to off-white crystalline compound with molecular formula of C 23 H 28 ClN 3 O 5 S and a molecular weight of 494.01. 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 to off-white crystalline compound with molecular formula of C 4 H 12 ClN 5 (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: Glyburide and metformin hydrochloride tablets, USP are available in film-coated containing 1.25 mg glyburide USP with 250 mg metformin hydrochloride USP, 2.5 mg glyburide USP with 500 mg metformin hydrochloride USP, and 5 mg glyburide USP with 500 mg metformin hydrochloride USP. In addition, each film-coated tablet contains the following inactive ingredients: microcrystalline cellulose, croscarmellose sodium, povidone, magnesium stearate, hypromellose, propylene glycol, polysorbate 80, talc, titanium dioxide and FD&C Yellow#6 aluminum lake. The 1.25 mg/250 mg and 5 mg/500 mg strengths also contain D&C Yellow#10 aluminum lake; The 2.5 mg/500 mg strength also contains FD&C Red#40 aluminum lake. Meets USP Dissolution Test 2 Glyburide Chemical Structure Metformin Hydrochloride Chemical Structure
Mechanism of action
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.
How supplied
Glyburide and Metformin Hydrochloride Tablets USP, 1.25 mg/250 mg: Yellow, capsule shaped, biconvex, film-coated tablet with ‘A’ debossed on one side and ‘46’ on the other side. Bottles of 100 NDC 57237-023-01 Bottles of 500 NDC 57237-023-05 Glyburide and Metformin Hydrochloride Tablets USP, 2.5 mg/500 mg: Light pink, capsule shaped, biconvex, film-coated tablet with ‘A’ debossed on one side and ‘47’ on the other side. Bottles of 100 NDC 57237-024-01 Bottles of 500 NDC 57237-024-05 Glyburide and Metformin Hydrochloride Tablets USP, 5 mg/500 mg: Yellow, capsule shaped, biconvex, film-coated tablet with ‘A’ debossed on one side and ‘48’ on the other side. Bottles of 100 NDC 57237-025-01 Bottles of 500 NDC 57237-025-05 Store at 20° to 25°C (68º to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Dispense in light-resistant containers.
Patient information
Advise the patient to read the FDA-approved patient labeling (Patient Information). Lactic Acidosis: Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development. Advise patients to discontinue glyburide and metformin hydrochloride 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 glyburide and metformin hydrochloride. Instruct patients to inform their doctor that they are taking glyburide and metformin hydrochloride prior to any surgical or radiological procedure, as temporary discontinuation may be required [see Warnings and Precautions (5.1) ]. Hypoglycemia: Inform patients that hypoglycemia may occur when taking glyburide and metformin hydrochloride. 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. Inform patients of the potential risks and benefits of glyburide and of alternative modes of therapy [see Warnings and Precautions (5.3) ]. Vitamin B 12 Deficiency: Inform patients about importance of regular hematological testing while receiving glyburide and metformin hydrochloride [see Warnings and Precautions (5.5) ]. Females of Reproductive Age: Inform females that treatment with glyburide and metformin hydrochloride may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy [see Use in Specific Populations (8.3) ]. Distributed by: Rising Pharma Holdings, Inc. East Brunswick, NJ 08816 Made in India Code: TS/DRUGS/19/1993 Trademarks are the property of their respective owners. Revised: 07/2026
Label text from the FDA structured product label by Rising Pharma Holdings, Inc. (revised Jul 3, 2026). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Glyburide in 21 products
- Metformin Hydrochloride in 21 products
Glyburide and Metformin Hydrochloride NDC products (21)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 50090-2031 | Glyburide 2.5 mg/1; Metformin Hydrochloride 500 mg/1 Tablet, Film Coated | A-S Medication Solutions | ANDA |
| 50090-2030 | Glyburide 5 mg/1; Metformin Hydrochloride 500 mg/1 Tablet, Film Coated | A-S Medication Solutions | ANDA |
| 65862-081 | Glyburide 2.5 mg/1; Metformin Hydrochloride 500 mg/1 Tablet, Film Coated | Aurobindo Pharma Limited | ANDA |
| 65862-082 | Glyburide 5 mg/1; Metformin Hydrochloride 500 mg/1 Tablet, Film Coated | Aurobindo Pharma Limited | ANDA |
| 65862-080 | Glyburide 1.25 mg/1; Metformin Hydrochloride 250 mg/1 Tablet, Film Coated | Aurobindo Pharma Limited | ANDA |
| 71335-0360 | Glyburide 5 mg/1; Metformin Hydrochloride 500 mg/1 Tablet, Film Coated | Bryant Ranch Prepack | ANDA |
| 71335-0967 | Glyburide 5 mg/1; Metformin Hydrochloride 500 mg/1 Tablet, Film Coated | Bryant Ranch Prepack | ANDA |
| 51655-942 | Glyburide 5 mg/1; Metformin Hydrochloride 500 mg/1 Tablet, Film Coated | Northwind Health Company, LLC | ANDA |
| 68071-4718 | Glyburide 5 mg/1; Metformin Hydrochloride 500 mg/1 Tablet, Film Coated | NuCare Pharmaceuticals,Inc. | ANDA |
| 68788-7180 | Glyburide 2.5 mg/1; Metformin Hydrochloride 500 mg/1 Tablet, Film Coated | Preferred Pharmaceuticals Inc. | ANDA |
| 68788-8341 | Glyburide 5 mg/1; Metformin Hydrochloride 500 mg/1 Tablet, Film Coated | Preferred Pharmaceuticals Inc. | ANDA |
| 68788-8634 | Glyburide 5 mg/1; Metformin Hydrochloride 500 mg/1 Tablet, Film Coated | Preferred Pharmaceuticals Inc. | ANDA |
| 57237-025 | Glyburide 5 mg/1; Metformin Hydrochloride 500 mg/1 Tablet, Film Coated | Rising Pharma Holdings, Inc. | ANDA |
| 57237-024 | Glyburide 2.5 mg/1; Metformin Hydrochloride 500 mg/1 Tablet, Film Coated | Rising Pharma Holdings, Inc. | ANDA |
| 57237-023 | Glyburide 1.25 mg/1; Metformin Hydrochloride 250 mg/1 Tablet, Film Coated | Rising Pharma Holdings, Inc. | ANDA |
| 65841-824 | Glyburide 1.25 mg/1; Metformin Hydrochloride 250 mg/1 Tablet | Zydus Lifesciences Limited | ANDA |
| 65841-825 | Glyburide 2.5 mg/1; Metformin Hydrochloride 500 mg/1 Tablet | Zydus Lifesciences Limited | ANDA |
| 65841-826 | Glyburide 5 mg/1; Metformin Hydrochloride 500 mg/1 Tablet | Zydus Lifesciences Limited | ANDA |
| 68382-653 | Glyburide 1.25 mg/1; Metformin Hydrochloride 250 mg/1 Tablet | Zydus Pharmaceuticals (USA) Inc. | ANDA |
| 68382-654 | Glyburide 2.5 mg/1; Metformin Hydrochloride 500 mg/1 Tablet | Zydus Pharmaceuticals (USA) Inc. | ANDA |
| 68382-655 | Glyburide 5 mg/1; Metformin Hydrochloride 500 mg/1 Tablet | Zydus Pharmaceuticals (USA) Inc. | ANDA |
Frequently asked questions
What is Glyburide and Metformin Hydrochloride used for?
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…
What are the side effects of Glyburide and Metformin Hydrochloride?
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%)… See the full label for the complete list.
Who makes Glyburide and Metformin Hydrochloride?
Glyburide and Metformin Hydrochloride is listed by 9 labelers in the FDA NDC directory, including A-S Medication Solutions, Aurobindo Pharma Limited, Bryant Ranch Prepack, Northwind Health Company, LLC.