Glyburide and Metformin Hydrochloride

Boxed Warning 03/2026

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)

DOSAGE AND ADMINISTRATION General Considerations Dosage of glyburide and metformin hydrochloride tablets must be individualized on the basis of both effectiveness and tolerance while not exceeding the maximum recommended daily dose of 20 mg glyburide/2000 mg metformin. Glyburide and metformin hydrochloride tablets should be given with meals and should be initiated at a low dose, with gradual dose escalation as described below, in order to avoid hypoglycemia (largely due to glyburide), reduce GI side effects (largely due to metformin), and permit determination of the minimum effective dose for adequate control of blood glucose for the individual patient. With initial treatment and during dose titration, appropriate blood glucose monitoring should be used to determine the therapeutic response to glyburide and metformin hydrochloride tablets and to identify the minimum effective dose for the patient. Thereafter, HbA 1c should be measured at intervals of approximately 3 months to assess the effectiveness of therapy. The therapeutic goal in all patients with type 2 diabetes is to decrease FPG, PPG, and HbA 1c to normal or as near normal as possible. Ideally, the response to therapy should be evaluated using HbA 1c (glycosylated hemoglobin), which is a better indicator of long-term glycemic control than FPG alone. No studies have been performed specifically examining the safety and efficacy of switching to glyburide and metformin hydrochloride tablets therapy in patients taking concomitant glyburide (or other sulfonylurea) plus metformin. Changes in glycemic control may occur in such patients, with either hyperglycemia or hypoglycemia possible. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring. In Patients with Inadequate Glycemic Control on Diet and Exercise Recommended starting dose: 1.25 mg glyburide and 250 mg metformin hydrochloride once or twice daily with meals. For patients with type 2 diabetes whose hyperglycemia cannot be satisfactorily managed with diet and exercise alone, the recommended starting dose is 1.25 mg glyburide and 250 mg metformin hydrochloride once a day with a meal. As initial therapy in patients with baseline HbA 1c >9% or an FPG >200 mg/dL, a starting dose of 1.25 mg glyburide and 250 mg metformin hydrochloride twice daily with the morning and evening meals may be used. Dosage increases should be made in increments of 1.25 mg glyburide and 250 mg metformin hydrochloride per day every 2 weeks up to the minimum effective dose necessary to achieve adequate control of blood glucose. In clinical trials of glyburide and metformin hydrochloride tablets as initial therapy, there was no experience with total daily doses >10 mg/2000 mg per day. Glyburide and metformin hydrochloride tablets 5 mg/500 mg should not be used as initial therapy due to an increased risk of hypoglycemia. Glyburide and Metformin Hydrochloride Tablets Use in Patients with Inadequate Glycemic Control on a Sulfonylurea and/or Metformin Recommended starting dose: 2.5 mg/500 mg or 5 mg/500 mg twice daily with meals. For patients not adequately controlled on either glyburide (or another sulfonylurea) or metformin alone, the recommended starting dose of glyburide and metformin hydrochloride tablets is 2.5 mg/500 mg or 5 mg/500 mg twice daily with the morning and evening meals. In order to avoid hypoglycemia, the starting dose of glyburide and metformin hydrochloride tablets should not exceed the daily doses of glyburide or metformin already being taken. The daily dose should be titrated in increments of no more than 5 mg/500 mg up to the minimum effective dose to achieve adequate control of blood glucose or to a maximum dose of 20 mg/2000 mg per day. For patients previously treated with combination therapy of glyburide (or another sulfonylurea) plus metformin, if switched to glyburide and metformin hydrochloride tablets, the starting dose should not exceed the daily dose of glyburide (or equivalent …

3 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)

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)

ADVERSE REACTIONS Glyburide and Metformin Hydrochloride In double-blind clinical trials involving glyburide and metformin hydrochloride as initial therapy or as second-line therapy, a total of 642 patients received glyburide and metformin hydrochloride, 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 glyburide and metformin hydrochloride (all strengths) as initial therapy and second-line therapy are listed in Table 6 . Table 6: Most Common Clinical Adverse Events (>5%) in Double-Blind Clinical Studies of Glyburide and Metformin Hydrochloride Used as Initial or Second-Line Therapy Adverse Event Number (%) of Patients Placebo N=161 Glyburide N=324 Metformin N=312 Glyburide and Metformin Hydrochloride 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) 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) 44 (6.9) Dizziness 7 (4.3) 18 (5.6) 12 (3.8) 35 (5.5) In a controlled clinical trial of rosiglitazone versus placebo in patients treated with glyburide and metformin hydrochloride (n=365), 181 patients received glyburide and metformin hydrochloride with rosiglitazone and 184 received glyburide and metformin hydrochloride with placebo. Edema was reported in 7.7% (14/181) of patients treated with rosiglitazone compared to 2.2% (4/184) of patients treated with placebo. A mean weight gain of 3 kg was observed in rosiglitazone-treated patients. Disulfiram-like reactions have very rarely been reported in patients treated with glyburide tablets. Hypoglycemia In controlled clinical trials of glyburide and metformin hydrochloride 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 glyburide and metformin hydrochloride are summarized in Table 7 . The frequency of hypoglycemic symptoms in patients treated with glyburide and metformin hydrochloride 1.25 mg/250 mg was highest in patients with a baseline HbA 1c 8%. For patients with a baseline HbA 1c 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. When rosiglitazone was added to glyburide and metformin hydrochloride therapy, 22% of patients reported 1 or more fingerstick glucose measurements ≤50 mg/dL compared to 3.3% of placebo-treated patients. All hypoglycemic events were managed by the patients and only 1 patient discontinued for hypoglycemia. (See PRECAUTIONS: General: Addition of Thiazolidinediones to Glyburide and Metformin Hydrochloride Therapy . ) Gastrointestinal Reactions The incidence of gastrointestinal (GI) side effects (diarrhea, nausea/vomiting, and abdominal pain) in the initial therapy trial are summarized in Table 7 . Across all glyburide and metformin hydrochloride trials, GI symptoms were the most common adverse events with glyburide and metformin hydrochloride and were more frequent at higher dose levels. In controlled trials, <2% of patients discontinued glyburide and metformin hydrochloride therapy due to GI adverse events. Table 7: Treatment Emergent Symptoms of Hypoglycemia or Gastrointestinal Adverse Events in a Placebo- and Active-Controlled Trial of Glyburide and Metformin Hydrochloride as Initial Therapy Variable Placebo N=161 Glyburide Tablets N=160 Metformin Tablets N=159 Glyburide and Metformin Hydrochloride 1.25 mg/250 mg Tablets N=158 Glyburi …

Drug Interactions Glyburide and Metformin Hydrochloride Certain drugs tend to produce hyperglycemia and may lead to loss of blood glucose control. These drugs include thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving glyburide and metformin hydrochloride, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving glyburide and metformin hydrochloride, the patient should be observed closely for hypoglycemia. Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid as compared to sulfonylureas, which are extensively bound to serum proteins. Glyburide The hypoglycemic action of sulfonylureas may be potentiated by certain drugs, including nonsteroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta-adrenergic blocking agents. When such drugs are administered to a patient receiving glyburide and metformin hydrochloride, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving glyburide and metformin hydrochloride, the patient should be observed closely for loss of blood glucose control. An increased risk of liver enzyme elevations was observed in patients receiving glyburide concomitantly with bosentan. Therefore concomitant administration of glyburide and metformin hydrochloride and bosentan is contraindicated. A possible interaction between glyburide and ciprofloxacin, a fluoroquinolone antibiotic, has been reported, resulting in a potentiation of the hypoglycemic action of glyburide. The mechanism for this interaction is not known. A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical, or vaginal preparations of miconazole is not known. Colesevelam: Concomitant administration of colesevelam and glyburide resulted in reductions in glyburide AUC and C max of 32% and 47%, respectively. The reductions in glyburide AUC and C max were 20% and 15%, respectively, when administered 1 hour before, and not significantly changed (−7% and 4%, respectively) when administered 4 hours before colesevelam. Metformin Hydrochloride Furosemide A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration. Furosemide increased the metformin plasma and blood C max by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the C max and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when coadministered chronically. Nifedipine A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration of nifedipine increased plasma metformin C max and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. T max and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine. Drugs that reduce metformin clearance Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transport-2 [OCT2] / …

8 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 establis …

Mechanism of Action Glyburide and metformin hydrochloride tablets combine 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 hydrochloride is an antihyperglycemic agent that improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin hydrochloride decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

DESCRIPTION Glyburide and metformin hydrochloride tablets, USP contain 2 oral antihyperglycemic drugs used in the management of type 2 diabetes, glyburide USP and metformin hydrochloride USP. Glyburide USP 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 USP is a white to off-white crystalline compound. The structural formula is represented below. Metformin hydrochloride USP is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride ( N , N- dimethylimidodicarbonimidic diamide monohydrochloride) is not chemically or pharmacologically related to sulfonylureas, thiazolidinediones, or α-glucosidase inhibitors. It is a white to off-white crystalline compound. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula is as shown: Glyburide and metformin hydrochloride tablets, USP are available for oral administration 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 Chemical Structure

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 Hydrochloride Overdose of metformin hydrochloride has occurred, including ingestion of amounts >50 g. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see WARNINGS ). Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

16 HOW SUPPLIED/STORAGE AND HANDLING 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 30 NDC 65862-080-30 Bottles of 100 NDC 65862-080-01 Bottles of 500 NDC 65862-080-05 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 30 NDC 65862-081-30 Bottles of 100 NDC 65862-081-01 Bottles of 500 NDC 65862-081-05 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 30 NDC 65862-082-30 Bottles of 100 NDC 65862-082-01 Bottles of 500 NDC 65862-082-05 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.