Glyburide and metformin hydrochloride

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.

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)

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

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.

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)

10 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.

7 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 C max : -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)

12 CLINICAL PHARMACOLOGY 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. 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.

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.

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.

20221116

5

3 DOSAGE FORMS AND STRENGTHS Glyburide and metformin hydrochloride tablets, USP are available as: Tablets: Glyburide, USP 1.25 mg and metformin hydrochloride, USP 250 mg white to off-white colored, capsule shaped, biconvex coated tablets, debossed with "653" on one side and plain on the other side Tablets: Glyburide, USP 2.5 mg and metformin hydrochloride, USP 500 mg tan to scarlet yellow colored, capsule shaped, biconvex coated tablets debossed with "654" on one side and plain on the other side Tablets: Glyburide, USP 5 mg and metformin hydrochloride, USP 500 mg are pale yellow colored, capsule shaped, biconvex coated tablets, debossed with "655" on one side and plain on the other side Tablets: 1.25 mg glyburide and 250 mg metformin hydrochloride (3) Tablets: 2.5 mg glyburide and 500 mg metformin hydrochloride (3) Tablets: 5 mg glyburide and 500 mg metformin hydrochloride (3)

glyburide and metformin hydrochloride glyburide and metformin hydrochloride GLYBURIDE GLYBURIDE METFORMIN HYDROCHLORIDE METFORMIN CALCIUM CARBONATE CELLULOSE, MICROCRYSTALLINE CROSCARMELLOSE SODIUM HYPROMELLOSE 2910 (6 MPA.S) LACTOSE MONOHYDRATE MAGNESIUM STEARATE POLYETHYLENE GLYCOL 6000 POVIDONE K30 TALC TITANIUM DIOXIDE white to off-white 653 glyburide and metformin hydrochloride glyburide and metformin hydrochloride GLYBURIDE GLYBURIDE METFORMIN HYDROCHLORIDE METFORMIN CALCIUM CARBONATE CELLULOSE, MICROCRYSTALLINE CROSCARMELLOSE SODIUM FD&C BLUE NO. 2 FD&C YELLOW NO. 5 FD&C YELLOW NO. 6 HYPROMELLOSE 2910 (15 MPA.S) LACTOSE MONOHYDRATE MAGNESIUM STEARATE POLYETHYLENE GLYCOL 4000 POVIDONE K30 TITANIUM DIOXIDE tan to scarlet yellow 654 glyburide and metformin hydrochloride glyburide and metformin hydrochloride GLYBURIDE GLYBURIDE METFORMIN HYDROCHLORIDE METFORMIN CALCIUM CARBONATE CELLULOSE, MICROCRYSTALLINE CROSCARMELLOSE SODIUM FERRIC OXIDE RED FERRIC OXIDE YELLOW FERROSOFERRIC OXIDE HYPROMELLOSE 2910 (15 MPA.S) LACTOSE MONOHYDRATE MAGNESIUM STEARATE POLYETHYLENE GLYCOL 4000 POVIDONE K30 TITANIUM DIOXIDE pale yellow 655

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No animal studies have been conducted with the combined products in glyburide and metformin hydrochloride. The following data are based on findings in studies performed with the individual products. Glyburide Studies in rats with glyburide alone at doses up to 300 mg/kg/day (approximately 145 times the maximum recommended human daily dose of 20 mg for the glyburide component of glyburide and metformin hydrochloride based on body surface area comparisons) for 18 months revealed no carcinogenic effects. In a 2-year oncogenicity study of glyburide in mice, there was no evidence of treatment-related tumors. There was no evidence of mutagenic potential of glyburide alone in the following in vitro tests: Salmonella microsome test (Ames test) and in the DNA damage/alkaline elution assay. No evidence of impaired fertility was observed when doses up to 500 times the maximum recommended human dose of 20 mg of glyburide, based on body surface area comparisons, were administered to rats in reproduction studies. Metformin Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1,500 mg/kg/day, respectively. These doses are both approximately 4 times the maximum recommendation human daily dose of 2,000 mg on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day. There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test ( S. typhimurium ), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative. Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose of 2,000 mg based on body surface area comparisons.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No animal studies have been conducted with the combined products in glyburide and metformin hydrochloride. The following data are based on findings in studies performed with the individual products. Glyburide Studies in rats with glyburide alone at doses up to 300 mg/kg/day (approximately 145 times the maximum recommended human daily dose of 20 mg for the glyburide component of glyburide and metformin hydrochloride based on body surface area comparisons) for 18 months revealed no carcinogenic effects. In a 2-year oncogenicity study of glyburide in mice, there was no evidence of treatment-related tumors. There was no evidence of mutagenic potential of glyburide alone in the following in vitro tests: Salmonella microsome test (Ames test) and in the DNA damage/alkaline elution assay. No evidence of impaired fertility was observed when doses up to 500 times the maximum recommended human dose of 20 mg of glyburide, based on body surface area comparisons, were administered to rats in reproduction studies. Metformin Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1,500 mg/kg/day, respectively. These doses are both approximately 4 times the maximum recommendation human daily dose of 2,000 mg on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day. There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test ( S. typhimurium ), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative. Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose of 2,000 mg based on body surface area comparisons.

ANDA206748

Glyburide and metformin hydrochloride

glyburide and metformin hydrochloride

68382-653

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL NDC 68382-653-01 in bottles of 100 tablets Glyburide and Metformin Hydrochloride Tablets USP, 1.25 mg/250 mg 100 Tablets Rx only Zydus NDC 68382-654-01 in bottles of 100 tablets Glyburide and Metformin Hydrochloride Tablets USP, 2.5 mg/500 mg 100 Tablets Rx only Zydus NDC 68382-655-01 in bottles of 100 tablets Glyburide and Metformin Hydrochloride Tablets USP, 5 mg/500 mg 100 Tablets Rx only Zydus figure figure figure

17 PATIENT COUNSELING 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 tablets 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 tablets. Instruct patients to inform their doctor that they are taking glyburide and metformin hydrochloride tablets 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 tablets. 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 tablets [see Warnings and Precautions (5.5) ]. Females of Reproductive Age : Inform females that treatment with glyburide and metformin hydrochloride tablets may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy [see Use in Specific Populations (8.3) ]. Manufactured by: Cadila Healthcare Ltd. Baddi, India Distributed by: Zydus Pharmaceuticals (USA) Inc. Pennington, NJ 08534 Revision: 05/2020 PATIENT INFORMATION Glyburide and Metformin Hydrochloride Tablets USP, for oral use (glye' bure ide and met for' min hye' droe klor' ide) What is the most important information I should know about glyburide and metformin hydrochloride tablets? Glyburide and metformin hydrochloride tablets can cause serious side effects, including: Lactic Acidosis. Metformin hydrochloride, a medicine in glyburide and metformin hydrochloride tablets, can cause a rare, but serious, side effect called lactic acidosis (a build-up of lactic acid in the blood) that can cause death. Lactic acidosis is a medical emergency and must be treated in a hospital. Stop taking glyburide and metformin hydrochloride tablets and call your healthcare provider right away if you get any of the following symptoms of lactic acidosis: feel very weak and tired have unusual sleepiness or sleep longer than usual have unusual (not normal) muscle pain feel cold, especially in your arms and legs have trouble breathing feel dizzy or lightheaded have unexplained stomach or intestinal problems with nausea and vomiting, or diarrhea have a slow or irregular heartbeat You have a higher chance of getting lactic acidosis if you: have severe kidney problems. "See "Do not take glyburide and metformin hydrochloride tablets if you:" have liver problems. drink a lot of alcohol (very often or short-term "binge" drinking). get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever, vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise and do not drink enough fluids. have certain x-ray tests with injectable dyes or contrast agents. have surgery or other procedures for which you need to restrict the amount of food and liquid you eat and drink. have congestive heart failure. have a heart attack, severe infection, or stroke. are 65 years of age or older. Tell your healthcare provider if you have any of the problems in the list above. Tell your healthcare provider that you are taking glyburide and metformin hydrochloride tablets before you have surgery or x-ray tests. Your healthcare provider may need to stop glyburide and metformin hydrochloride tablets for a while if you have surgery or certain x-ray tests. Glyburide and metformin hydrochloride tablets can have other serious side effects. See "What are the possible side effects of glyburide and metformin hydrochloride tablets What is glyburide and metformin hydrochloride tablets? Glyburide and metformin hydrochloride tablets are a prescription medicine that contains glyburide (sulfonylurea) and metformin hydrochloride. Glyburide and metformin hydrochloride tablets are used with diet and exercise to help control high blood sugar (hyperglycemia) in adults with type 2 diabetes. It is not known if glyburide and metformin hydrochloride tablets are safe and effective in children under 18 years of age. Do not take glyburide and metformin hydrochloride tablets if you: have severe kidney problems. are allergic to metformin hydrochloride, glyburide or any of the ingredients in glyburide and metformin hydrochloride tablets. See the end of this Patient Information leaflet for a complete list of ingredients in glyburide and metformin hydrochloride tablets. have a condition called metabolic acidosis, including diabetic ketoacidosis (high levels of certain acids called "ketones" in your blood or urine). take bosentan. Before taking glyburide and metformin hydrochloride tablets tell your healthcare provider about all medical conditions, including if you: have a history or risk for diabetic ketoacidosis. See "Do not take glyburide and metformin hydrochloride tablets if you:" have kidney problems. have liver problems. have heart problems, including congestive heart failure. are 65 year of age or older. drink alcohol very often, or drink a lot of alcohol in short-term "binge" drinking. have or any members of your family have glucose-6-phosphate dehydrogenase (G6PD) deficiency. are taking insulin or another sulfonylurea medicine. are pregnant or plan to become pregnant. It is not known if glyburide and metformin hydrochloride tablets will harm your unborn baby. You should not take glyburide and metformin hydrochloride tablets during the last 2 weeks of your pregnancy. If you are pregnant, talk with your healthcare provider about the best way to control your blood sugar while you are pregnant. are a woman who has not gone through menopause (premenopausal) who does not have periods regularly or at all. Glyburide and metformin hydrochloride tablets can cause the release of an egg from an ovary in a woman (ovulation). This can increase your chance of getting pregnant. are breastfeeding or plan to breastfeed. It is not known if glyburide one of the medicines in glyburide and metformin hydrochloride tablets passes into your breast milk. Metformin the other medicine in glyburide and metformin hydrochloride tablets can pass into your breastmilk. Talk with your healthcare provider about the best way to feed your baby while you take glyburide and metformin hydrochloride tablets. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. Glyburide and metformin hydrochloride tablets may affect the way other medicines work, and other medicines may affect how glyburide and metformin hydrochloride tablets work. How should I take glyburide and metformin hydrochloride tablets? Take glyburide and metformin hydrochloride tablets exactly as your healthcare provider tells you. Glyburide and metformin hydrochloride tablets should be taken 2 times each day with meals to help decrease an upset stomach side effect and avoid hypoglycemia. If you are taking colesevelam and glyburide and metformin hydrochloride tablets, take your glyburide and metformin hydrochloride tablets at least 4 hours before taking your colesevelam. Your healthcare provider should do blood tests to check how well your kidneys are working before and during your treatment with glyburide and metformin hydrochloride tablets. Your healthcare provider will check your diabetes with regular blood tests, including your blood sugar levels and your hemoglobin A 1c . Low blood sugar (hypoglycemia) can happen more often when glyburide and metformin hydrochloride tablets are taken with certain other diabetes medicines. Talk to your healthcare provider about how to prevent, recognize, and manage low blood sugar. See "What are the possible side effects of glyburide and metformin hydrochloride tablets?" Check your blood sugar as your healthcare provider tells you to. If you take too many glyburide and metformin hydrochloride tablets, call your healthcare provider or go to the nearest hospital emergency room right away. What should I avoid while taking glyburide and metformin hydrochloride tablets? Do not drink a lot of alcoholic drinks while taking glyburide and metformin hydrochloride tablets. This means you should not binge drink for short periods, and you should not drink a lot of alcohol on a regular basis. Alcohol can increase the chance of getting lactic acidosis. Do not drive, operate machinery, or do other dangerous activities until you know how glyburide and metformin hydrochloride tablets affect you. What are the possible side effects of glyburide and metformin hydrochloride tablets? Glyburide and metformin hydrochloride tablets can cause serious side effects, including: See "What is the most important information I should know about glyburide and metformin hydrochloride tablets?" low blood sugar (hypoglycemia). Low blood sugar is a serious, but common side effect of glyburide and metformin hydrochloride tablets. If you take glyburide and metformin hydrochloride tablets with another medicine that can cause low blood sugar, such as insulin, you have a higher risk of getting low blood sugar. The dose of insulin or other diabetic medicines may need to be lowered while you take glyburide and metformin hydrochloride tablets. Signs and symptoms of low blood sugar may include: o headache o hunger o dizziness o drowsiness o fast heartbeat o sweating o weakness o confusion o blurred vision o irritability o shaking or feeling jittery o anxiety o slurred speech o mood changes increased risk of cardiovascular deaths. Taking oral hypoglycemic medicines like glyburide and metformin hydrochloride tablets to treat diabetes have increased the risk of death from heart disease or stroke compared to treating diabetes with diet alone or diet and insulin. hemolytic anemia. People with G6PD deficiency who take glyburide and metformin hydrochloride tablets may develop hemolytic anemia (fast breakdown of red blood cells). low vitamin B 12 (vitamin B 12 deficiency). Using glyburide and metformin hydrochloride tablets may cause a decrease in the amount of vitamin B 12 in your blood, especially if you have had low vitamin B 12 levels before. Your healthcare provider may do blood tests to check your vitamin B 12 levels. The most common side effects of glyburide and metformin hydrochloride tablets include: o diarrhea o vomiting o headache o stomach pain o nausea o dizziness These are not all the possible side effects of glyburide and metformin hydrochloride tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store glyburide and metformin hydrochloride tablets ? Store glyburide and metformin hydrochloride tablets at room temperature between 68°F to 77°F (20°C to 25°C). Keep glyburide and metformin hydrochloride tablets and all medicines out of the reach of children. General information about the safe and effective use glyburide and metformin hydrochloride tablets . Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use glyburide and metformin hydrochloride tablets for a condition for which they was not prescribed. Do not give glyburide and metformin hydrochloride tablets to other people, even if they have the same symptoms you have. They may harm them. You can ask your pharmacist or healthcare provider for information about glyburide and metformin hydrochloride tablets that is written for health professionals. What are the ingredients in glyburide and metformin hydrochloride tablets ? Active ingredients: Glyburide, USP and Metformin hydrochloride, USP. 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. Manufactured by: Cadila Healthcare Ltd. Baddi, India Distributed by: Zydus Pharmaceuticals (USA) Inc. Pennington, NJ 08534 This Patient Package Insert has been approved by the U.S. Food and Drug Administration. Revision: 05/2020

14 CLINICAL STUDIES Patients with Inadequate Glycemic Control on Diet and Exercise Alone In a 20-week, double-blind, placebo-controlled, multicenter U.S. clinical study, involving 806 drug-naive patients with type 2 diabetes, whose hyperglycemia was not adequately controlled with dietary management alone (baseline fasting plasma glucose [FPG] below 240 mg/dL, baseline hemoglobin A 1c [HbA1c] between 7% and 11%), were randomized to receive initial therapy with placebo, 2.5 mg glyburide, 500 mg metformin HCl, glyburide and metformin hydrochloride 1.25 mg/250 mg, or glyburide and metformin hydrochloride 2.5 mg/500 mg. After 4 weeks, the dose was progressively increased to a maximum of 4 tablets daily as needed to reach a target FPG of 126 mg/dL. Study data at 20 weeks are summarized in Table 5 . Table 5: Mean Change in Hemoglobin A1c and Fasting Plasma Glucose in Patients Receiving Placebo, Glyburide, Metformin HCl or Glyburide and Metformin Hydrochloride at 20 Weeks Placebo Glyburide 2.5 mg tablets Metformin HCl 500 mg tablets Glyburide and Metformin Hydrochloride 1.25 mg/250 mg tablets Glyburide and Metformin Hydrochloride 2.5 mg/500 mg tablets Mean Final Dose 0 mg 5.3 mg 1,317 mg 2.78 mg/557 mg 4.1 mg/824 mg Hemoglobin A 1c N=147 N=142 N=141 N=149 N=152 Baseline Mean (%) 8.14 8.14 8.23 8.22 8.20 Mean Change from Baseline −0.21 −1.24 −1.03 −1.48 −1.53 Difference from Placebo −1.02 −0.82 −1.26 a −1.31 a Difference from Glyburide −0.24 b −0.29 b Difference from Metformin −0.44 b −0.49 b Fasting Plasma Glucose N=159 N=158 N=156 N=153 N=154 Baseline Mean FPG (mg/dL) 177.2 178.9 175.1 178 176.6 Mean Change from Baseline 4.6 −35.7 −21.2 −41.5 −40.1 Difference from Placebo −40.3 −25.8 −46.1 a −44.7 a Difference from Glyburide −5.8 c −4.5 c Difference from Metformin −20.3 c −18.9 c Final HbA1c Distribution (%) N=147 N=142 N=141 N=149 N=152 <7% 19.7% 59.9% 50.4% 66.4% 71.7% ≥7% and <8% 37.4% 26.1% 29.8% 25.5% 19.1% ≥8% 42.9% 14.1% 19.9% 8.1% 9.2% a p<0.001 b p<0.05 c p=NS Mean baseline body weight was 87 kg, 87 kg, 89 kg, 89 kg and 87 kg in the placebo, glyburide 2.5mg, metformin 500mg, glyburide and metformin hydrochloride 1.25 mg/250 mg and 2.5 mg/500 mg arms, respectively. Mean change in body weight from baseline to week 20 was -0.7 kg, +1.7 kg, -0.6 kg, +1.4 kg and +1.9 in the placebo, glyburide, metformin, glyburide and metformin hydrochloride 1.25 mg/250 mg and 2.5 mg/500 mg arms, respectively. Patients with Inadequate Glycemic Control on Sulfonylurea Alone In a 16-week, double-blind, active-controlled U.S. clinical study, a total of 639 patients with type 2 diabetes not adequately controlled (mean baseline HbA1c 9.5%, mean baseline FPG 213 mg/dL) while being treated with at least one-half the maximum dose of a sulfonylurea (e.g., glyburide 10 mg, glipizide 20 mg) were randomized to receive glyburide (fixed dose, 20 mg), metformin HCl (500 mg), glyburide and metformin hydrochloride 2.5 mg/500 mg, or glyburide and metformin hydrochloride 5 mg/500 mg. The doses of metformin HCl and glyburide and metformin hydrochloride were titrated to a maximum of 4 tablets daily as needed to achieve FPG <140 mg/dL. Study data at 16 weeks are summarized in Table 6. Table 6: Mean Change in Hemoglobin A1c and Fasting Plasma Glucose in Patients Receiving Glyburide, Metformin HCl or Glyburide and Metformin Hydrochloride at 16 Weeks Glyburide 5 mg tablets Metformin HCl 500 mg tablets Glyburide and Metformin Hydrochloride 2.5 mg/500 mg tablets Glyburide and Metformin Hydrochloride 5 mg/500 mg tablets Mean Final Dose 20 mg 1,840 mg 8.8 mg/1,760 mg 17 mg/1,740 mg Hemoglobin A 1c N=158 N=142 N=154 N=159 Baseline Mean (%) 9.63 9.51 9.43 9.44 Final Mean 9.61 9.82 7.92 7.91 Difference from Glyburide −1.69a −1.70a Difference from Metformin −1.90a −1.91a Fasting Plasma Glucose N=163 N=152 N=160 N=160 Baseline Mean (mg/dL) 218.4 213.4 212.2 210.2 Final Mean 221.0 233.8 169.6 161.1 Difference from Glyburide −51.3a −59.9a Difference from Metformin −64.2a −72.7a Final HbA1c Distribution (%) N=158 N=142 N=154 N=159 <7% 2.5% 2.8% 24.7% 22.6% ≥7% and <8% 9.5% 11.3% 33.1% 37.1% ≥8% 88% 85.9% 42.2% 40.3% a p<0.001 Weight gain due to glyburide was comparable in all three exposed groups.

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) ].

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 2,000 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 2,000 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 USE IN SPECIFIC POPULATIONS Pregnancy: Glyburide and metformin hydrochloride tablets 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 2,000 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 2,000 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). Data Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants. 8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as therapy with glyburide and metformin hydrochloride may result in ovulation in some anovulatory women. 8.4 Pediatric Use Safety and effectiveness of glyburide and metformin hydrochloride have not been established in pediatric patients. 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) ]. 8.6 Renal Impairment Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Glyburide and metformin hydrochloride is contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m 2 [see Dosage and Administration (2.3), Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3) ]. 8.7 Hepatic Impairment Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Glyburide and metformin hydrochloride is not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1) ].

16 HOW SUPPLIED/STORAGE AND HANDLING Glyburide and metformin hydrochloride tablets, USP are available as follows: Glyburide and metformin hydrochloride tablets, 1.25 mg/250 mg are white to off-white colored, capsule shaped, biconvex coated tablets, debossed with "653" on one side and plain on the other side and are supplied as follows: NDC 68382-653-06 in bottles of 30 tablets NDC 68382-653-16 in bottles of 90 tablets NDC 68382-653-01 in bottles of 100 tablets NDC 68382-653-05 in bottles of 500 tablets NDC 68382-653-10 in bottles of 1000 tablets NDC 68382-653-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets Glyburide and metformin hydrochloride tablets, 2.5 mg/500 mg are tan to scarlet yellow colored, capsule shaped, biconvex coated tablets debossed with "654" on one side and plain on the other side and are supplied as follows: NDC 68382-654-06 in bottles of 30 tablets NDC 68382-654-16 in bottles of 90 tablets NDC 68382-654-01 in bottles of 100 tablets NDC 68382-654-05 in bottles of 500 tablets NDC 68382-654-10 in bottles of 1000 tablets NDC 68382-654-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets Glyburide and metformin hydrochloride tablets, 5 mg/500 mg are pale yellow colored, capsule shaped, biconvex coated tablets, debossed with "655" on one side and plain on the other side and are supplied as follows: NDC 68382-655-06 in bottles of 30 tablets NDC 68382-655-16 in bottles of 90 tablets NDC 68382-655-01 in bottles of 100 tablets NDC 68382-655-05 in bottles of 500 tablets NDC 68382-655-10 in bottles of 1000 tablets NDC 68382-655-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets Store at temperatures up to 25°C (77°F). [See USP Controlled Room Temperature.] Dispense in light-resistant containers.

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