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.

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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 diarrhea, headache, nausea/vomiting, abdominal pain, and dizziness.

(6.1) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc.

at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

In double-blind clinical studies with glyburide and metformin hydrochloride as initial therapy or as second-line therapy of 20 and 14 weeks, respectively (see section 14 ), a total of 642 patients received glyburide and metformin hydrochloride, 312 received metformin HCl, 324 received glyburide, and 161 received placebo.

Adverse reactions are listed in Table 1.

Table 1: Adverse Reactions Occurring >5% in Double-Blind Clinical Studies of Glyburide And Metformin Hydrochloride Used as Initial (20 Weeks) or Second-Line (14 Weeks) Therapy Adverse Reaction Number (%) of Patients Placebo N=161 Glyburide N=324 Metformin HCl N=312 Glyburide and Metformin Hydrochloride N=642 Diarrhea 6% 6% 21% 17% Headache 11% 11% 9% 9% Nausea/vomiting 6% 5% 12% 8% Abdominal pain 4% 3% 8% 7% Dizziness 4% 6% 4% 6% Hypoglycemia The incidence of reported symptoms of hypoglycemia (such as dizziness, shakiness, sweating, and hunger), in the initial therapy study of glyburide and metformin hydrochloride are summarized in Table 2.

For patients with a baseline HbA1c between 8% and 11% treated with glyburide and metformin hydrochloride 2.5 mg/500 mg as initial therapy, the frequency of hypoglycemic symptoms was 30% to 35%.

As second-line therapy in patients inadequately controlled on sulfonylurea alone, approximately 6.8% of all patients treated with glyburide and metformin hydrochloride experienced hypoglycemic symptoms.

Gastrointestinal Reactions The incidence of gastrointestinal (GI) side effects (diarrhea, nausea/vomiting, and abdominal pain) in the glyburide and metformin hydrochloride initial therapy study are summarized in Table 2.

Across all glyburide and metformin hydrochloride studies, GI symptoms were the most common adverse events with glyburide and metformin hydrochloride and were more frequent at higher dose levels.

In controlled studies, <2% of patients discontinued glyburide and metformin hydrochloride therapy due to GI adverse events.

Table 2: Hypoglycemia or Gastrointestinal Adverse Reactions in a Placebo- and Active-Controlled Study of Glyburide and Metformin Hydrochloride as Initial Therapy (20 Weeks) Variable Placebo N=161 Glyburide Tablets N=160 Metformin HCl Tablets N=159 Glyburide and Metformin Hydrochloride 1.25 mg/250 mg Tablets N=158 Glyburide and Metformin Hydrochloride 2.5 mg/500 mg Tablets N=162 Number (%) of patients with symptoms of hypoglycemia 3% 21% 3% 11% 38% Number (%) of patients with gastrointestinal adverse events 24% 24% 43% 32% 38% Dermatologic Reactions Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in 1.5% of glyburide-treated patients.

These may be transient and may disappear despite continued use.

6.2 Postmarketing Adverse Reactions The following adverse reactions have been identified during post-approval use of glyburide and metformin hydrochloride.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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

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

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

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

Cholestatic jaundice and hepatitis may occur rarely with glyburide, which may progress to liver failure.

Liver function abnormalities, including isolated transaminase elevations, have been reported.

Metabolic: Hepatic porphyria reactions have been reported with sulfonylureas; however, these have not been reported with glyburide.

Disulfiram-like reactions have been reported very rarely with glyburide.

Cases of hyponatremia have been reported with glyburide and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone.

Other Reactions: Changes in accommodation and/or blurred vision have been reported with glyburide and other sulfonylureas.

These are thought to be related to fluctuation in glucose levels.