WARNING: LACTIC ACIDOSIS Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated 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 PRECAUTIONS ). 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 , CONTRAINDICATIONS , and PRECAUTIONS ). If metformin-associated lactic acidosis is suspected, immediately discontinue GLUCOVANCE and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended (see PRECAUTIONS ).
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WARNINGS Metformin Hydrochloride WARNING: LACTIC ACIDOSIS Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated 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 PRECAUTIONS ). 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 , CONTRAINDICATIONS , and PRECAUTIONS ). If metformin-associated lactic acidosis is suspected, immediately discontinue GLUCOVANCE and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended (see PRECAUTIONS ). SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to 1 of 4 treatment groups ( Diabetes 19 (Suppl. 2):747-830, 1970). UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 g per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and benefits of glyburide and of alternative modes of therapy. Although only 1 drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.
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 Number (%) of Patients Adverse Event 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 <7%, lower in those with a baseline HbA 1c of between 7% and 8%, and was comparable to placebo and metformin in those 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 Glyburide and Metformin Hydrochloride 2.5 mg/500 mg Tablets N=162 Mean Final Dose 0 mg 5.3 mg 1317 mg 2.78 mg/557 mg 4.1 mg/824 mg Number (%) of patients with symptoms of hypoglycemia 5 (3.1) 34 (21.3) 5 (3.1) 18 (11.4) 61 (37.7) Number (%) of patients with gastrointestinal adverse events 39 (24.2) 38 (23.8) 69 (43.3) 50 (31.6) 62 (38.3) Metformin Hydrochloride Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin. Glyburide Gastrointestinal Reactions Cholestatic jaundice and hepatitis may occur rarely which may progress to liver failure; the drug should be discontinued if this occurs. Liver function abnormalities, including isolated transaminase elevations, have been reported. 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; if skin reactions persist, the drug should be discontinued. Postmarketing Adverse Reactions The following adverse reactions have been identified during post-approval use. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not 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. 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.