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WARNINGS: 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, hepatic impairment, and mitochondrial disease. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided [see PRECAUTIONS ]. If metformin-associated lactic acidosis is suspected, immediately discontinue glipizide and metformin hydrochloride and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see PRECAUTIONS ].
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<table ID="ID221" width="590" styleCode="Noautorules"><col width="590"/><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule Rrule" align="left"><content styleCode="bold"> 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 <linkHtml href="#ID65">PRECAUTIONS</linkHtml>] </content> <content styleCode="bold"> 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, hepatic impairment, and mitochondrial disease. </content> <content styleCode="bold"> Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided [see <linkHtml href="#ID65">PRECAUTIONS</linkHtml>].</content> <content styleCode="bold"> If metformin-associated lactic acidosis is suspected, immediately discontinue glipizide and metformin hydrochloride and institute general supportive measures in a hospital setting. </content> <content styleCode="bold"> Prompt hemodialysis is recommended [see <linkHtml href="#ID65">PRECAUTIONS</linkHtml>].</content> </td></tr></tbody></table>
ADVERSE REACTIONS Glipizide and Metformin Hydrochloride Tablets: In a double-blind 24 week clinical trial involving glipizide and metformin hydrochloride tablets as initial therapy, a total of 172 patients received glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg, 173 received glipizide and metformin hydrochloride tablets, 2.5 mg/500 mg, 170 received glipizide, and 177 received metformin. The most common clinical adverse events in these treatment groups are listed in Table 4 . Table 4 Clinical Adverse Events >5% in any Treatment Group, by Primary Term, in Initial Therapy Study Adverse Event Number (%) of Patients Glipizide Tablets 5 mg N=170 Metformin Tablets 500 mg N=177 Glipizide and Metformin Hydrochloride Tablets 2.5 mg/250 mg N=172 Glipizide and Metformin Hydrochloride Tablets 2.5 mg/500 mg N=173 Upper respiratory infection 12 (7.1) 15 (8.5) 17 (9.9) 14 (8.1) Diarrhea 8 (4.7) 15 (8.5) 4 (2.3) 9 (5.2) Dizziness 9 (5.3) 2 (1.1) 3 (1.7) 9 (5.2) Hypertension 17 (10) 10 (5.6) 5 (2.9) 6 (3.5) Nausea/vomiting 6 (3.5) 9 (5.1) 1 (0.6) 3 (1.7) In a double-blind 18 week clinical trial involving glipizide and metformin hydrochloride tablets as second-line therapy, a total of 87 patients received glipizide and metformin hydrochloride tablets, 84 received glipizide, and 75 received metformin. The most common clinical adverse events in this clinical trial are listed in Table 5 . Table 5 Clinical Adverse Events >5% in any Treatment Group, by Primary Term, in Second-Line Therapy Study a The dose of glipizide was fixed at 30 mg daily; doses of metformin and glipizide and metformin hydrochloride tablets were titrated. Adverse Event Number (%) of Patients Glipizide Tablets a 5 mg N=84 Metformin Tablets a 500 mg N=75 Glipizide and Metformin Hydrochloride Tablets a 5 mg/500 mg N=87 Diarrhea 11 (13.1) 13 (17.3) 16 (18.4) Headache 5 (6) 4 (5.3) 11 (12.6) Upper respiratory infection 11 (13.1) 8 (10.7) 9 (10.3) Musculoskeletal pain 6 (7.1) 5 (6.7) 7 (8) Nausea/vomiting 5 (6) 6 (8) 7 (8) Abdominal pain 7 (8.3) 5 (6.7) 5 (5.7) UTI 4 (4.8) 6 (8) 1 (1.1) Hypoglycemia: In a controlled initial therapy trial of glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg and 2.5 mg/500 mg the numbers of patients with hypoglycemia documented by symptoms (such as dizziness, shakiness, sweating, and hunger) and a fingerstick blood glucose measurement ≤50 mg/dL were 5 (2.9%) for glipizide, 0 (0%) for metformin, 13 (7.6%) for glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg, and 16 (9.3%) for glipizide and metformin hydrochloride tablets, 2.5 mg/500 mg. Among patients taking either glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg or glipizide and metformin hydrochloride tablets, 2.5 mg/500 mg, 9 (2.6%) patients discontinued glipizide and metformin hydrochloride tablets due to hypoglycemic symptoms and 1 required medical intervention due to hypoglycemia. In a controlled second-line therapy trial of glipizide and metformin hydrochloride tablets, 5 mg/500 mg, the numbers of patients with hypoglycemia documented by symptoms and a fingerstick blood glucose measurement ≤50 mg/dL were 0 (0%) for glipizide, 1 (1.3%) for metformin, and 11 (12.6%) for glipizide and metformin hydrochloride tablets. One (1.1%) patient discontinued glipizide and metformin hydrochloride tablets therapy due to hypoglycemic symptoms and none required medical intervention due to hypoglycemia (see PRECAUTIONS ). Gastrointestinal Reactions: Among the most common clinical adverse events in the initial therapy trial were diarrhea and nausea/vomiting; the incidences of these events were lower with both glipizide and metformin hydrochloride tablets dosage strengths than with metformin therapy. There were 4 (1.2%) patients in the initial therapy trial who discontinued glipizide and metformin hydrochloride tablets therapy due to gastrointestinal (GI) adverse events. Gastrointestinal symptoms of diarrhea, nausea/vomiting, and abdominal pain were comparable among glipizide and metformin hydrochloride tablets, glipizide and metformin in the second-line therapy trial. There were 4 (4.6%) patients in the second-line therapy trial who discontinued glipizide and metformin hydrochloride tablets therapy due to GI adverse events. Glipizide Gastrointestinal Reactions Cholestatic and hepatocellular forms of liver injury accompanied by jaundice have been reported rarely in association with glipizide; glipizide and metformin hydrochloride tablets should be discontinued if this occurs.