Metformin

WARNINGS LACTIC ACIDOSIS: Postmarketing 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 evidenceof 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, concamitent 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 metformin hydrochloride extend release tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended (see PRECAUTIONS ).

ADVERSE REACTIONS In A US double blind clinical study of metformin hydrochloride tablets in patients with type 2 diabetes, a total of 141 patients received metformin hydrochloride tablets therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the metformin hydrochloride tablets patients, and that were more common in metformin hydrochloride tablets than placebo treated patients, are listed in Table 6. Table 6: Most Common Adverse Reactions (>5 Percent) in a Placebo-Controlled Clinical Study of Metformin Hydrochloride Tablets Monotherapy* Adverse Reaction Metformin Hydrochloride Tablets (n=141) Placebo (n=145) % of Patients Diarrhea 53.2 11.7 Nausea/Vomiting 25.5 8.3 Flatulence 12.1 5.5 Asthenia 9.2 5.5 Indigestion 7.1 4.1 Abdominal Discomfort 6.4 4.8 Headache 5.7 4.8 *Reactions that were more common in metformin hydrochloride tablets than placebo treated patients. Diarrhea led to discontinuation of study medication in 6% of patients treated with metformin hydrochloride tablets. Additionally, the following adverse reactions were reported in ≥1 - ≤5% of metformin hydrochloride tablets patients and myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, and palpitation. In worldwide clinical trials over 900 patients with type 2 diabetes have been treated with metformin hydrochloride extended-release tablets in placebo and active controlled studies. In placebo controlled trails, 781 patients were administered metformin hydrochloride extended-release tablets and 195 patients received placebo. Adverse reactions reported in greater than 5% of the metformin hydrochloride extended release tablets patients, and that were more common in metformin hydrochloride extended-release tablets than placebo treated patients are listed in Table 7. Table 7: Most Common Adverse Reactions (>5 Percent) in Placebo-Controlled Studies of Metformin Hydrochloride Extended-Release Tablets* Metformin Hydrochloride Extended-Release Tablets(N=781) Placebo (N=195) Adverse Reactions % of patients Diarrhea 9.6 2.6 Nausea/Vomiting 6.5 1.5 Diarrhea led to discontinuation of study medication in 0.6% of patients treated with metformin hydrochloride extended-release tablets. Additionally, the following adverse reactions were reported in ≥1 - ≤5% of metformin hydrochloride extended-release tablets patients and were more commonly reported with metformin hydrochloride extended-release tablets than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance.*Reactions that were more common in metformin hydrochloride extended-release tablets than placebo treated patients.

<table border="0" width="50%"><tbody><tr><td colspan="3"><paragraph><content styleCode="bold">Table 6: Most Common Adverse Reactions (&gt;5 Percent) in a Placebo-Controlled Clinical Study of Metformin Hydrochloride Tablets Monotherapy*</content></paragraph></td></tr><tr><td colspan="1" rowspan="2"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td><paragraph><content styleCode="bold">Metformin Hydrochloride Tablets (n=141)</content></paragraph></td><td colspan="1" rowspan="2"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(n=145)</content></paragraph></td></tr><tr><td><paragraph><content styleCode="bold">% of Patients</content></paragraph></td></tr><tr><td>Diarrhea</td><td>53.2</td><td>11.7</td></tr><tr><td><paragraph>Nausea/Vomiting</paragraph></td><td>25.5</td><td>8.3</td></tr><tr><td>Flatulence</td><td><paragraph>12.1</paragraph></td><td><paragraph>5.5</paragraph></td></tr><tr><td><paragraph>Asthenia</paragraph></td><td>9.2</td><td>5.5</td></tr><tr><td>Indigestion</td><td><paragraph>7.1</paragraph></td><td>4.1</td></tr><tr><td><paragraph>Abdominal Discomfort</paragraph></td><td>6.4</td><td>4.8</td></tr><tr><td><paragraph>Headache</paragraph></td><td>5.7</td><td><paragraph>4.8</paragraph><paragraph/></td></tr></tbody></table>

<table border="0" width="50%"><tbody><tr><td colspan="3"><paragraph><content styleCode="bold">Table 7: Most Common Adverse Reactions (&gt;5 Percent) in Placebo-Controlled Studies of Metformin Hydrochloride Extended-Release Tablets*</content></paragraph></td></tr><tr><td/><td><paragraph><content styleCode="bold">Metformin Hydrochloride Extended-Release Tablets(N=781)</content></paragraph></td><td><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(N=195)</content></paragraph></td></tr><tr><td><paragraph><content styleCode="bold">Adverse Reactions</content></paragraph></td><td colspan="2" rowspan="1"><paragraph><content styleCode="bold">% of patients</content></paragraph></td></tr><tr><td>Diarrhea</td><td>9.6</td><td><paragraph>2.6</paragraph></td></tr><tr><td><paragraph>Nausea/Vomiting</paragraph></td><td><paragraph>6.5</paragraph></td><td>1.5</td></tr></tbody></table>