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warnings
WARNINGS WARNING: 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 evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally > 5 µg/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 metformin hydrochloride tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended (see PRECAUTIONS ).
warnings table
<table width="100%"> <col width="100%"/> <tbody> <tr> <td align="center" styleCode="Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">WARNING: LACTIC ACIDOSIS</content> </paragraph> </td> </tr> <tr> <td styleCode="Botrule Lrule " valign="top"> <paragraph> </paragraph> <paragraph> <content styleCode="bold">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 evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally > 5 µg/mL (see <linkHtml href="#i4i_precautions_id_5baf9798-0d24-4713-b5fa-9cb2a3ae69c1">PRECAUTIONS</linkHtml>). </content> </paragraph> <paragraph> </paragraph> <paragraph>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.</paragraph> <paragraph> </paragraph> <paragraph>Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided (see <linkHtml href="#i4i_dosage_admin_id_1ec1d7bd-1f1e-4278-8e96-3d42207d89c9">DOSAGE AND ADMINISTRATION</linkHtml>, <linkHtml href="#i4i_contraindications_id_63bc702c-591d-43a9-86f7-20b655a568b5">CONTRAINDICATIONS</linkHtml>, and <linkHtml href="#i4i_precautions_id_5baf9798-0d24-4713-b5fa-9cb2a3ae69c1">PRECAUTIONS</linkHtml>). </paragraph> <paragraph> </paragraph> <paragraph>If metformin-associated lactic acidosis is suspected, immediately discontinue metformin hydrochloride tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended (see <linkHtml href="#i4i_precautions_id_5baf9798-0d24-4713-b5fa-9cb2a3ae69c1">PRECAUTIONS</linkHtml>). </paragraph> </td> </tr> </tbody> </table>
ADVERSE REACTIONS In a U.S. double-blind clinical study of metformin hydrochloride tablets in patients with type 2 diabetes, a total of 141 patients received metformin hydrochloride tablet therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the metformin hydrochloride tablet patients, and that were more common in metformin hydrochloride tablet- than placebo-treated patients, are listed in Table 11. Table 11: Most Common Adverse Reactions (> 5.0%) in a Placebo-Controlled Clinical Study of Metformin Hydrochloride Tablet Monotherapy Reactions that were more common in metformin hydrochloride tablet- than placebo-treated patients. Adverse Reaction Metformin Hydrochloride Tablet Monotherapy (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 Diarrhea led to discontinuation of study medication in 6% of patients treated with metformin hydrochloride tablets. Additionally, the following adverse reactions were reported in ≥ 1.0% to ≤ 5.0% of metformin hydrochloride tablet patients and were more commonly reported with metformin hydrochloride tablets than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation. Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin. Pediatric Patients In clinical trials with metformin hydrochloride tablets in pediatric patients with type 2 diabetes, the profile of adverse reactions was similar to that observed in adults.