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boxed warning
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 mcg/mL [see Warnings and Precautions ( 5.1 )] . 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 in the full prescribing information [see Dosage and Administration ( 2.2 ), Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), and Drug Interactions ( 7 )] . If metformin-associated lactic acidosis is suspected, immediately discontinue Metformin Hydrochloride Extended-Release Tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions ( 5.1 ) ] . WARNING: LACTIC ACIDOSIS See full prescribing information for complete boxed warning. Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL. ( 5.1 ) Risk factors include renal impairment, concomitant use of certain drugs, age ≥65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk gro...
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warnings and cautions
5 WARNINGS AND PRECAUTIONS Lactic Acidosis : See boxed warning. ( 5.1 ) Vitamin B 12 Deficiency : Metformin may lower vitamin B 12 levels. Monitor hematological parameters annually and vitamin B 12 at 2 to 3 year intervals and manage any abnormalities. ( 5.2 ) Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues : Increased risk of hypoglycemia when used in combination with insulin and/or an insulin secretagogue. Lower dose of insulin or insulin secretagogue may be required. ( 5.3 ) 5.1 Lactic Acidosis There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate/pyruvate ratio; metformin plasma levels were generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of Metformin Hydrochloride Extended-Release Tablets. In Metformin Hydrochloride Extended-Release Tablets-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin HCl is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur, instruct them to discontinue Metformin Hydrochloride Extended-Release Tablets and report these symptoms to their healthcare provider. For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal Impairment: The pos...
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adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Lactic Acidosis [see Boxed Warning and Warnings and Precautions ( 5.1 )] Vitamin B 12 Deficiency [see Warnings and Precautions ( 5.2 )] Hypoglycemia [see Warnings and Precautions ( 5.3 )] Adverse reactions occurring >5% in Metformin Hydrochloride Extended-Release Tablets clinical trials: hypoglycemia, diarrhea, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Oceanside Pharmaceuticals at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials conducted in the U.S., over 1,000 patients with type 2 diabetes mellitus have been treated with Metformin Hydrochloride Extended-Release Tablets 1,500 to 2,000 mg/day in active-controlled and placebo-controlled studies with the 500 mg dosage form. In the add-on to sulfonylurea study, patients receiving background glyburide therapy were randomized to receive add-on treatment of either one of three different regimens of Metformin Hydrochloride Extended-Release Tablets or placebo. In total, 431 patients received Metformin Hydrochloride Extended-Release Tablets and glyburide and 144 patients received placebo and glyburide. Adverse reactions reported in greater than 5% of patients treated with Metformin Hydrochloride Extended-Release Tablets that were more common in the combined Metformin Hydrochloride Extended-Release Tablets and glyburide group than in the placebo and glyburide group are shown in Table 1. In 0.7% of patients treated with Metformin Hydrochloride Extended-Release Tablets and glyburide, diarrhea was responsible for discontinuation of study medication compared to no patients in the placebo and glyburide group. Table 1: Adverse Reactions Reported by >5% Adverse reactions that were more common in the Metformin Hydrochloride Extended-Release Tablets-treated than in the placebo-treated patients. of Patients for the Combined Metformin Hydrochloride Extended-Release Tablets Groups Versus Placebo Group Adverse Reaction Metformin Hydrochloride Extended-Release Tablet...
adverse reactions table
Table 1: Adverse Reactions Reported by >5% Adverse reactions that were more common in the Metformin Hydrochloride Extended-Release Tablets-treated than in the placebo-treated patients.of Patients for the Combined Metformin Hydrochloride Extended-Release Tablets Groups Versus Placebo Group Adverse Reaction Metformin Hydrochloride Extended-Release Tablets + Glyburide (n=431)Placebo + Glyburide (n=144)Hypoglycemia14%5%Diarrhea13%6%Nausea7%4%