FDA label 248836bc-0561-146c-e063-6294a90a501b

WARNING: LACTIC ACIDOSIS 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 groups are provided in the Full Prescribing Information. ( 5.1) If lactic acidosis is suspected, discontinue Metformin Hydrochloride Tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. ( 5.1) 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 [ see Dosage and Administration (2.3), Contraindications (4), Warnings and Precautions (5.1)]. If metformin-associated lactic acidosis is suspected, immediately discontinue metformin and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [ see Warnings and Precautions (5.1)].

5 WARNINGS AND PRECAUTIONS Lactic Acidosis: See boxed warning.( 5.1) Vitamin B 12 Deficiency: Metformin may lower vitamin B 12 levels. Measure 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)

6 ADVERSE REACTIONS The following adverse reactions are also discussed elsewhere in 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)] For Metformin Hydrochloride Tablets, the most common adverse reactions (>5.0%) are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache. ( 6.1) To report SUSPECTED ADVERSE REACTIONS, contact ScieGen at (855) 724-3436 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Studies 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. Metformin Hydrochloride Tablets In a U.S. clinical trial of Metformin Hydrochloride in patients with type 2 diabetes mellitus, a total of 141 patients received Metformin Hydrochloride up to 2550 mg per day. Adverse reactions reported in greater than 5% of Metformin Hydrochloride treated patients and that were more common than in placebo-treated patients, are listed in Table 1. Table 1: Adverse Reactions from a Clinical Trial of Metformin Hydrochloride Occurring >5% and More Common than Placebo in Patients with Type 2 Diabetes Mellitus Metformin Hydrochloride (n=141) Placebo (n=145) Diarrhea 53% 12% Nausea/Vomiting 26% 8% Flatulence 12% 6% Asthenia 9% 6% Indigestion 7% 4% Abdominal Discomfort 6% 5% Headache 6% 5% Diarrhea led to discontinuation of Metformin Hydrochloride in 6% of patients. Additionally, the following adverse reactions were reported in ≥1% to ≤5% of Metformin Hydrochloride treated patients and were more commonly reported with Metformin Hydrochloride than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation. In Metformin Hydrochloride clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients. Pediatric Patients In clinical trials with Metformin Hydrochloride Tablets in pediatric patients with type 2 diabetes mellitus, the profile of adverse reactions was similar to that observed in adults. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of metformin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.