Browse the corpus

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 groups are provided in the Full Prescribing Information. ( 5.1 ) • If lactic acidosis is suspected, discontinue metformin hydrochloride extended-release tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. ( 5.1 )

1 INDICATIONS AND USAGE Metformin hydrochloride extended-release tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Metformin hydrochloride extended-release tablets are a biguanide indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 )

2 DOSAGE AND ADMINISTRATION • Starting dose: 500 mg orally once daily with the evening meal ( 2.1 ) • Increase the dose in increments of 500 mg every 1 to 2 weeks, up to a maximum of 2,000 mg once daily with the evening meal. ( 2.1 ) • Patients receiving metformin hydrochloride (HCl) tablets may be switched to metformin hydrochloride extended-release tablets once daily at the same total daily dose, up to 2,000 mg once daily. ( 2.1 ) • Swallow metformin hydrochloride extended-release tablets whole and never crush, cut or chew. ( 2.1 ) Renal Impairment: • Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR). ( 2.2 ) • Do not use in patients with eGFR below 30 mL/minute/1.73 m 2 . • Initiation is not recommended in patients with eGFR between 30 to 45 mL/minute/1.73 m 2 . • Assess risk/benefit of continuing metformin hydrochloride extended-release tablets if eGFR falls below 45 mL/minute/1.73 m 2 . • Discontinue if eGFR falls below 30 mL/minute/1.73 m 2 . Discontinuation for Iodinated Contrast Imaging Procedures: • Metformin hydrochloride extended-release tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. ( 2.3 ) 2.1 Adult Dosage and Administration • The recommended starting dose of metformin hydrochloride extended-release tablets is 500 mg orally once daily with the evening meal. • Increase the dose in increments of 500 mg every 1 to 2 weeks on the basis of glycemic control and tolerability, up to a maximum of 2,000 mg once daily with the evening meal. • Patients receiving metformin hydrochloride (HCl) may be switched to metformin hydrochloride extended-release tablets once daily at the same total daily dose, up to 2,000 mg once daily. • Swallow metformin hydrochloride extended-release tablets whole and never crush, cut or chew. • If a dose of metformin hydrochloride extended-release tablet is missed, instruct patients not to take two doses the same day and to resume their usual dose of metformin hydrochloride extended-release tablets with the next schedule dose. 2.2 Recommendations for Use in Renal Impairment • Assess renal function prior to initiation of metformin hydrochloride extended-release tablets and periodically thereafter. • Metformin hydrochloride extended-release tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m 2 . • Initiation of metformin hydrochloride extended-release tablets in patients with an eGFR between 30 to 45 mL/minute/1.73 m 2 is not recommended. • In patients taking metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/minute/1.73 m 2 , assess the benefit risk of continuing therapy. • Discontinue metformin hydrochloride extended-release tablets if the patient’s eGFR later falls below 30 mL/minute/1.73 m 2 [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] . 2.3 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/minute/1.73 m 2 ; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast.

hydrochloride extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/minute/1.73 m 2 ; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart metformin hydrochloride extended-release tablets if renal function is stable [see Warnings and Precautions ( 5.1 )] .

3 DOSAGE FORMS AND STRENGTHS Metformin Hydrochloride Extended-Release Tablets, USP are available as: • Extended-release tablets : 500 mg white to off-white, oval shaped, coated tablets, imprinted with ‘G520’ on one side and plain on the other side. • Extended-release tablets: 1,000 mg white to off-white, oval shaped, coated tablets, imprinted with ‘G521’ on one side and plain on the other side. Metformin Hydrochloride Extended-Release Tablets, USP: 500 mg and 1,000 mg ( 3 )

4 CONTRAINDICATIONS Metformin hydrochloride extended-release tablets are contraindicated in patients with: • Severe renal impairment (eGFR below 30 mL/minute/1.73 m 2 ) [see Warnings and Precautions ( 5.1 )] . • Known hypersensitivity to metformin. • Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. • Severe renal impairment: (eGFR below 30 mL/minute/1.73 m 2 ) ( 4 , 5.1 ) • Known hypersensitivity to metformin ( 4 ) • Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma ( 4 )

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 postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include [see Dosage and Administration ( 2.2 ) and Clinical Pharmacology ( 12.3 )]: • Before initiating metformin hydrochloride extended-release tablets, obtain an estimated glomerular filtration rate (eGFR). • Metformin hydrochloride extended-release tablets are contraindicated in patients with an eGFR less than 30 mL/minute/1.73 m 2 [see Contraindications ( 4 )] . • Initiation of metformin hydrochloride extended-release tablets are not recommended in patients with eGFR between 30 to 45 mL/minute/1.73 m 2 . • Obtain an eGFR at least annually in all patients taking metformin hydrochloride extended-release tablets.

GFR less than 30 mL/minute/1.73 m 2 [see Contraindications ( 4 )] . • Initiation of metformin hydrochloride extended-release tablets are not recommended in patients with eGFR between 30 to 45 mL/minute/1.73 m 2 . • Obtain an eGFR at least annually in all patients taking metformin hydrochloride extended-release tablets. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. • In patients taking metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/minute/1.73 m 2 , assess the benefit and risk of continuing therapy . • Drug Interactions: The concomitant use of metformin hydrochloride extended-release tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see Drug Interactions ( 7 )]. Therefore, consider more frequent monitoring of patients. • Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations ( 8.5 )]. • Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/minute/1.73 m 2 ; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re‑evaluate eGFR 48 hours after the imaging procedure, and restart metformin hydrochloride extended-release tablets if renal function is stable. • Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. Metformin hydrochloride extended-release tablets should be temporarily discontinued while patients have restricted food and fluid intake. • Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue metformin hydrochloride extended-release tablets. • Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism, and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving metformin hydrochloride extended-release tablets. • Hepatic Impairment: Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of metformin hydrochloride extended-release tablets in patients with clinical or laboratory evidence of hepatic disease. 5.2 Vitamin B 12 Deficiency In clinical trials of 29-week duration with metformin HCl tablets, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients.

hloride extended-release tablets in patients with clinical or laboratory evidence of hepatic disease. 5.2 Vitamin B 12 Deficiency In clinical trials of 29-week duration with metformin HCl tablets, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation. Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. Measure hematologic parameters on an annual basis and vitamin B 12 at 2 to 3 year intervals in patients on metformin hydrochloride extended-release tablets and manage any abnormalities [ see Adverse Reactions ( 6.1 )] . 5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. Metformin hydrochloride extended-release tablets may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with metformin hydrochloride extended-release tablets [see Drug Interactions ( 7 )] . 5.4 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin hydrochloride extended-release tablets.

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 Glenmark Pharmaceuticals, Inc., USA at 1 (888) 721-7115 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% * 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) Hypoglycemia 14% 5% Diarrhea 13% 6% Nausea 7% 4% * Adverse reactions that were more common in the metformin hydrochloride extended-release tablets -treated than in the placebo-treated patients. Laboratory Tests Vitamin B 12 Concentrations In clinical trials of 29-week duration with metformin HCl tablets, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of metformin hydrochloride extended-release tablets. 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.

<table styleCode="Noautorules" width="84.62%"><col width="23%"/><col width="42%"/><col width="33%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Adverse Reaction </content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><list listType="unordered"><item><caption> </caption><content styleCode="bold">Metformin Hydrochloride Extended-Release Tablets + Glyburide</content></item></list><paragraph><content styleCode="bold">(n = 431)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Placebo + Glyburide</content> <content styleCode="bold">(n=144)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hypoglycemia </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>14%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Diarrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>13%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>7%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>4%</paragraph></td></tr></tbody></table>

7 DRUG INTERACTIONS Table 2 presents clinically significant drug interactions with metformin hydrochloride extended-release tablets. Table 2: Clinically Significant Drug Interactions with Metformin Hydrochloride Extended-Release Tablets Carbonic Anhydrase Inhibitors Clinical Impact: Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with metformin hydrochloride extended-release tablets may increase the risk for lactic acidosis. Intervention: Consider more frequent monitoring of these patients. Examples: Topiramate, zonisamide, acetazolamide or dichlorphenamide. Drugs that Reduce Metformin Hydrochloride Extended-Release Tablets Clearance Clinical Impact: Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology ( 12.3 )]. Intervention: Consider the benefits and risks of concomitant use with metformin hydrochloride extended-release tablets. Examples: Ranolazine, vandetanib, dolutegravir, and cimetidine. Alcohol Clinical Impact: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Intervention: Warn patients against excessive alcohol intake while receiving metformin hydrochloride extended-release tablets. Insulin Secretagogues or Insulin Clinical Impact: Coadministration of metformin hydrochloride extended-release tablets with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia. Intervention: Patients receiving an insulin secretagogue or insulin may require lower doses of the insulin secretagogue or insulin. Drugs Affecting Glycemic Control Clinical Impact: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. Intervention: When such drugs are administered to a patient receiving metformin hydrochloride extended-release tablets, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin hydrochloride extended-release tablets, observe the patient closely for hypoglycemia. Examples: Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. • Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring. ( 7 ) • Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin. Consider the benefits and risks of concomitant use. ( 7 ) • Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake. ( 7 )

<table width="96.2%"><col width="18%"/><col width="82%"/><tbody><tr><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Carbonic Anhydrase Inhibitors</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Clinical Impact: </content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis.

"Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Clinical Impact: </content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with metformin hydrochloride extended-release tablets may increase the risk for lactic acidosis.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Intervention: </content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Consider more frequent monitoring of these patients.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Examples: </content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Topiramate, zonisamide, acetazolamide or dichlorphenamide.</paragraph></td></tr><tr><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Drugs that Reduce Metformin Hydrochloride Extended-Release Tablets Clearance</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Clinical Impact: </content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis <content styleCode="italics">[see Clinical Pharmacology (<linkHtml href="#ID_2f06e5cf-2e55-41e5-9189-8e7d060885bc">12.3</linkHtml>)].</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Intervention: </content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Consider the benefits and risks of concomitant use with metformin hydrochloride extended-release tablets.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Examples: </content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Ranolazine, vandetanib, dolutegravir, and cimetidine.</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Alcohol</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Clinical Impact: </content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Alcohol is known to potentiate the effect of metformin on lactate metabolism.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Intervention: </content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Warn patients against excessive alcohol intake while receiving metformin hydrochloride extended-release tablets.</paragraph></td></tr><tr><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Insulin Secretagogues or Insulin</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Clinical Impact: </content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Coadministration of metformin hydrochloride extended-release tablets with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypo

" valign="top"><paragraph><content styleCode="italics">Clinical Impact: </content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Coadministration of metformin hydrochloride extended-release tablets with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypo glycemia.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Intervention: </content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Patients receiving an insulin secretagogue or insulin may require lower doses of the insulin secretagogue or insulin.</paragraph></td></tr><tr><td align="center" colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Drugs Affecting Glycemic Control</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Clinical Impact: </content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Intervention: </content></paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>When such drugs are administered to a patient receiving metformin hydrochloride extended-release tablets, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin hydrochloride extended-release tablets, observe the patient closely for hypoglycemia.</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph><content styleCode="italics">Examples: </content></paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid.</paragraph></td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS • Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. ( Error! Hyperlink reference not valid. ) • Geriatric Use: Assess renal function more frequently. ( 8.5 ) • Hepatic Impairment: Avoid use in patients with hepatic impairment. ( 8.7 ) 8.1 Pregnancy Risk Summary Limited data with metformin hydrochloride extended-release tablets in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy [see Clinical Considerations]. No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 3 and 1 times, respectively, a 2,000 mg clinical dose, based on body surface area [see Data]. The estimated background risk of major birth defects is 6 to 10% in women with pregestational diabetes mellitus with an HbA1c >7 and has been reported to be as high as 20 to 25% in women with an HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity. Data Human Data Published data from post-marketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. Animal Data Metformin HCl was not teratogenic or embyrolethal when administered to rats prior to pregnancy through the period of organogenesis at doses up to 900 mg/kg, or when administered to rabbits during the period of organogenesis at doses up to 90 mg/kg. 8.2 Lactation Risk Summary Limited published studies report that metformin is present in human milk [see Data]. However, there is insufficient information to determine the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for metformin hydrochloride extended-release tablets and any potential adverse effects on the breastfed child from metformin hydrochloride extended-release tablets or from the underlying maternal condition.

the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for metformin hydrochloride extended-release tablets and any potential adverse effects on the breastfed child from metformin hydrochloride extended-release tablets or from the underlying maternal condition. Data Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants. 8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin hydrochloride extended-release tablets may result in ovulation in some anovulatory women. 8.4 Pediatric Use Safety and effectiveness of metformin hydrochloride extended-release tablets in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of metformin hydrochloride extended-release tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [see Dosage and Administration ( 2.2 ) and Warnings and Precautions ( 5.1 )]. 8.6 Renal Impairment Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. metformin hydrochloride extended-release tablets are contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m 2 [see Dosage and Administration ( 2.2 ), Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), and Clinical Pharmacology ( 12.3 )] . 8.7 Hepatic Impairment Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. metformin hydrochloride extended-release tablets are not recommended in patients with hepatic impairment [see Warnings and Precautions ( 5.1 )].

8.1 Pregnancy Risk Summary Limited data with metformin hydrochloride extended-release tablets in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy [see Clinical Considerations]. No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 3 and 1 times, respectively, a 2,000 mg clinical dose, based on body surface area [see Data]. The estimated background risk of major birth defects is 6 to 10% in women with pregestational diabetes mellitus with an HbA1c >7 and has been reported to be as high as 20 to 25% in women with an HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity. Data Human Data Published data from post-marketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. Animal Data Metformin HCl was not teratogenic or embyrolethal when administered to rats prior to pregnancy through the period of organogenesis at doses up to 900 mg/kg, or when administered to rabbits during the period of organogenesis at doses up to 90 mg/kg.

8.5 Geriatric Use Clinical studies of metformin hydrochloride extended-release tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [see Dosage and Administration ( 2.2 ) and Warnings and Precautions ( 5.1 )].

10 OVERDOSAGE Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions ( 5.1 )]. Metformin is dialyzable with a clearance of up to 170 mL/minute under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

11 DESCRIPTION Metformin Hydrochloride Extended-Release Tablets, USP contains the biguanide antihyperglycemic agent metformin in the form of monohydrochloride salt. The chemical name of metformin hydrochloride is N,N-dimethylimidodicarbonimidic diamide hydrochloride. The structural formula is as shown: Metformin hydrochloride is a white crystalline powder with a molecular formula of C 4 H 11 N 5 •HCl and a molecular weight of 165.62 g/mol. Metformin hydrochloride is freely soluble in water, slightly soluble in alcohol, practically insoluble in acetone and in methylene chloride. The pKa of metformin is 2.8 and 11.5 at 32°C. The pH of a 5% aqueous solution of metformin hydrochloride is 6 to 7. Metformin Hydrochloride Extended-Release Tablets, USP contain 500 mg or 1,000 mg of metformin hydrochloride, which is equivalent to 389.93 mg or 779.86 mg metformin, respectively. Each 500 mg and 1,000 mg tablet contains ammonio methacrylate copolymer dispersion type A, ammonio methacrylate copolymer dispersion type B, hypromellose, magnesium stearate, povidone K 30, talc, titanium dioxide, and triethyl citrate. The tablets are imprinted using a water-soluble black ink which contains shellac, black iron oxide, propylene glycol and ammonium hydroxide. Meets USP Dissolution Test 12. structure.jpg

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Metformin is a biguanide that improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease. 12.3 Pharmacokinetics Absorption Following a single oral dose of 1,000 mg (2x500 mg tablets) metformin hydrochloride extended-release tablets after a meal, the time to reach maximum plasma metformin concentration (T max ) is achieved at approximately 7 to 8 hours. In both single- and multiple-dose studies in healthy subjects, once daily 1,000 mg (2x500 mg tablets) dosing provides equivalent systemic exposure, as measured by area under the curve (AUC), and up to 35% higher C max , of metformin relative to the immediate-release given as 500 mg twice daily. At usual clinical doses and dosing schedules of metformin, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 mcg/mL. In a two-way, single-dose, crossover study in healthy volunteers, the 1,000 mg tablet was found to be similar to two 500 mg tablets under fed conditions based on equivalent C max and AUCs for the two formulations. Single oral doses of metformin hydrochloride extended-release tablets from 500 mg to 2,500 mg resulted in less than proportional increase in both AUC and C max . Effect of food: Low-fat and high-fat meals increased the systemic exposure (as measured by AUC) from metformin hydrochloride extended-release tablets by about 38% and 73%, respectively, relative to fasting. Both meals prolonged metformin T max by approximately 3 hours but C max was not affected. Distribution The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg metformin HCl averaged 654±358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. Metabolism Intravenous, single-dose studies in healthy subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans), nor biliary excretion. Excretion Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. Special Populations Renal Impairment Following a single-dose administration of metformin hydrochloride extended-release tablets 500 mg in subjects with mild and moderate renal impairment, the oral and renal clearance of metformin were decreased by 33% and 50% and 16% and 53%, respectively.

compartment of distribution. Special Populations Renal Impairment Following a single-dose administration of metformin hydrochloride extended-release tablets 500 mg in subjects with mild and moderate renal impairment, the oral and renal clearance of metformin were decreased by 33% and 50% and 16% and 53%, respectively. Metformin peak and systemic exposure was 27% and 61% greater, respectively in subjects with mild renal impairment and 74% and 2.36‑fold greater in subjects with moderate renal impairment as compared to healthy subjects [see Dosage and Administration ( 2.2 ), Contraindications ( 4 ), and Warnings and Precautions ( 5.1 )]. Hepatic Impairment No pharmacokinetic studies of metformin hydrochloride extended-release tablets have been conducted in subjects with hepatic impairment [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.7 )] . Geriatrics Limited data from controlled pharmacokinetic studies of metformin HCl in healthy elderly subjects suggest that total plasma clearance of metformin is decreased by 35%, the half-life is prolonged by 64% and C max is increased by 76%, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function [see Dosage and Administration ( 2 ) and Warnings and Precautions ( 5.1 )]. Gender In the pharmacokinetic studies in healthy volunteers, there were no important differences between male and female subjects with respect to metformin AUC and t 1/2 . However, C max for metformin was 40% higher in female subjects as compared to males. In controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin HCl tablets was comparable in males and females. The gender differences for C max are unlikely to be clinically important. Race A trend towards 10% higher metformin C max and AUC values for metformin are obtained in Asian subjects when compared to Caucasian, Hispanic and Black subjects. The differences between the Asian and Caucasian groups are unlikely to be clinically important. In controlled clinical studies of metformin HCl in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51) and Hispanics (n=24). Pediatrics There are no available pharmacokinetic data with metformin hydrochloride extended-release tablets in pediatric patients. Drug Interaction Specific pharmacokinetic drug interaction studies with metformin hydrochloride extended-release tablets have not been performed except for one with glyburide. However, such studies have been performed on metformin HCl tablets. Table 3: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure Coadministered Drug Dose of Coadministered Drug 1 Dose of Metformin HCl 1 Geometric Mean Ratio (ratio with/without coadministered drug) No Effect=1.00 AUC 2 C max No dosing adjustments required for the following: Glyburide 5 mg 500 mg 4 0.98 3 0.99 3 Furosemide 40 gm 850 mg 1.09 3 1.22 3 Nifedipine 10 mg 850 mg 1.16 1.21 Propranolol 40 mg 850 mg 0.90 0.94 Ibuprofen 400 mg 850 mg 1.05 3 1.07 3 Cationic drugs that are eliminated by renal tubular secretion may increase the accumulation of metformin: [see Warnings and Precautions (5.1) and Drug Interactions (7)]. Cimetidine 400 mg 850 mg 1.40 1.61 Carbonic anhydrase inhibitors may cause metabolic acidosis: [see Warnings and Precautions (5.1) and Drug Interactions (7)].

drugs that are eliminated by renal tubular secretion may increase the accumulation of metformin: [see Warnings and Precautions (5.1) and Drug Interactions (7)]. Cimetidine 400 mg 850 mg 1.40 1.61 Carbonic anhydrase inhibitors may cause metabolic acidosis: [see Warnings and Precautions (5.1) and Drug Interactions (7)]. Topiramate 100 mg 5 500 mg 1.25 5 1.17 1 All metformin HCl and coadministered drugs were given as single doses 2 AUC = AUC 0 to inf 3 Ratio of arithmetic means 4 Metformin hydrochloride extended-release tablets 500 mg 5 At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC 0 to 12h Table 4: Effect of Metformin on Coadministered Drug Systemic Exposure Coadministered Drug Dose of Coadministered Drug 1 Dose of Metformin HCl 1 Geometric Mean Ratio (ratio with/without coadministered drug) No Effect=1.00 AUC 2 C max No dosing adjustments required for the following: Glyburide 5 mg 500 mg 4 0.78 3 0.63 3 Furosemide 40 gm 850 mg 0.87 3 1.69 3 Nifedipine 10 mg 850 mg 1.10 4 1.08 Propranolol 40 mg 850 mg 1.01 4 0.94 Ibuprofen 400 mg 850 mg 0.97 5 1.01 3 Cimetidine 400 mg 850 mg 0.95 4 1.01 1 All metformin HCl and coadministered drugs were given as single doses 2 AUC = AUC 0 to inf unless otherwise noted 3 Ratio of arithmetic means, p-value of difference <0.05 4 AUC 0 to 24hr reported 5 Ratio of arithmetic means

12.1 Mechanism of Action Metformin is a biguanide that improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

12.3 Pharmacokinetics Absorption Following a single oral dose of 1,000 mg (2x500 mg tablets) metformin hydrochloride extended-release tablets after a meal, the time to reach maximum plasma metformin concentration (T max ) is achieved at approximately 7 to 8 hours. In both single- and multiple-dose studies in healthy subjects, once daily 1,000 mg (2x500 mg tablets) dosing provides equivalent systemic exposure, as measured by area under the curve (AUC), and up to 35% higher C max , of metformin relative to the immediate-release given as 500 mg twice daily. At usual clinical doses and dosing schedules of metformin, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 mcg/mL. In a two-way, single-dose, crossover study in healthy volunteers, the 1,000 mg tablet was found to be similar to two 500 mg tablets under fed conditions based on equivalent C max and AUCs for the two formulations. Single oral doses of metformin hydrochloride extended-release tablets from 500 mg to 2,500 mg resulted in less than proportional increase in both AUC and C max . Effect of food: Low-fat and high-fat meals increased the systemic exposure (as measured by AUC) from metformin hydrochloride extended-release tablets by about 38% and 73%, respectively, relative to fasting. Both meals prolonged metformin T max by approximately 3 hours but C max was not affected. Distribution The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg metformin HCl averaged 654±358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. Metabolism Intravenous, single-dose studies in healthy subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans), nor biliary excretion. Excretion Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. Special Populations Renal Impairment Following a single-dose administration of metformin hydrochloride extended-release tablets 500 mg in subjects with mild and moderate renal impairment, the oral and renal clearance of metformin were decreased by 33% and 50% and 16% and 53%, respectively. Metformin peak and systemic exposure was 27% and 61% greater, respectively in subjects with mild renal impairment and 74% and 2.36‑fold greater in subjects with moderate renal impairment as compared to healthy subjects [see Dosage and Administration ( 2.2 ), Contraindications ( 4 ), and Warnings and Precautions ( 5.1 )]. Hepatic Impairment No pharmacokinetic studies of metformin hydrochloride extended-release tablets have been conducted in subjects with hepatic impairment [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.7 )] .

ministration ( 2.2 ), Contraindications ( 4 ), and Warnings and Precautions ( 5.1 )]. Hepatic Impairment No pharmacokinetic studies of metformin hydrochloride extended-release tablets have been conducted in subjects with hepatic impairment [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.7 )] . Geriatrics Limited data from controlled pharmacokinetic studies of metformin HCl in healthy elderly subjects suggest that total plasma clearance of metformin is decreased by 35%, the half-life is prolonged by 64% and C max is increased by 76%, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function [see Dosage and Administration ( 2 ) and Warnings and Precautions ( 5.1 )]. Gender In the pharmacokinetic studies in healthy volunteers, there were no important differences between male and female subjects with respect to metformin AUC and t 1/2 . However, C max for metformin was 40% higher in female subjects as compared to males. In controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin HCl tablets was comparable in males and females. The gender differences for C max are unlikely to be clinically important. Race A trend towards 10% higher metformin C max and AUC values for metformin are obtained in Asian subjects when compared to Caucasian, Hispanic and Black subjects. The differences between the Asian and Caucasian groups are unlikely to be clinically important. In controlled clinical studies of metformin HCl in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51) and Hispanics (n=24). Pediatrics There are no available pharmacokinetic data with metformin hydrochloride extended-release tablets in pediatric patients. Drug Interaction Specific pharmacokinetic drug interaction studies with metformin hydrochloride extended-release tablets have not been performed except for one with glyburide. However, such studies have been performed on metformin HCl tablets. Table 3: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure Coadministered Drug Dose of Coadministered Drug 1 Dose of Metformin HCl 1 Geometric Mean Ratio (ratio with/without coadministered drug) No Effect=1.00 AUC 2 C max No dosing adjustments required for the following: Glyburide 5 mg 500 mg 4 0.98 3 0.99 3 Furosemide 40 gm 850 mg 1.09 3 1.22 3 Nifedipine 10 mg 850 mg 1.16 1.21 Propranolol 40 mg 850 mg 0.90 0.94 Ibuprofen 400 mg 850 mg 1.05 3 1.07 3 Cationic drugs that are eliminated by renal tubular secretion may increase the accumulation of metformin: [see Warnings and Precautions (5.1) and Drug Interactions (7)]. Cimetidine 400 mg 850 mg 1.40 1.61 Carbonic anhydrase inhibitors may cause metabolic acidosis: [see Warnings and Precautions (5.1) and Drug Interactions (7)].

<table styleCode="Noautorules" width="100%"><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><tbody><tr><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Coadministered Drug</content></paragraph></td><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Dose of Coadministered Drug¹</content></paragraph></td><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Dose of</content></paragraph><paragraph><content styleCode="bold">Metformin</content></paragraph><paragraph><content styleCode="bold">HCl¹</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Geometric Mean Ratio (ratio</content></paragraph><paragraph><content styleCode="bold">with/without coadministered</content></paragraph><paragraph><content styleCode="bold">drug)</content></paragraph><paragraph><content styleCode="bold">No Effect=1.00</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">AUC²</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">C_max</content></paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>No dosing adjustments required for the following:</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Glyburide</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5 mg</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>500 mg⁴</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.98³</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.99³</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Furosemide</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>40 gm</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>850 mg</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.09³</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.22³</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nifedipine</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10 mg</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>850 mg</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.16</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.21</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Propranolol</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>40 mg</paragraph></td><td align="center"

n="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.21</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Propranolol</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>40 mg</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>850 mg</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.90</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.94</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Ibuprofen</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>400 mg</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>850 mg</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.05³</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.07³</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Cationic drugs that are eliminated by renal tubular secretion may increase the accumulation of</content></paragraph><paragraph><content styleCode="bold">metformin: </content><content styleCode="italics">[see Warnings and Precautions (5.1) and Drug Interactions (7)].</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Cimetidine</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>400 mg</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>850 mg</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.40</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.61</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Carbonic anhydrase inhibitors may cause metabolic acidosis:</content></paragraph><paragraph><content styleCode="italics">[see Warnings and Precautions (5.1) and Drug Interactions (7)].</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Topiramate</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>100 mg⁵</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>500 mg</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1.25⁵</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1.17</paragraph></td></tr></tbody></table>

paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>500 mg</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1.25⁵</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1.17</paragraph></td></tr></tbody></table> <table styleCode="Noautorules" width="100%"><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><tbody><tr><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Coadministered Drug</content></paragraph></td><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Dose of Coadministered Drug¹</content></paragraph></td><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Dose of</content></paragraph><paragraph><content styleCode="bold">Metformin</content></paragraph><paragraph><content styleCode="bold">HCl¹</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Geometric Mean Ratio (ratio</content></paragraph><paragraph><content styleCode="bold">with/without coadministered</content></paragraph><paragraph><content styleCode="bold">drug)</content></paragraph><paragraph><content styleCode="bold">No Effect=1.00</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">AUC²</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">C_max</content></paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>No dosing adjustments required for the following:</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Glyburide</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5 mg</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>500 mg⁴</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.78³</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.63³</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Furosemide</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>40 gm</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>850 mg</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.87³</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.69³</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nifedipine</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10 mg</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>850 mg</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.10⁴</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.08</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Propranolol</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>40 mg</paragraph></td><td ali

/td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.08</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Propranolol</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>40 mg</paragraph></td><td ali gn="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>850 mg</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.01⁴</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.94</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Ibuprofen</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>400 mg</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>850 mg</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.97⁵</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.01³</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Cimetidine</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>400 mg</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>850 mg</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0.95⁴</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1.01</paragraph></td></tr></tbody></table>

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term carcinogenicity studies have been performed in Sprague Dawley rats at doses of 150, 300, and 450 mg/kg/day in males and 150, 450, 900, and 1,200 mg/kg/day in females. These doses are approximately 2, 4, and 8 times in males, and 3, 7, 12, and 16 times in females of the maximum recommended human daily dose of 2,000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female rats. A carcinogenicity study was also performed in Tg.AC transgenic mice at doses up to 2,000 mg applied dermally. No evidence of carcinogenicity was observed in male or female mice. Genotoxicity assessments in the Ames test, gene mutation test (mouse lymphoma cells), chromosomal aberrations test (human lymphocytes) and in vivo mouse micronucleus tests were negative. Fertility of male or female rats was not affected by metformin when administered at doses up to 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose based on body surface area comparisons.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term carcinogenicity studies have been performed in Sprague Dawley rats at doses of 150, 300, and 450 mg/kg/day in males and 150, 450, 900, and 1,200 mg/kg/day in females. These doses are approximately 2, 4, and 8 times in males, and 3, 7, 12, and 16 times in females of the maximum recommended human daily dose of 2,000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female rats. A carcinogenicity study was also performed in Tg.AC transgenic mice at doses up to 2,000 mg applied dermally. No evidence of carcinogenicity was observed in male or female mice. Genotoxicity assessments in the Ames test, gene mutation test (mouse lymphoma cells), chromosomal aberrations test (human lymphocytes) and in vivo mouse micronucleus tests were negative. Fertility of male or female rats was not affected by metformin when administered at doses up to 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose based on body surface area comparisons.

14 CLINICAL STUDIES In a multicenter, randomized, double-blind, active-controlled, dose-ranging, parallel group study conducted in patients type 2 diabetes mellitus, metformin hydrochloride extended-release tablets 1,500 mg once daily, metformin hydrochloride extended-release tablets 1,500 per day in divided doses (500 mg in the morning and 1,000 mg in the evening), and metformin hydrochloride extended-release tablets 2,000 mg once daily were compared to immediate-release metformin HCl tablets 1,500 mg per day in divided doses (500 mg in the morning and 1,000 mg in the evening). This study included patients (n=338) who were newly diagnosed with diabetes, patients treated only with diet and exercise, patients treated with a single antidiabetic medication (sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, or meglitinides), and patients (n=368) receiving metformin HCl tablets up to 1,500 mg/day plus a sulfonylurea at a dose equal to or less than one-half the maximum dose. Patients who were enrolled on monotherapy or combination antidiabetic therapy underwent a 6-week washout. Patients randomized to metformin hydrochloride extended-release tablets began titration from 1,000 mg/day up to their assigned treatment dose over 3 weeks. Patients randomized to immediate-release metformin initiated 500 mg twice daily for 1 week followed by 500 mg with breakfast and 1,000 mg with dinner for the second week. The 3-week treatment period was followed by an additional 21-week period at the randomized dose. The results are presented in Table 4. Table 5: Mean Changes from Baseline in HbA1c and Fasting Plasma Glucose at Week 24 Comparing Metformin Hydrochloride Extended-Release Tablets versus Metformin HCl Tablets * in Patients with Type 2 Diabetes Mellitus Metformin hydrochloride extended-release tablets Metformin HCl Tablets* 1,500 mg in Divided Doses (n=174) 1,500 mg Once Daily (n=178) 1,500 mg in Divided Doses (n=182) 2,000 mg Once Daily (n=172) HbA 1c (%), N 169 175 159 170 Baseline 8.2 8.5 8.3 8.7 Mean Change at Final Visit -0.7 -0.7 -1.1 -0.7 Mean Difference from Metformin HCl Tablets * (98.4% CI) 0 (-0.3, 0.3) 0 (-0.3, 0.3) -0.4 (-0.7, -0.1) N/A Fasting Plasma Glucose (mg/dL), N 175 179 170 172 Baseline 190 192.3 184 197 Mean Change at Final Visit -39 -32 -42 -32 Mean Difference from Metformin HCl Tablets * (95% CI) -6 (-15, 2) 0 (-8, 9) -10 (-19, -1) N/A * Immediate-release metformin HCl tablets Mean baseline body weight was 88.2 kg, 90.5 kg, 87.7 kg and 88.7 kg in the metformin hydrochloride extended-release tablets 1,500 mg once daily, metformin hydrochloride extended-release tablets 1,500 mg in divided doses, metformin hydrochloride extended-release tablets 2,000 mg once daily and metformin HCl tablets 1,500 mg in divided doses arms, respectively. Mean change in body weight from baseline to week 24 was -0.9 kg, -0.7 kg, -1.1 kg, and -0.9 kg in the metformin hydrochloride extended-release tablets 1,500 mg once daily, metformin hydrochloride extended-release tablets 1,500 mg in divided doses, metformin hydrochloride extended-release tablets 2,000 mg once daily and metformin HCl tablets 1,500 mg in divided doses arms, respectively.

7 kg, -1.1 kg, and -0.9 kg in the metformin hydrochloride extended-release tablets 1,500 mg once daily, metformin hydrochloride extended-release tablets 1,500 mg in divided doses, metformin hydrochloride extended-release tablets 2,000 mg once daily and metformin HCl tablets 1,500 mg in divided doses arms, respectively. A double-blind, randomized, placebo-controlled (glyburide add-on) multicenter study enrolled patients with type 2 diabetes mellitus who were newly diagnosed or treated with diet and exercise (n=144), or who were receiving monotherapy with metformin, sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, or meglitinides, or treated with combination therapy consisting of metformin HCl/glyburide at doses up to 1,000 mg metformin + 10 mg glyburide per day (or equivalent doses of glipizide or glimepiride up to half the maximum therapeutic dose) (n=431). All patients were stabilized on glyburide for a 6-week run-in period, and then randomized to 1 of 4 treatments: placebo + glyburide (glyburide alone); metformin hydrochloride extended-release tablets 1,500 mg once a day + glyburide, metformin hydrochloride extended-release tablets 2,000 mg once a day + glyburide, or metformin hydrochloride extended-release tablets 1,000 mg twice a day + glyburide. A 3-week metformin hydrochloride extended-release tablets titration period was followed by a 21-week maintenance treatment period. Use of insulin and oral hypoglycemic agents other than the study drugs were prohibited. The results are presented in Table 5. Table 6: Mean Changes from Baseline in HbA1c and Fasting Plasma Glucose at Week 24 for the Metformin Hydrochloride Extended-Release Tablets + Glyburide Groups and Placebo+ Glyburide Treatment Group in Patients with Type 2 Diabetes Mellitus Metformin Hydrochloride Extended-Release Tablets + Glyburide * Placebo + Glyburide * (n=144) 1,500 mg Once Daily (n=144) 1,000 mg Twice Daily (n=141) 2,000 mg Once Daily (n=146) HbA 1c (%), N 136 136 144 141 Baseline 7.9 7.8 7.7 8.1 Mean Change at Final Visit -0.7 -0.8 -0.7 -0.1 Mean Difference from Glyburide Alone (95% CI) -0.8 a (-1, -0.6) -0.9 a (-1.1, -0.7) -0.8 a (-1, -0.6) N/A Fasting Plasma Glucose (mg/dL), N 143 141 145 144 Baseline 163 163 159 164 Mean Change at Final Visit -14 -16 -9 16 Mean Difference from Glyburide Alone (95% CI) -29.2 a (-39, -20) -31.2 a (-41, -22) -24.9 a (-35, -15) N/A * Glyburide was administered as 10 mg at breakfast and 5 mg at dinner. a p-value for pairwise comparison <0.001 Mean baseline body weight was 89.4 kg, 103.7 kg, 102.9 kg and 95.6 kg in the metformin hydrochloride extended-release tablets 1,500 mg once daily, metformin hydrochloride extended-release tablets 1,500 mg in divided doses, metformin hydrochloride extended-release tablets 2,000 mg once daily and metformin HCl tablets 1,500 mg in divided doses arms, respectively. Mean change in body weight from baseline to week 24 was 0.3 kg, 0.1 kg, 0 kg, and 0.7 kg in the metformin hydrochloride extended-release tablets 1,500 mg once daily, metformin hydrochloride extended-release tablets 1,500 mg in divided doses, metformin hydrochloride extended-release tablets 2,000 mg once daily and metformin HCl tablets 1,500 mg in divided doses arms, respectively.

<table width="90.84%"><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><thead><tr><th align="left" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"/><th align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Metformin hydrochloride extended-release tablets</content></th><th align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Metformin HCl Tablets*</content> <content styleCode="bold">1,500 mg in </content> <content styleCode="bold">Divided Doses</content> <content styleCode="bold">(n=174)</content></th></tr><tr><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">1,500 mg Once Daily</content> <content styleCode="bold">(n=178)</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">1,500 mg in Divided Doses</content> <content styleCode="bold">(n=182)</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">2,000 mg Once Daily</content> <content styleCode="bold">(n=172)</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">HbA_1c (%), N</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>169</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>175</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>159</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>170</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Baseline</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>8.2</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>8.5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>8.3</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>8.7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Mean Change at Final Visit</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>-0.7</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>-0.7</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>-1.1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>-0.7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Mean Difference from Metformin HCl Tablets^* (98.4% CI) </paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0 (-0.3, 0.3)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>0 (-0.3, 0.3)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>-0.4 (-0.7, -0.1)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>N/A</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Fasting Plasma Glucose (mg

ter" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>-0.4 (-0.7, -0.1)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>N/A</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Fasting Plasma Glucose (mg /dL), N</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>175</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>179</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>170</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>172</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Baseline</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>190</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>192.3</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>184</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>197</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Mean Change at Final Visit</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>-39</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>-32</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>-42</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>-32</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Mean Difference from Metformin HCl Tablets^* (95% CI)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>-6 (-15, 2)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>0 (-8, 9)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>-10 (-19, -1)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>N/A</paragraph></td></tr></tbody></table>

ter" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>0 (-8, 9)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>-10 (-19, -1)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>N/A</paragraph></td></tr></tbody></table> <table width="98.78%"><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><thead><tr><th align="left" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"/><th align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Metformin Hydrochloride Extended-Release Tablets + Glyburide^*</content></th><th align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Placebo +</content> <content styleCode="bold">Glyburide^*</content> <content styleCode="bold">(n=144)</content></th></tr><tr><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">1,500 mg Once Daily</content> <content styleCode="bold">(n=144)</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">1,000 mg Twice Daily </content> <content styleCode="bold">(n=141)</content></th><th align="center" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">2,000 mg Once Daily </content> <content styleCode="bold">(n=146)</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">HbA_1c (%), N</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>136</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>136</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>144</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>141</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Baseline</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>7.9</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>7.8</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>7.7</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>8.1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Mean Change at Final Visit</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>-0.7</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>-0.8</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>-0.7</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>-0.1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Mean Difference from Glyburide Alone (95% CI)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>-0.8^a (-1, -0.6)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>-0.9^a (-1.1, -0.7)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>-0.8^a (-1, -0.6)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>N/A</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Fasting Plasma Glucose (mg/dL), N</conte

ule Botrule " valign="middle"><paragraph>-0.8^a (-1, -0.6)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>N/A</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Fasting Plasma Glucose (mg/dL), N</conte nt></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>143</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>141</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>145</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>144</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Baseline</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>163</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>163</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>159</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>164</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Mean Change at Final Visit</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>-14</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>-16</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>-9</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>16</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Mean Difference from Glyburide Alone (95% CI)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>-29.2^a (-39, -20)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>-31.2^a (-41, -22)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>-24.9^a (-35, -15)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>N/A</paragraph></td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING Metformin Hydrochloride Extended-Release Tablets, USP are supplied as: 500 mg Bottles of 100 NDC 68462-520-01 white to off-white, oval shaped, coated tablets, imprinted with ‘G520’ on one side and plain on the other side 500 mg Bottles of 500 NDC 68462-520-05 white to off-white, oval shaped, coated tablets, imprinted with ‘G520’ on one side and plain on the other side 500 mg Bottles of 1,000 NDC 68462-520-10 white to off-white, oval shaped, coated tablets, imprinted with ‘G520’ on one side and plain on the other side 1,000 mg Bottles of 90 NDC 68462-521-90 white to off-white, oval shaped, coated tablets, imprinted with ‘G521’ on one side and plain on the other side 1,000 mg Bottles of 100 NDC 68462-521-01 white to off-white, oval shaped, coated tablets, imprinted with ‘G521’ on one side and plain on the other side 1,000 mg Bottles of 500 NDC 68462-521-05 white to off-white, oval shaped, coated tablets, imprinted with ‘G521’ on one side and plain on the other side Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

<table width="89.28%"><col width="15%"/><col width="17%"/><col width="23%"/><col width="46%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>500 mg</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>Bottles of 100</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>NDC 68462-520-01</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>white to off-white, oval shaped, coated tablets, imprinted with &#x2018;G520&#x2019; on one side and plain on the other side</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><list listType="unordered"><item><caption> </caption>500 mg</item></list></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Bottles of 500</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>NDC 68462-520-05</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>white to off-white, oval shaped, coated tablets, imprinted with &#x2018;G520&#x2019; on one side and plain on the other side</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><list listType="unordered"><item><caption> </caption>500 mg</item></list></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Bottles of 1,000</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>NDC 68462-520-10</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>white to off-white, oval shaped, coated tablets, imprinted with &#x2018;G520&#x2019; on one side and plain on the other side</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>1,000 mg</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Bottles of 90</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>NDC 68462-521-90</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>white to off-white, oval shaped, coated tablets, imprinted with &#x2018;G521&#x2019; on one side and plain on the other side</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><list listType="unordered"><item><caption> </caption>1,000 mg</item></list></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Bottles of 100</paragraph></td><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>NDC 68462-521-01</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>white to off-white, oval shaped, coated tablets, imprinted with &#x2018;G521&#x2019; on one side and plain on the other side</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="middle"><list listType="unordered"><item><caption> </caption>1,000 mg</item></list></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Bottles of 500</paragraph></td><td styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>NDC 68462-521-05</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>white to off-white, oval shaped, coated tablets, imprinted with &#x2018;G521&#x2019; on one side and plain on the other side</paragraph></td></tr></tbody></table>

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Lactic Acidosis: Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development. Advise patients to discontinue metformin hydrochloride extended-release tablets immediately and to promptly notify their healthcare provider if unexplained hyperventilation, myalgias, malaise, unusual somnolence or other nonspecific symptoms occur. Counsel patients against excessive alcohol intake and inform patients about importance of regular testing of renal function while receiving metformin hydrochloride extended-release tablets. Instruct patients to inform their doctor that they are taking metformin hydrochloride extended-release tablets prior to any surgical or radiological procedure, as temporary discontinuation may be required [see Warnings and Precautions ( 5.1 )]. Hypoglycemia Inform patients that hypoglycemia may occur when metformin hydrochloride extended-release tablets are coadministered with oral sulfonylureas and insulin. Explain to patients receiving concomitant therapy the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development [see Warnings and Precautions ( 5.3 )]. Vitamin B 12 Deficiency: Inform patients about importance of regular hematological parameters while receiving metformin hydrochloride extended-release tablets [see Warnings and Precautions ( 5.2 )]. Females of Reproductive Age: Inform females that treatment with metformin hydrochloride extended-release tablets may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy [see Use in Specific Populations ( Error! Hyperlink reference not valid. )]. Administration Information: Inform patients that metformin hydrochloride extended-release tablets must be swallowed whole and not crushed, cut, or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet. Distributed by: Glenmark Pharmaceuticals Inc., USA Elmwood Park, NJ 07407 Questions? 1 (888) 721-7115 www.glenmarkpharma-us.com July 2025 logo1

PATIENT INFORMATION Metformin Hydrochloride (met for' min hye'' droe klor' ide) Extended-Release Tablets, for Oral Use What is the most important information I should know about metformin hydrochloride extended-release tablets? Metformin hydrochloride extended-release tablets can cause serious side effects, including: Lactic acidosis. Metformin hydrochloride, the medicine in metformin hydrochloride extended-release tablets, can cause a rare, but serious side effect called lactic acidosis (a buildup of lactic acid in the blood) that can cause death. Lactic acidosis is a medical emergency and must be treated in the hospital. Stop taking metformin hydrochloride extended-release tablets and call your doctor right away if you get any of the following symptoms of lactic acidosis: • feel very weak and tired • have unusual sleepiness or sleep longer than usual • have unusual (not normal) muscle pain • feel cold, especially in your arms and legs • have trouble breathing • feel dizzy or lightheaded • have unexplained stomach or intestinal problems with nausea and vomiting, or diarrhea • have a slow or irregular heartbeat You have a higher chance of getting lactic acidosis if you: • have severe kidney problems. See “Do not take metformin hydrochloride extended-release tablets if you” • have liver problems. • drink a lot of alcohol (very often or short-term “binge” drinking). • get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever, vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise and do not drink enough fluids. • have certain x-ray tests with injectable dyes or contrast agents. • have surgery or other procedure for which you need to restrict the amount of food and liquid you eat and drink. • have congestive heart failure. • have a heart attack, severe infection, or stroke. • are 65 years of age or older. Tell your doctor if you have any of the problems in the list above. Tell your doctor that you are taking metformin hydrochloride extended-release tablets before you have surgery or x-ray tests. Your doctor may need to stop metformin hydrochloride extended-release tablets for a while if you have surgery or certain x-ray tests. Metformin hydrochloride extended-release tablets can have other serious side effects. See “What are the possible side effects of metformin hydrochloride extended-release tablets?”. What are metformin hydrochloride extended-release tablets? • Metformin hydrochloride extended-release tablets are a prescription medicine that contains metformin hydrochloride. Metformin hydrochloride extended-release tablets are used with diet and exercise to help control high blood sugar (hyperglycemia) in adults with type 2 diabetes. It is not known if metformin hydrochloride extended-release tablets are safe and effective in children. Do not take metformin hydrochloride extended-release tablets if you: • have severe kidney problems. • are allergic to metformin hydrochloride or any of the ingredients in metformin hydrochloride extended-release tablets. See the end of this Patient Information leaflet for a complete list of ingredients in metformin hydrochloride extended-release tablets. • have a condition called metabolic acidosis, including diabetic ketoacidosis (high levels of certain acids called “ketones” in your blood or urine).

chloride extended-release tablets. See the end of this Patient Information leaflet for a complete list of ingredients in metformin hydrochloride extended-release tablets. • have a condition called metabolic acidosis, including diabetic ketoacidosis (high levels of certain acids called “ketones” in your blood or urine). Before taking metformin hydrochloride extended-release tablets tell your doctor about all of your medical conditions, including if you: • have a history or risk for diabetic ketoacidosis. See “Do not take metformin hydrochloride extended-release tablets if you:”. • have kidney problems. • have liver problems. • have heart problems, including congestive heart failure. • are 65 years of age or older. • drink alcohol very often, or drink a lot of alcohol in short-term “binge” drinking. • are taking insulin or a sulfonylurea medicine. • are pregnant or plan to become pregnant. It is not known if metformin hydrochloride extended-release tablets can harm your unborn baby. If you are pregnant, talk with your doctor about the best way to control your blood sugar while you are pregnant. • are a woman who has not gone through menopause (premenopausal) who does not have periods regularly or at all. Metformin hydrochloride extended-release tablets can cause the release of an egg from an ovary in a woman (ovulation). This can increase your chance of getting pregnant. • are breastfeeding or plan to breastfeed. Metformin hydrochloride can pass into your breast milk. Talk with your doctor about the best way to feed your baby while you take metformin hydrochloride extended-release tablets. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Know the medicines you take. Keep a list of them to show your doctor and pharmacist. Talk to your doctor before you start any new medicine. Metformin hydrochloride extended-release tablets may affect the way other medicines work, and other medicines may affect how metformin hydrochloride extended-release tablets works. How should I take metformin hydrochloride extended-release tablets? • Take metformin hydrochloride extended-release tablets exactly as your doctor tells you. • Metformin hydrochloride extended-release tablets should be taken 1 time each day with your evening meal to help decrease an upset stomach. • Swallow metformin hydrochloride extended-release tablets whole. Do not crush, cut, or chew the tablets. • You may sometimes pass a soft mass in your stools (bowel movement) that looks like metformin hydrochloride extended-release tablets. This is normal and will not affect the way metformin hydrochloride extended-release tablets works. • When your body is under some type of stress, such as fever, trauma (such as a car accident), infection, or surgery, the amount of diabetes medicine that you need may change. Tell your doctor right away if you have any of these problems. • Your doctor should do blood tests to check how well your kidneys are working before and during your treatment with metformin hydrochloride extended-release tablets. • Your doctor will check your diabetes with regular blood tests, including your blood sugar levels and your hemoglobin A1C. • Low blood sugar (hypoglycemia) can happen more often when metformin hydrochloride extended-release tablets are taken with certain other diabetes medicines. Talk to your doctor about how to prevent, recognize, and manage low blood sugar. See “What are the possible side effects of metformin hydrochloride extended-release tablets?”. • Check your blood sugar as your doctor tells you to. • Stay on your prescribed diet and exercise program while taking metformin hydrochloride extended-release tablets.

t how to prevent, recognize, and manage low blood sugar. See “What are the possible side effects of metformin hydrochloride extended-release tablets?”. • Check your blood sugar as your doctor tells you to. • Stay on your prescribed diet and exercise program while taking metformin hydrochloride extended-release tablets. • If you miss a dose of metformin hydrochloride extended-release tablets, take your next dose at the normal schedule. Do not take 2 doses of metformin hydrochloride extended-release tablets on the same day. • If you take too many metformin hydrochloride extended-release tablets, call your doctor or go to the nearest hospital emergency room right away. What should I avoid while taking metformin hydrochloride extended-release tablets? Do not drink a lot of alcoholic drinks while taking metformin hydrochloride extended-release tablets. This means you should not binge drink for short periods, and you should not drink a lot of alcohol on a regular basis. Alcohol can increase the chance of getting lactic acidosis. What are the possible side effects of metformin hydrochloride extended-release tablets? Metformin hydrochloride extended-release tablets can cause serious side effects, including: • See “What is the most important information I should know about metformin hydrochloride extended-release tablets?”. • Low vitamin B 12 (vitamin B 12 deficiency). Using metformin hydrochloride extended-release tablets may cause a decrease in the amount of vitamin B 12 in your blood, especially if you have had low vitamin B 12 levels before. Your doctor may do blood tests to check your vitamin B 12 levels. • Low blood sugar (hypoglycemia). Low blood sugar is a serious, but common, side effect of metformin hydrochloride extended-release tablets. If you take metformin hydrochloride extended-release tablets with another medicine that can cause low blood sugar, such as sulfonylureas or insulin, you have a higher risk of getting low blood sugar. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take metformin hydrochloride extended-release tablets. Signs and symptoms of low blood sugar may include: • headache • hunger • dizziness • drowsiness • fast heartbeat • sweating • weakness • confusion • irritability • shaking or feeling jittery The most common side effects of metformin hydrochloride extended-release tablets include: • diarrhea • nausea These are not all of the possible side effects of metformin hydrochloride extended-release tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store metformin hydrochloride extended-release tablets? • Store metformin hydrochloride extended-release tablets at 68°F to 77°F (20°C to 25°C). Keep metformin hydrochloride extended-release tablets and all medicines out of the reach of children. General information about the safe and effective use of metformin hydrochloride extended-release tablets. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use metformin hydrochloride extended-release tablets for a condition for which it was not prescribed. Do not give metformin hydrochloride extended-release tablets to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or doctor for information about metformin hydrochloride extended-release tablets that is written for health professionals. For more information about metformin hydrochloride extended-release tablets, you can contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115. What are the ingredients in metformin hydrochloride extended-release tablets?

ut metformin hydrochloride extended-release tablets that is written for health professionals. For more information about metformin hydrochloride extended-release tablets, you can contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115. What are the ingredients in metformin hydrochloride extended-release tablets? Active Ingredient : metformin hydrochloride Inactive Ingredient: ammonio methacrylate copolymer dispersion type A, ammonio methacrylate copolymer dispersion type B, hypromellose, magnesium stearate, povidone K 30, talc, titanium dioxide, and triethyl citrate. The tablets are imprinted using a water-soluble black ink which contains shellac, black iron oxide, propylene glycol and ammonium hydroxide. Distributed by: Glenmark Pharmaceuticals Inc., USA Elmwood Park, NJ 07407 Questions? 1 (888) 721-7115 www.glenmarkpharma-us.com July 2025 logo2

<table width="99.72%"><col width="50%"/><col width="50%"/><tbody><tr><td styleCode="Toprule " valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>feel very weak and tired</item></list></td><td styleCode="Toprule " valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>have unusual sleepiness or sleep longer than usual</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>have unusual (not normal) muscle pain</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>feel cold, especially in your arms and legs</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>have trouble breathing</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>feel dizzy or lightheaded</item></list></td></tr><tr><td styleCode="Botrule " valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>have unexplained stomach or intestinal problems with nausea and vomiting, or diarrhea</item></list></td><td styleCode="Botrule " valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>have a slow or irregular heartbeat</item></list></td></tr></tbody></table>

unordered"><item><caption>&#x2022;</caption>have unexplained stomach or intestinal problems with nausea and vomiting, or diarrhea</item></list></td><td styleCode="Botrule " valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>have a slow or irregular heartbeat</item></list></td></tr></tbody></table> <table width="88.74%"><col width="27%"/><col width="40%"/><col width="33%"/><tbody><tr><td styleCode="Toprule " valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>headache</item></list></td><td styleCode="Toprule " valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>hunger</item></list></td><td styleCode="Toprule " valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>dizziness </item></list></td></tr><tr><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>drowsiness</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>fast heartbeat</item></list></td><td rowspan="3" valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>sweating</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>weakness</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>confusion</item></list></td></tr><tr><td styleCode="Botrule " valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>irritability</item></list></td><td styleCode="Botrule " valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>shaking or feeling jittery</item></list></td></tr></tbody></table>

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 [ see Dosage and Administration ( 2.2 ), Contraindications ( 4 ), Warnings and Precautions ( 5.1 ) ]. 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 groups are provided in the Full Prescribing Information. ( 5.1 ) If lactic acidosis is suspected, discontinue metformin hydrochloride extended-release tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. ( 5.1 )

1 INDICATIONS AND USAGE Metformin hydrochloride extended-release tablets, USP are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Metformin hydrochloride extended-release tablets, USP are a biguanide indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 )

2 DOSAGE AND ADMINISTRATION Swallow metformin hydrochloride extended-release tablets whole and never crush, cut or chew ( 2.1 ) Starting dose: 500 mg orally once daily with the evening meal ( 2.1 ) Increase the dose in increments of 500 mg weekly, up to a maximum of 2,000 mg once daily with the evening meal ( 2.1 ) Patients receiving metformin hydrochloride (HCl) tablets may be switched to metformin hydrochloride extended-release tablets once daily at the same total daily dose, up to 2,000 mg once daily ( 2.1 ) Renal Impairment: Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) ( 2.2 ) Do not use in patients with eGFR below 30 mL/minute/1.73 m 2 ( 2.2 ) Initiation is not recommended in patients with eGFR between 30 mL/minute/1.73 m 2 to 45 mL/minute/1.73 m 2 ( 2.2 ) Assess risk/benefit of continuing if eGFR falls below 45 mL/minute/1.73 m 2 ( 2.2 ) Discontinue if eGFR falls below 30 mL/minute/1.73 m 2 ( 2.2 ) Discontinuation for Iodinated Contrast Imaging Procedures: Metformin hydrochloride extended-release tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures ( 2.3 ) 2.1 Adult Dosage and Administration Swallow metformin hydrochloride extended-release tablets whole and never crush, cut or chew. The recommended starting dose of metformin hydrochloride extended-release tablets is 500 mg orally once daily with the evening meal. Increase the dose in increments of 500 mg weekly on the basis of glycemic control and tolerability, up to a maximum of 2,000 mg once daily with the evening meal. If glycemic control is not achieved with metformin hydrochloride extended-release tablets 2,000 mg once daily, consider a trial of metformin hydrochloride extended-release tablets 1,000 mg twice daily. Patients receiving metformin hydrochloride (HCl) may be switched to metformin hydrochloride extended-release tablets once daily at the same total daily dose, up to 2,000 mg once daily. 2.2 Recommendations for Use in Renal Impairment Assess renal function prior to initiation of metformin hydrochloride extended-release tablets and periodically thereafter. Metformin hydrochloride extended-release tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m 2 . Initiation of metformin hydrochloride extended-release tablets in patients with an eGFR between 30 mL/minute/1.73 m 2 to 45 mL/minute/1.73 m 2 is not recommended. In patients taking metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/min/1.73 m 2 , assess the benefit risk of continuing therapy. Discontinue metformin hydrochloride extended-release tablets if the patient’s eGFR later falls below 30 mL/minute/1.73 m 2 [ see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 ) ]. 2.3 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 mL/min/1.73 m 2 and 60 mL/min/1.73 m 2 ; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart metformin hydrochloride extended-release tablets if renal function is stable.

3 DOSAGE FORMS AND STRENGTHS Metformin hydrochloride extended-release tablets, USP is available as: Extended-release tablets : 1,000 mg white to off-white colored, oval shaped, biconvex, unscored coated tablets imprinted with “ME2” in black ink on one side and plain on the other side. Extended-Release Tablets: 1,000 mg ( 3 )

4 CONTRAINDICATIONS Metformin hydrochloride extended-release tablets are contraindicated in patients with: Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) [ see Warnings and Precautions ( 5.1 ) ]. Hypersensitivity to metformin. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) ( 4 , 5.1 ) Hypersensitivity to metformin ( 4 ) Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. ( 4 )

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 year 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, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (> 5 mmol/L), 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 hydrochloride is dialyzable with a clearance of up to 170 mL/min 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 postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include [ see Dosage and Administration ( 2.2 ), Clinical Pharmacology ( 12.3 ) ]: Before initiating metformin hydrochloride extended-release tablets, obtain an estimated glomerular filtration rate (eGFR). Metformin hydrochloride extended-release tablets are contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2 [see Contraindications ( 4 ) ]. Initiation of metformin hydrochloride extended-release tablets are not recommended in patients with eGFR between 30 mL/min/1.73 m 2 to 45 mL/min/1.73 m 2 . Obtain an eGFR at least annually in all patients taking metformin hydrochloride extended-release tablets.

ss than 30 mL/min/1.73 m 2 [see Contraindications ( 4 ) ]. Initiation of metformin hydrochloride extended-release tablets are not recommended in patients with eGFR between 30 mL/min/1.73 m 2 to 45 mL/min/1.73 m 2 . Obtain an eGFR at least annually in all patients taking metformin hydrochloride extended-release tablets. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. In patients taking metformin hydrochloride extended-release tablets whose eGFR falls below 45 mL/min/1.73 m 2 , assess the benefit and risk of continuing therapy. Drug interactions — The concomitant use of metformin hydrochloride extended-release tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation [see Drug Interactions ( 7 )] . Consider more frequent monitoring of patients. Age 65 or greater — The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients. Radiologic studies with contrast — Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 mL/min/1.73 m 2 and 60 mL/min/1.73 m 2 ; in patients with a history of hepatic impairment, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart metformin hydrochloride extended-release tablets if renal function is stable. Surgery and other procedures — Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment. Metformin hydrochloride extended-release tablets should be temporarily discontinued while patients have restricted food and fluid intake. Hypoxic states — Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may cause prerenal azotemia. When such an event occurs, discontinue metformin hydrochloride extended-release tablets. Excessive alcohol intake — Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving metformin hydrochloride extended-release tablets. Hepatic impairment — Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of metformin hydrochloride extended-release tablets in patients with clinical or laboratory evidence of hepatic disease. 5.2 Vitamin B 12 Deficiency In clinical trials of 29-week duration with metformin HCl tablets, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients.

hloride extended-release tablets in patients with clinical or laboratory evidence of hepatic disease. 5.2 Vitamin B 12 Deficiency In clinical trials of 29-week duration with metformin HCl tablets, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation. Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. Measure hematologic parameters on an annual basis and vitamin B 12 at 2 year to 3 year intervals in patients on metformin hydrochloride extended-release tablets and manage any abnormalities [ see Adverse Reactions ( 6.1 ) ]. 5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. Metformin hydrochloride extended-release tablets may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with metformin hydrochloride extended-release tablets [ see Drug Interactions ( 7 ) ]. 5.4 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin hydrochloride extended-release tablets.

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 ) ] Common adverse reactions are diarrhea, nausea/vomiting, abdominal pain, constipation, abdomen distention, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ajanta Pharma USA Inc. at 855-664-7744 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. In placebo-controlled trials, 781 patients were administered metformin hydrochloride extended-release tablets. Adverse reactions reported in greater than 5% of the patients treated with metformin hydrochloride extended-release tablets and that were more common than in placebo-treated patients are listed in Table 1. Table 1: Adverse Reactions from Clinical Trials of Metformin Hydrochloride Extended-Release Tablets Occurring > 5% and More Common than Placebo in Patients with Type 2 Diabetes Mellitus Adverse Reaction Metformin Hydrochloride Extended-Release Tablets (n=781) Placebo (n=195) Diarrhea 10% 3% Nausea/Vomiting 7% 2% Diarrhea led to the discontinuation of metformin hydrochloride extended-release tablets in 0.6% of patients. Additionally, the following adverse reactions were reported in 1.0% to 5.0% of patients treated with metformin hydrochloride extended-release tablets and were more commonly reported than in placebo-treated patients: abdominal pain, constipation, abdomen distention, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance. Laboratory Tests Vitamin B 12 Concentrations In clinical trials of 29-week duration with metformin HCl tablets, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients. 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.

<table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 1: Adverse Reactions from Clinical Trials of Metformin Hydrochloride Extended-Release Tablets Occurring &gt; 5% and More Common than Placebo in Patients with Type 2 Diabetes Mellitus</caption><col width="33.34%"/><col width="49.88%"/><col width="16.78%"/><tbody><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Adverse Reaction </td><td align="center" styleCode="Rrule" valign="top">Metformin Hydrochloride Extended-Release Tablets (n=781) </td><td align="center" styleCode="Rrule" valign="top">Placebo (n=195) </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Diarrhea </td><td align="center" styleCode="Rrule" valign="top">10% </td><td align="center" styleCode="Rrule" valign="top">3% </td></tr><tr><td align="justify" styleCode="Lrule Rrule" valign="top">Nausea/Vomiting </td><td align="center" styleCode="Rrule" valign="top">7% </td><td align="center" styleCode="Rrule" valign="top">2% </td></tr></tbody></table>

7 DRUG INTERACTIONS Table 2 presents clinically significant drug interactions with metformin hydrochloride extended-release tablets. Table 2: Clinically Significant Drug Interactions with Metformin hydrochloride extended-release tablets Carbonic Anhydrase Inhibitors Clinical Impact: Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with metformin hydrochloride extended-release tablets may increase the risk for lactic acidosis. Intervention: Consider more frequent monitoring of these patients. Examples: Topiramate, zonisamide, acetazolamide or dichlorphenamide. Drugs that Reduce Metformin hydrochloride extended-release tablets Clearance Clinical Impact: Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology ( 12.3 )]. Intervention: Consider the benefits and risks of concomitant use with metformin hydrochloride extended-release tablets. Examples: Ranolazine, vandetanib, dolutegravir, and cimetidine. Alcohol Clinical Impact: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Intervention: Warn patients against excessive alcohol intake while receiving metformin hydrochloride extended-release tablets. Insulin Secretagogues or Insulin Clinical Impact: Coadministration of metformin hydrochloride extended-release tablets with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia. Intervention: Patients receiving an insulin secretagogue or insulin may require lower doses of the insulin secretagogue or insulin. Drugs Affecting Glycemic Control Clinical Impact: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. Intervention: When such drugs are administered to a patient receiving metformin hydrochloride extended-release tablets, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin hydrochloride extended-release tablets, observe the patient closely for hypoglycemia. Examples: Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring ( 7 ) Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin. Consider the benefits and risks of concomitant use ( 7 ) Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake ( 7 )

<table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 2: Clinically Significant Drug Interactions with Metformin hydrochloride extended-release tablets</caption><col width="19.16%"/><col width="80.84%"/><tbody><tr styleCode="Botrule"><td colspan="2" align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Carbonic Anhydrase Inhibitors</content> </td></tr><tr styleCode="Botrule"><td align="right" styleCode="Lrule Rrule" valign="middle"><content styleCode="italics">Clinical Impact:</content><content styleCode="bold"/> </td><td align="justify" styleCode="Rrule" valign="top">Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with metformin hydrochloride extended-release tablets may increase the risk for lactic acidosis. </td></tr><tr styleCode="Botrule"><td align="right" styleCode="Lrule Rrule" valign="middle"><content styleCode="italics">Intervention:</content><content styleCode="bold"/> </td><td align="justify" styleCode="Rrule" valign="top">Consider more frequent monitoring of these patients. </td></tr><tr styleCode="Botrule"><td align="right" styleCode="Lrule Rrule" valign="middle"><content styleCode="italics">Examples:</content> </td><td align="justify" styleCode="Rrule" valign="top">Topiramate, zonisamide, acetazolamide or dichlorphenamide. </td></tr><tr styleCode="Botrule"><td colspan="2" align="justify" styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Drugs that Reduce</content><content styleCode="bold">Metformin hydrochloride extended-release tablets Clearance</content> </td></tr><tr styleCode="Botrule"><td align="right" styleCode="Lrule Rrule" valign="middle"><content styleCode="italics">Clinical Impact:</content> </td><td align="justify" styleCode="Rrule" valign="top">Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis <content styleCode="italics">[see Clinical Pharmacology ( <linkHtml href="#Section_12.3">12.3</linkHtml>)]. </content> </td></tr><tr styleCode="Botrule"><td align="right" styleCode="Lrule Rrule" valign="middle"><content styleCode="italics">Intervention:</content> </td><td align="justify" styleCode="Rrule" valign="top">Consider the benefits and risks of concomitant use with metformin hydrochloride extended-release tablets. </td></tr><tr styleCode="Botrule"><td align="right" styleCode="Lrule Rrule" valign="middle"><content styleCode="italics">Examples:</content> </td><td styleCode="Rrule" valign="middle">Ranolazine, vandetanib, dolutegravir, and cimetidine. </td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Alcohol</content> </td></tr><tr styleCode="Botrule"><td align="right" styleCode="Lrule Rrule" valign="middle"><content styleCode="italics">Clinical Impact:</content><content styleCode="bold"/> </td><td align="justify" styleCode="Rrule" valign="top">Alcohol is known to potentiate the effect of metformin on lactate metabolism.

l</content> </td></tr><tr styleCode="Botrule"><td align="right" styleCode="Lrule Rrule" valign="middle"><content styleCode="italics">Clinical Impact:</content><content styleCode="bold"/> </td><td align="justify" styleCode="Rrule" valign="top">Alcohol is known to potentiate the effect of metformin on lactate metabolism. </td></tr><tr styleCode="Botrule"><td align="right" styleCode="Lrule Rrule" valign="middle"><content styleCode="italics">Intervention:</content><content styleCode="bold"/> </td><td align="justify" styleCode="Rrule" valign="top">Warn patients against excessive alcohol intake while receiving metformin hydrochloride extended-release tablets. </td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Insulin Secretagogues or Insulin</content> </td></tr><tr styleCode="Botrule"><td align="right" styleCode="Lrule Rrule" valign="middle"><content styleCode="italics">Clinical Impact:</content> </td><td align="justify" styleCode="Rrule" valign="top">Coadministration of metformin hydrochloride extended-release tablets with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia. </td></tr><tr styleCode="Botrule"><td align="right" styleCode="Lrule Rrule" valign="middle"><content styleCode="italics">Intervention:</content> </td><td align="justify" styleCode="Rrule" valign="top">Patients receiving an insulin secretagogue or insulin may require lower doses of the insulin secretagogue or insulin. </td></tr><tr styleCode="Botrule"><td colspan="2" styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Drugs Affecting Glycemic Control</content> </td></tr><tr styleCode="Botrule"><td align="right" styleCode="Lrule Rrule" valign="middle"><content styleCode="italics">Clinical Impact:</content> </td><td align="justify" styleCode="Rrule" valign="top">Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. </td></tr><tr styleCode="Botrule"><td align="right" styleCode="Lrule Rrule" valign="middle"><content styleCode="italics">Intervention:</content> </td><td align="justify" styleCode="Rrule" valign="top">When such drugs are administered to a patient receiving metformin hydrochloride extended-release tablets, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin hydrochloride extended-release tablets, observe the patient closely for hypoglycemia. </td></tr><tr><td align="right" styleCode="Lrule Rrule" valign="middle"><content styleCode="italics">Examples:</content> </td><td align="justify" styleCode="Rrule" valign="top">Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. </td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. ( 8.3 ) Geriatric Use: Assess renal function more frequently. ( 8.5 ) Hepatic Impairment: Avoid use in patients with hepatic impairment. ( 8.7 ) 8.1 Pregnancy Risk Summary Limited data with metformin hydrochloride extended-release tablets in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see Data] . There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy [ see Clinical Considerations ]. No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- and 5- times, respectively, a 2,550 mg clinical dose, based on body surface area [see Data]. The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes mellitus with an HbA1C > 7 and has been reported to be as high as 20% to 25% in women with a HbA1C > 10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly-controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Human Data Published data from post-marketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. Animal Data Metformin hydrochloride did not adversely affect development outcomes when administered to pregnant rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 5 times a 2,550 mg clinical dose based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin. 8.2 Lactation Risk Summary Limited published studies report that metformin is present in human milk [ see Data ]. However, there is insufficient information to determine the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for metformin hydrochloride extended-release tablets and any potential adverse effects on the breastfed child from metformin hydrochloride extended-release tablets or from the underlying maternal condition.

the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for metformin hydrochloride extended-release tablets and any potential adverse effects on the breastfed child from metformin hydrochloride extended-release tablets or from the underlying maternal condition. Data Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants. 8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin hydrochloride extended-release tablets may result in ovulation in some anovulatory women. 8.4 Pediatric Use Safety and effectiveness of metformin hydrochloride extended-release tablets in pediatric patients have not been established. 8.5 Geriatric Use Controlled clinical studies of metformin hydrochloride extended-release tablets did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [ see Warnings and Precautions ( 5.1 ) ]. 8.6 Renal Impairment Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Metformin hydrochloride extended-release tablets are contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m 2 [ see Dosage and Administration ( 2.2 ), Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), and Clinical Pharmacology ( 12.3 ) ]. 8.7 Hepatic Impairment Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Metformin hydrochloride extended-release tablets are not recommended in patients with hepatic impairment [ see Warnings and Precautions ( 5.1 ) ].

8.1 Pregnancy Risk Summary Limited data with metformin hydrochloride extended-release tablets in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see Data] . There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy [ see Clinical Considerations ]. No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- and 5- times, respectively, a 2,550 mg clinical dose, based on body surface area [see Data]. The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes mellitus with an HbA1C > 7 and has been reported to be as high as 20% to 25% in women with a HbA1C > 10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly-controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Human Data Published data from post-marketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. Animal Data Metformin hydrochloride did not adversely affect development outcomes when administered to pregnant rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 5 times a 2,550 mg clinical dose based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

8.2 Lactation Risk Summary Limited published studies report that metformin is present in human milk [ see Data ]. However, there is insufficient information to determine the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for metformin hydrochloride extended-release tablets and any potential adverse effects on the breastfed child from metformin hydrochloride extended-release tablets or from the underlying maternal condition. Data Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants.

8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin hydrochloride extended-release tablets may result in ovulation in some anovulatory women.

8.5 Geriatric Use Controlled clinical studies of metformin hydrochloride extended-release tablets did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [ see Warnings and Precautions ( 5.1 ) ].

10 OVERDOSAGE Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [ see Warnings and Precautions ( 5.1 ) ]. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

11 DESCRIPTION Metformin hydrochloride extended-release tablets, USP contain the biguanidine antihyperglycemic agent, metformin, in the form of monohydrochloride salt. The chemical name of metformin hydrochloride USP is N, N-dimethylimidodicarbonimidic diamide hydrochloride with a molecular formula of C 4 H 11 N 5 •HCl and a molecular weight of 165.62. Its structural formula is: Metformin hydrochloride USP is a white crystalline powder that is freely soluble in water and practically insoluble in acetone, ether and chloroform. The pKa of metformin are 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. Metformin hydrochloride extended-release tablets, USP deliver 500 mg or 1,000 mg of metformin hydrochloride, which is equivalent to 389.93 mg or 779.86 mg metformin, respectively. In addition to the active ingredient metformin hydrochloride, each tablet contains the following inactive ingredients: hypromellose, magnesium stearate, polyethylene glycol (PEG 400), povidone, pregelatinized starch, ethyl cellulose. Imprinting ink contains: shellac, ferrosoferric oxide, propylene glycol and ammonium hydroxide. Metformin hydrochloride extended-release tablets meets USP Dissolution Test 18. structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease. 12.3 Pharmacokinetics Absorption In a multiple-dose crossover study, 23 patients with type 2 diabetes mellitus were administered either metformin hydrochloride extended-release tablets 2,000 mg once a day (after dinner) or metformin hydrochloride tablets 1,000 mg twice a day (after breakfast and after dinner). After 4 weeks of treatment, steady-state pharmacokinetic parameters, area under the concentration-time curve (AUC), time to peak plasma concentration (T max ), and maximum concentration (C max ) were evaluated. The appearance of metformin in plasma from metformin hydrochloride extended-release tablets is slower and more prolonged compared to metformin HCl tablets. Results are presented in Table 3. *Immediate-release metformin HCl tablets Table 3: Metformin hydrochloride extended-release tablets vs. Metformin HCl Tablets Steady-State Pharmacokinetic Parameters at 4 Weeks Pharmacokinetic Parameters (mean ± SD) Metformin hydrochloride extended-release tablets 2,000 mg (administered once daily after dinner) Metformin HCl tablets* 2,000 mg (1,000 mg twice daily) AUC 0-24hr (ng•hr/mL) 26,811 ± 7,055 27,371 ± 5,781 T max (hr) 6 (3-10) 3 (1-8) C max (ng/mL) 2,849 ± 797 1,820 ± 370 In four single-dose studies and one multiple-dose study, the bioavailability of metformin hydrochloride extended-release tablets 2,000 mg given once daily, in the evening, under fed conditions [as measured by AUC] was similar to the same total daily dose administered as metformin HCl tablets 1,000 mg given twice daily. The geometric mean ratios (metformin hydrochloride extended-release tablets/ metformin HCl tablets) of AUC 0-24hr , AUC 0-72hr , and AUC 0-inf for these five studies ranged from 0.96 to 1.08. In a single-dose, four-period replicate crossover design study, comparing two 500 mg metformin hydrochloride extended-release tablets to one 1,000 mg metformin hydrochloride extended-release tablet administered in the evening with food to 29 healthy male subjects, two 500 mg metformin hydrochloride extended-release tablets were found to be equivalent to one 1,000 mg metformin hydrochloride extended-release tablet. In a study carried out with metformin hydrochloride extended-release tablets, there was a dose-associated increase in metformin exposure over 24 hours following oral administration of 1,000 mg, 1,500 mg, 2,000 mg, and 2,500 mg. In three studies with metformin hydrochloride extended-release tablets using different treatment regimens (2,000 mg after dinner; 1,000 mg after breakfast and after dinner; and 2,500 mg after dinner), the pharmacokinetics of metformin as measured by AUC appeared linear following multiple-dose administration. Effect of food : The extent of metformin absorption (as measured by AUC) from metformin hydrochloride extended-release tablets increased by approximately 60% when given with food.

er; and 2,500 mg after dinner), the pharmacokinetics of metformin as measured by AUC appeared linear following multiple-dose administration. Effect of food : The extent of metformin absorption (as measured by AUC) from metformin hydrochloride extended-release tablets increased by approximately 60% when given with food. When metformin hydrochloride extended-release tablets was administered with food, C max was increased by approximately 30% and T max was more prolonged compared with the fasting state (6.1 versus 4.0 hours). Distribution The apparent volume of distribution (V/F) of metformin following single oral doses of metformin HCl tablets 850 mg averaged 654 L ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. Metabolism Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Elimination Renal clearance (see Table 4) is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. Specific Populations Renal Impairment In patients with decreased renal function the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased (see Table 4) [ See Dosage and Administration ( 2.2 ), Contraindications ( 4 ), and Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.6 ) ] . Hepatic Impairment No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment [ See Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.7 ) ]. Geriatrics Limited data from controlled pharmacokinetic studies of metformin HCl tablets in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and C max is increased, compared to healthy young subjects. It appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 4). [ See Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.5 ) ].

decreased, the half-life is prolonged, and C max is increased, compared to healthy young subjects. It appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 4). [ See Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.5 ) ]. Table 4: Select Mean (±S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin HCl Tablets a All doses given fasting except the first 18 doses of the multiple dose studies b Peak plasma concentration c Time to peak plasma concentration d Combined results (average means) of five studies: mean age 32 years (range 23 years to 59 years) e Kinetic study done following dose 19, given fasting f Elderly subjects, mean age 71 years (range 65 years to 81 years) g CLcr = creatinine clearance normalized to body surface area of 1.73 m 2 Subject Groups: Metformin Hydrochloride dose a (number of subjects) C max b (mcg/mL) T max c (hrs) Renal Clearance (mL/min) Healthy, nondiabetic adults: 500 mg single dose (24) 1.03 (±0.33) 2.75 (±0.81) 600 (±132) 850 mg single dose (74) d 1.60 (±0.38) 2.64 (±0.82) 552 (±139) 850 mg three times daily for 19 doses e (9) 2.01 (±0.42) 1.79 (±0.94) 642 (±173) Adults with type 2 diabetes mellitus: 850 mg single dose (23) 1.48 (±0.5) 3.32 (±1.08) 491 (±138) 850 mg three times daily for 19 doses e (9) 1.90 (±0.62) 2.01 (±1.22) 550 (±160) Elderly f , healthy nondiabetic adults: 850 mg single dose (12) 2.45 (±0.70) 2.71 (±1.05) 412 (±98) Renal-impaired adults: 850 mg single dose Mild (CLcr g 61 mL/min to 90 mL/min) (5) 1.86 (±0.52) 3.20 (±0.45) 384 (±122) Moderate (CLcr 31 mL/min to 60 mL/min) (4) 4.12 (±1.83) 3.75 (±0.50) 108 (±57) Severe (CLcr 10 mL/min to 30 mL/min) (6) 3.93 (±0.92) 4.01 (±1.10) 130 (±90) Pediatrics There are no available pharmacokinetic data with metformin hydrochloride extended-release tablets in pediatric patients. Gender Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes mellitus when analyzed according to gender (males=19, females=16). Race No studies of metformin pharmacokinetic parameters according to race have been performed. Drug Interactions In Vivo Assessment of Drug Interactions Table 5: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure * All metformin hydrochloride and coadministered drugs were given as single doses † AUC = AUC inf ‡ Ratio of arithmetic means § At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC 0-12h Coadministered Drug Dose of Coadministered Drug* Dose of Metformin hydrochloride* Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00 AUC † C max No dosing adjustments required for the following: Glyburide 5 mg 850 mg metformin 0.91 ‡ 0.93 ‡ Furosemide 40 mg 850 mg metformin 1.09 ‡ 1.22 ‡ Nifedipine 10 mg 850 mg metformin 1.16 1.21 Propranolol 40 mg 850 mg metformin 0.90 0.94 Ibuprofen 400 mg 850 mg metformin 1.05 ‡ 1.07 ‡ Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination [ See Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7 ).

50 mg metformin 1.09 ‡ 1.22 ‡ Nifedipine 10 mg 850 mg metformin 1.16 1.21 Propranolol 40 mg 850 mg metformin 0.90 0.94 Ibuprofen 400 mg 850 mg metformin 1.05 ‡ 1.07 ‡ Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination [ See Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7 ). ] Cimetidine 400 mg 850 mg metformin 1.40 1.61 Carbonic anhydrase inhibitors may cause metabolic acidosis [See Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7 ).] Topiramate 100 mg § 500 mg § metformin 1.25 § 1.17 Table 6: Effect of Metformin on Coadministered Drug Systemic Exposure * All metformin hydrochloride and coadministered drugs were given as single doses † AUC = AUC inf unless otherwise noted ‡ Ratio of arithmetic means, p-value of difference < 0.05 § AUC 0-24 hr reported ¶ Ratio of arithmetic means Coadministered Drug Dose of Coadministered Drug* Dose of Metformin hydrochloride* Geometric Mean Ratio (ratio with/without metformin) No Effect = 1.00 AUC † C max No dosing adjustments required for the following: Glyburide 5 mg 850 mg glyburide 0.78 ‡ 0.63 ‡ Furosemide 40 mg 850 mg furosemide 0.87 ‡ 0.69 ‡ Nifedipine 10 mg 850 mg nifedipine 1.10 § 1.08 Propranolol 40 mg 850 mg propranolol 1.01 § 1.02 Ibuprofen 400 mg 850 mg ibuprofen 0.97 ¶ 1.01 ¶ Cimetidine 400 mg 850 mg cimetidine 0.95 § 1.01

12.1 Mechanism of Action Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

12.3 Pharmacokinetics Absorption In a multiple-dose crossover study, 23 patients with type 2 diabetes mellitus were administered either metformin hydrochloride extended-release tablets 2,000 mg once a day (after dinner) or metformin hydrochloride tablets 1,000 mg twice a day (after breakfast and after dinner). After 4 weeks of treatment, steady-state pharmacokinetic parameters, area under the concentration-time curve (AUC), time to peak plasma concentration (T max ), and maximum concentration (C max ) were evaluated. The appearance of metformin in plasma from metformin hydrochloride extended-release tablets is slower and more prolonged compared to metformin HCl tablets. Results are presented in Table 3. *Immediate-release metformin HCl tablets Table 3: Metformin hydrochloride extended-release tablets vs. Metformin HCl Tablets Steady-State Pharmacokinetic Parameters at 4 Weeks Pharmacokinetic Parameters (mean ± SD) Metformin hydrochloride extended-release tablets 2,000 mg (administered once daily after dinner) Metformin HCl tablets* 2,000 mg (1,000 mg twice daily) AUC 0-24hr (ng•hr/mL) 26,811 ± 7,055 27,371 ± 5,781 T max (hr) 6 (3-10) 3 (1-8) C max (ng/mL) 2,849 ± 797 1,820 ± 370 In four single-dose studies and one multiple-dose study, the bioavailability of metformin hydrochloride extended-release tablets 2,000 mg given once daily, in the evening, under fed conditions [as measured by AUC] was similar to the same total daily dose administered as metformin HCl tablets 1,000 mg given twice daily. The geometric mean ratios (metformin hydrochloride extended-release tablets/ metformin HCl tablets) of AUC 0-24hr , AUC 0-72hr , and AUC 0-inf for these five studies ranged from 0.96 to 1.08. In a single-dose, four-period replicate crossover design study, comparing two 500 mg metformin hydrochloride extended-release tablets to one 1,000 mg metformin hydrochloride extended-release tablet administered in the evening with food to 29 healthy male subjects, two 500 mg metformin hydrochloride extended-release tablets were found to be equivalent to one 1,000 mg metformin hydrochloride extended-release tablet. In a study carried out with metformin hydrochloride extended-release tablets, there was a dose-associated increase in metformin exposure over 24 hours following oral administration of 1,000 mg, 1,500 mg, 2,000 mg, and 2,500 mg. In three studies with metformin hydrochloride extended-release tablets using different treatment regimens (2,000 mg after dinner; 1,000 mg after breakfast and after dinner; and 2,500 mg after dinner), the pharmacokinetics of metformin as measured by AUC appeared linear following multiple-dose administration. Effect of food : The extent of metformin absorption (as measured by AUC) from metformin hydrochloride extended-release tablets increased by approximately 60% when given with food. When metformin hydrochloride extended-release tablets was administered with food, C max was increased by approximately 30% and T max was more prolonged compared with the fasting state (6.1 versus 4.0 hours). Distribution The apparent volume of distribution (V/F) of metformin following single oral doses of metformin HCl tablets 850 mg averaged 654 L ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time.

h the fasting state (6.1 versus 4.0 hours). Distribution The apparent volume of distribution (V/F) of metformin following single oral doses of metformin HCl tablets 850 mg averaged 654 L ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. Metabolism Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Elimination Renal clearance (see Table 4) is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. Specific Populations Renal Impairment In patients with decreased renal function the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased (see Table 4) [ See Dosage and Administration ( 2.2 ), Contraindications ( 4 ), and Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.6 ) ] . Hepatic Impairment No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment [ See Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.7 ) ]. Geriatrics Limited data from controlled pharmacokinetic studies of metformin HCl tablets in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and C max is increased, compared to healthy young subjects. It appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 4). [ See Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.5 ) ]. Table 4: Select Mean (±S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin HCl Tablets a All doses given fasting except the first 18 doses of the multiple dose studies b Peak plasma concentration c Time to peak plasma concentration d Combined results (average means) of five studies: mean age 32 years (range 23 years to 59 years) e Kinetic study done following dose 19, given fasting f Elderly subjects, mean age 71 years (range 65 years to 81 years) g CLcr = creatinine clearance normalized to body surface area of 1.73 m 2 Subject Groups: Metformin Hydrochloride dose a (number of subjects) C max b (mcg/mL) T max c (hrs) Renal Clearance (mL/min) Healthy, nondiabetic adults: 500 mg single dose (24) 1.03 (±0.33) 2.75 (±0.81) 600 (±132) 850 mg single dose (74) d 1.60 (±0.38) 2.64 (±0.82) 552 (±139) 850 mg three times daily for 19 doses e (9) 2.01 (±0.42) 1.79 (±0.94) 642 (±173) Adults with type 2 diabetes mellitus: 850 mg single dose (23) 1.48 (±0.5) 3.32 (±1.08) 491 (±138) 850 mg three times daily for 19 doses e (9) 1.90 (±0.62) 2.01 (±1.22) 550 (±160) Elderly f , healthy nondiabetic adults: 850 mg single dose (12) 2.45 (±0.70) 2.71 (±1.05) 412 (±98) Renal-impaired adults: 850 mg single dose Mild (CLcr g 61 mL/min to 90 mL/min) (5) 1.86 (±0.52) 3.20 (±0.45) 384 (±122) Moderate (CLcr 31 mL/min to 60 mL/min) (4) 4.12 (±1.83) 3.75 (±0.50) 108 (±57) Severe (CLcr 10 mL/min to 30 mL/min) (6) 3.93 (±0.92) 4.01 (±1.10) 130 (±90) Pediatrics There are no available pharmacokinetic data with metformin hydrochloride extended-release tablets in pediatric patients.

(±0.52) 3.20 (±0.45) 384 (±122) Moderate (CLcr 31 mL/min to 60 mL/min) (4) 4.12 (±1.83) 3.75 (±0.50) 108 (±57) Severe (CLcr 10 mL/min to 30 mL/min) (6) 3.93 (±0.92) 4.01 (±1.10) 130 (±90) Pediatrics There are no available pharmacokinetic data with metformin hydrochloride extended-release tablets in pediatric patients. Gender Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes mellitus when analyzed according to gender (males=19, females=16). Race No studies of metformin pharmacokinetic parameters according to race have been performed. Drug Interactions In Vivo Assessment of Drug Interactions Table 5: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure * All metformin hydrochloride and coadministered drugs were given as single doses † AUC = AUC inf ‡ Ratio of arithmetic means § At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC 0-12h Coadministered Drug Dose of Coadministered Drug* Dose of Metformin hydrochloride* Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00 AUC † C max No dosing adjustments required for the following: Glyburide 5 mg 850 mg metformin 0.91 ‡ 0.93 ‡ Furosemide 40 mg 850 mg metformin 1.09 ‡ 1.22 ‡ Nifedipine 10 mg 850 mg metformin 1.16 1.21 Propranolol 40 mg 850 mg metformin 0.90 0.94 Ibuprofen 400 mg 850 mg metformin 1.05 ‡ 1.07 ‡ Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination [ See Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7 ). ] Cimetidine 400 mg 850 mg metformin 1.40 1.61 Carbonic anhydrase inhibitors may cause metabolic acidosis [See Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7 ).] Topiramate 100 mg § 500 mg § metformin 1.25 § 1.17 Table 6: Effect of Metformin on Coadministered Drug Systemic Exposure * All metformin hydrochloride and coadministered drugs were given as single doses † AUC = AUC inf unless otherwise noted ‡ Ratio of arithmetic means, p-value of difference < 0.05 § AUC 0-24 hr reported ¶ Ratio of arithmetic means Coadministered Drug Dose of Coadministered Drug* Dose of Metformin hydrochloride* Geometric Mean Ratio (ratio with/without metformin) No Effect = 1.00 AUC † C max No dosing adjustments required for the following: Glyburide 5 mg 850 mg glyburide 0.78 ‡ 0.63 ‡ Furosemide 40 mg 850 mg furosemide 0.87 ‡ 0.69 ‡ Nifedipine 10 mg 850 mg nifedipine 1.10 § 1.08 Propranolol 40 mg 850 mg propranolol 1.01 § 1.02 Ibuprofen 400 mg 850 mg ibuprofen 0.97 ¶ 1.01 ¶ Cimetidine 400 mg 850 mg cimetidine 0.95 § 1.01

<table cellspacing="0" cellpadding="0" border="0" width="100%"><col width="33.32%"/><col width="33.32%"/><col width="33.34%"/><tfoot><tr><td colspan="15">*Immediate-release metformin HCl tablets</td></tr></tfoot><tbody><tr styleCode="Botrule"><td colspan="3" align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Table 3:</content> <content styleCode="bold">Metformin hydrochloride extended-release tablets vs.</content> <content styleCode="bold">Metformin HCl Tablets</content> <content styleCode="bold">Steady-State Pharmacokinetic Parameters at 4 Weeks</content> </td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Pharmacokinetic</content> <content styleCode="bold">Parameters</content> <content styleCode="bold">(mean &#xB1; SD)</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Metformin hydrochloride extended-release tablets 2,000 mg</content> <content styleCode="bold">(administered once daily after dinner)</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Metformin HCl tablets*</content> <content styleCode="bold">2,000 mg</content> <content styleCode="bold">(1,000 mg twice daily)</content> </td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="middle">AUC _0-24hr(ng&#x2022;hr/mL) </td><td align="center" styleCode="Rrule" valign="middle">26,811 &#xB1; 7,055 </td><td align="center" styleCode="Rrule" valign="middle">27,371 &#xB1; 5,781 </td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="middle">T _max(hr) </td><td align="center" styleCode="Rrule" valign="middle">6 (3-10) </td><td align="center" styleCode="Rrule" valign="middle">3 (1-8) </td></tr><tr><td align="center" styleCode="Lrule Rrule" valign="middle">C _max(ng/mL) </td><td align="center" styleCode="Rrule" valign="middle">2,849 &#xB1; 797 </td><td align="center" styleCode="Rrule" valign="middle">1,820 &#xB1; 370 </td></tr></tbody></table>

ter" styleCode="Rrule" valign="middle">3 (1-8) </td></tr><tr><td align="center" styleCode="Lrule Rrule" valign="middle">C _max(ng/mL) </td><td align="center" styleCode="Rrule" valign="middle">2,849 &#xB1; 797 </td><td align="center" styleCode="Rrule" valign="middle">1,820 &#xB1; 370 </td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 4: Select Mean (&#xB1;S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin HCl Tablets</caption><col width="39.36%"/><col width="23.42%"/><col width="18.98%"/><col width="18.24%"/><tfoot><tr><td colspan="60" align="justify">^aAll doses given fasting except the first 18 doses of the multiple dose studies ^bPeak plasma concentration ^cTime to peak plasma concentration ^dCombined results (average means) of five studies: mean age 32 years (range 23 years to 59 years) ^eKinetic study done following dose 19, given fasting ^fElderly subjects, mean age 71 years (range 65 years to 81 years) ^gCLcr = creatinine clearance normalized to body surface area of 1.73 m ² </td></tr></tfoot><tbody><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Subject Groups: Metformin</content> <content styleCode="bold">Hydrochloride dose ^a</content> <content styleCode="bold">(number of subjects)</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">C _max^b</content> <content styleCode="bold">(mcg/mL)</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">T _max^c</content> <content styleCode="bold">(hrs)</content> </td><td align="center" styleCode="Rrule" valign="middle"><content styleCode="bold">Renal Clearance</content> <content styleCode="bold">(mL/min)</content> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Healthy, nondiabetic adults:</content> </td><td align="justify" styleCode="Rrule" valign="top"> </td><td align="justify" styleCode="Rrule" valign="top"> </td><td align="justify" styleCode="Rrule" valign="top"> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"> 500 mg single dose (24) </td><td align="center" styleCode="Rrule" valign="top">1.03 (&#xB1;0.33) </td><td align="center" styleCode="Rrule" valign="top">2.75 (&#xB1;0.81) </td><td align="center" styleCode="Rrule" valign="top">600 (&#xB1;132) </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"> 850 mg single dose (74) ^d </td><td align="center" styleCode="Rrule" valign="top">1.60 (&#xB1;0.38) </td><td align="center" styleCode="Rrule" valign="top">2.64 (&#xB1;0.82) </td><td align="center" styleCode="Rrule" valign="top">552 (&#xB1;139) </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"> 850 mg three times daily for 19 doses ^e(9) </td><td align="center" styleCode="Rrule" valign="top">2.01 (&#xB1;0.42) </td><td align="center" styleCode="Rrule" valign="top">1.79 (&#xB1;0.94) </td><td align="center" styleCode="Rrule" valign="top">642 (&#xB1;173) </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Adults with type 2 diabetes</content> <content styleCode="bold">mellitus:</content> </td><td align="justify" styleCode="Rrule" valign="top"> </td><td align="justify" styleCode="Rrule" valign="top"> </td><td align="justify" styleCode="Rrule" valign="top"> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"> 850 mg single dose (23) <

Code="bold">mellitus:</content> </td><td align="justify" styleCode="Rrule" valign="top"> </td><td align="justify" styleCode="Rrule" valign="top"> </td><td align="justify" styleCode="Rrule" valign="top"> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"> 850 mg single dose (23) < /td><td align="center" styleCode="Rrule" valign="top">1.48 (&#xB1;0.5) </td><td align="center" styleCode="Rrule" valign="top">3.32 (&#xB1;1.08) </td><td align="center" styleCode="Rrule" valign="top">491 (&#xB1;138) </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"> 850 mg three times daily for 19 doses ^e(9) </td><td align="center" styleCode="Rrule" valign="top">1.90 (&#xB1;0.62) </td><td align="center" styleCode="Rrule" valign="top">2.01 (&#xB1;1.22) </td><td align="center" styleCode="Rrule" valign="top">550 (&#xB1;160) </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Elderly ^f, healthy nondiabetic adults: </content> </td><td align="justify" styleCode="Rrule" valign="top"> </td><td align="justify" styleCode="Rrule" valign="top"> </td><td align="justify" styleCode="Rrule" valign="top"> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"> 850 mg single dose (12) </td><td align="center" styleCode="Rrule" valign="top">2.45 (&#xB1;0.70) </td><td align="center" styleCode="Rrule" valign="top">2.71 (&#xB1;1.05) </td><td align="center" styleCode="Rrule" valign="top">412 (&#xB1;98) </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Renal-impaired adults:</content> </td><td align="justify" styleCode="Rrule" valign="top"> </td><td align="justify" styleCode="Rrule" valign="top"> </td><td align="justify" styleCode="Rrule" valign="top"> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"> 850 mg single dose </td><td align="justify" styleCode="Rrule" valign="top"> </td><td align="justify" styleCode="Rrule" valign="top"> </td><td align="justify" styleCode="Rrule" valign="top"> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold"> Mild</content>(CLcr ^g61 mL/min to 90 mL/min) (5) </td><td align="center" styleCode="Rrule" valign="top">1.86 (&#xB1;0.52) </td><td align="center" styleCode="Rrule" valign="top">3.20 (&#xB1;0.45) </td><td align="center" styleCode="Rrule" valign="top">384 (&#xB1;122) </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold"> Moderate</content>(CLcr 31 mL/min to 60 mL/min) (4) <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">4.12 (&#xB1;1.83) </td><td align="center" styleCode="Rrule" valign="top">3.75 (&#xB1;0.50) </td><td align="center" styleCode="Rrule" valign="top">108 (&#xB1;57) </td></tr><tr><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold"> Severe</content>(CLcr 10 mL/min to 30 mL/min) (6) <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">3.93 (&#xB1;0.92) </td><td align="center" styleCode="Rrule" valign="top">4.01 (&#xB1;1.10) </td><td align="center" styleCode="Rrule" valign="top">130 (&#xB1;90) </td></tr></tbody></table>

Severe</content>(CLcr 10 mL/min to 30 mL/min) (6) <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">3.93 (&#xB1;0.92) </td><td align="center" styleCode="Rrule" valign="top">4.01 (&#xB1;1.10) </td><td align="center" styleCode="Rrule" valign="top">130 (&#xB1;90) </td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 5: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure</caption><col width="20.22%"/><col width="18.84%"/><col width="13.06%"/><col width="15.76%"/><col width="14.32%"/><col width="17.8%"/><tfoot><tr><td colspan="69">^*All metformin hydrochloride and coadministered drugs were given as single doses ^&#x2020;AUC = AUC _inf ^&#x2021;Ratio of arithmetic means ^&#xA7;At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC _0-12h</td></tr></tfoot><tbody><tr styleCode="Botrule"><td rowspan="2" align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Coadministered</content> <content styleCode="bold">Drug</content> </td><td rowspan="2" align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Dose of</content> <content styleCode="bold">Coadministered Drug*</content> </td><td rowspan="2" align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Dose of</content> <content styleCode="bold">Metformin hydrochloride*</content> </td><td colspan="3" align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Geometric Mean Ratio</content> <content styleCode="bold">(ratio with/without coadministered</content> <content styleCode="bold">drug)</content> <content styleCode="bold">No Effect = 1.00</content> </td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top"/><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">AUC</content>^&#x2020;<content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">C _max</content> </td></tr><tr styleCode="Botrule"><td colspan="5" align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">No dosing adjustments required for the following:</content> </td><td align="justify" styleCode="Rrule" valign="top"/></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Glyburide <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">5 mg <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">850 mg <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">metformin <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">0.91 ^&#x2021; </td><td align="center" styleCode="Rrule" valign="top">0.93 ^&#x2021; </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Furosemide <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">40 mg <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">850 mg <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">metformin <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">1.09 ^&#x2021; </td><td align="center" styleCode="Rrule" valign="top">1.22 ^&#x2021; </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Nifedipine <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">10 mg <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">850 mg <content styleCode="bold"/> </td><td align="center" styl

leCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Nifedipine <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">10 mg <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">850 mg <content styleCode="bold"/> </td><td align="center" styl eCode="Rrule" valign="top">metformin <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">1.16 </td><td align="center" styleCode="Rrule" valign="top">1.21 </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Propranolol </td><td align="center" styleCode="Rrule" valign="top">40 mg <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">850 mg <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">metformin <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">0.90 </td><td align="center" styleCode="Rrule" valign="top">0.94 </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Ibuprofen </td><td align="center" styleCode="Rrule" valign="top">400 mg <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">850 mg <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">metformin <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">1.05 ^&#x2021; </td><td align="center" styleCode="Rrule" valign="top">1.07 ^&#x2021; </td></tr><tr styleCode="Botrule"><td colspan="6" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination</content>[ <content styleCode="italics">See Warnings and Precautions ( <linkHtml href="#Section_5.1">5.1</linkHtml>) and Drug Interactions ( <linkHtml href="#Section_7">7</linkHtml>).

rule Rrule" valign="top"><content styleCode="bold">Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination</content>[ <content styleCode="italics">See Warnings and Precautions ( <linkHtml href="#Section_5.1">5.1</linkHtml>) and Drug Interactions ( <linkHtml href="#Section_7">7</linkHtml>). </content>] </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Cimetidine </td><td align="center" styleCode="Rrule" valign="top">400 mg </td><td align="center" styleCode="Rrule" valign="top">850 mg </td><td align="center" styleCode="Rrule" valign="top">metformin </td><td align="center" styleCode="Rrule" valign="top">1.40 </td><td align="center" styleCode="Rrule" valign="top">1.61 </td></tr><tr styleCode="Botrule"><td colspan="6" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Carbonic anhydrase inhibitors may cause metabolic acidosis</content><content styleCode="italics">[See Warnings and Precautions ( <linkHtml href="#Section_5.1">5.1</linkHtml>) and Drug Interactions ( <linkHtml href="#Section_7">7</linkHtml>).] </content> </td></tr><tr><td align="justify" styleCode="Lrule Rrule" valign="top">Topiramate </td><td align="center" styleCode="Rrule" valign="top">100 mg ^&#xA7; </td><td align="center" styleCode="Rrule" valign="top">500 mg ^&#xA7; </td><td align="center" styleCode="Rrule" valign="top">metformin </td><td align="center" styleCode="Rrule" valign="top">1.25 ^&#xA7; </td><td align="center" styleCode="Rrule" valign="top">1.17 </td></tr></tbody></table>

xA7;</sup> </td><td align="center" styleCode="Rrule" valign="top">500 mg ^&#xA7; </td><td align="center" styleCode="Rrule" valign="top">metformin </td><td align="center" styleCode="Rrule" valign="top">1.25 ^&#xA7; </td><td align="center" styleCode="Rrule" valign="top">1.17 </td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 6: Effect of Metformin on Coadministered Drug Systemic Exposure</caption><col width="20.22%"/><col width="18.84%"/><col width="13.06%"/><col width="15.96%"/><col width="14.52%"/><col width="17.4%"/><tfoot><tr><td colspan="51">^*All metformin hydrochloride and coadministered drugs were given as single doses ^&#x2020;AUC = AUC _infunless otherwise noted ^&#x2021;Ratio of arithmetic means, p-value of difference &lt; 0.05 ^&#xA7;AUC _{0-24 hr}reported ^&#xB6;Ratio of arithmetic means </td></tr></tfoot><tbody><tr styleCode="Botrule"><td rowspan="2" align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Coadministered</content> <content styleCode="bold">Drug</content> </td><td rowspan="2" align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Dose of</content> <content styleCode="bold">Coadministered Drug*</content> </td><td rowspan="2" align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Dose of</content> <content styleCode="bold">Metformin hydrochloride*</content> </td><td colspan="3" align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Geometric Mean Ratio</content> <content styleCode="bold">(ratio with/without metformin)</content> <content styleCode="bold">No Effect = 1.00</content> </td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top"/><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">AUC</content>^&#x2020;<content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">C _max</content> </td></tr><tr styleCode="Botrule"><td colspan="5" align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">No dosing adjustments required for the following:</content> </td><td align="justify" styleCode="Rrule" valign="top"/></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Glyburide <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">5 mg <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">850 mg <content styleCode="bold"/> </td><td align="justify" styleCode="Rrule" valign="top">glyburide <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">0.78 ^&#x2021; </td><td align="center" styleCode="Rrule" valign="top">0.63 ^&#x2021; </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Furosemide <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">40 mg <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">850 mg <content styleCode="bold"/> </td><td align="justify" styleCode="Rrule" valign="top">furosemide <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">0.87 ^&#x2021; </td><td align="center" styleCode="Rrule" valign="top">0.69 ^&#x2021; </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Nifedipine <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">10 mg <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">850 mg <content styleCode="bold"/> </td><td align="justify" styleCode="Rrule" valign="top">nifedipine

tyleCode="Lrule Rrule" valign="top">Nifedipine <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">10 mg <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">850 mg <content styleCode="bold"/> </td><td align="justify" styleCode="Rrule" valign="top">nifedipine <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">1.10 ^&#xA7; </td><td align="center" styleCode="Rrule" valign="top">1.08 </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Propranolol </td><td align="center" styleCode="Rrule" valign="top">40 mg <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">850 mg <content styleCode="bold"/> </td><td align="justify" styleCode="Rrule" valign="top">propranolol <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">1.01 ^&#xA7; </td><td align="center" styleCode="Rrule" valign="top">1.02 </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Ibuprofen </td><td align="center" styleCode="Rrule" valign="top">400 mg <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">850 mg <content styleCode="bold"/> </td><td align="justify" styleCode="Rrule" valign="top">ibuprofen <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">0.97 ^&#xB6; </td><td align="center" styleCode="Rrule" valign="top">1.01 ^&#xB6; </td></tr><tr><td styleCode="Lrule Rrule" valign="top">Cimetidine <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">400 mg <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">850 mg <content styleCode="bold"/> </td><td align="justify" styleCode="Rrule" valign="top">cimetidine <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">0.95 ^&#xA7; </td><td align="center" styleCode="Rrule" valign="top">1.01 </td></tr></tbody></table>

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1,500 mg/kg/day, respectively. These doses are both approximately 3 times the maximum recommended human daily dose of 2,550 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day. There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative. Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately 2 times the maximum recommended human daily dose of 2,550 mg based on body surface area comparisons.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1,500 mg/kg/day, respectively. These doses are both approximately 3 times the maximum recommended human daily dose of 2,550 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day. There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative. Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately 2 times the maximum recommended human daily dose of 2,550 mg based on body surface area comparisons.

14 CLINICAL STUDIES A 24-week, double-blind, placebo-controlled study of metformin hydrochloride extended-release tablets, taken once daily with the evening meal, was conducted in patients with type 2 diabetes mellitus who had failed to achieve glycemic control with diet and exercise. Patients entering the study had a mean baseline HbA 1c of 8.0% and a mean baseline FPG of 176 mg/dL. The treatment dose was increased to 1,500 mg once daily if at Week 12 HbA 1c was ≥ 7.0% but < 8.0% (patients with HbA 1c ≥ 8.0% were discontinued from the study). At the final visit (24-week), mean HbA 1c had increased 0.2% from baseline in placebo patients and decreased 0.6% with metformin hydrochloride extended-release tablets. A 16-week, double-blind, placebo-controlled, dose-response study of metformin hydrochloride extended-release tablets, taken once daily with the evening meal or twice daily with meals, was conducted in patients with type 2 diabetes mellitus who had failed to achieve glycemic control with diet and exercise. The results are shown in Table 7. Table 7: Mean Changes from Baseline* in HbA1c and Fasting Plasma Glucose at Week 16 Comparing Metformin Hydrochloride Extended-Release Tablets vs Placebo in Patients with Type 2 Diabetes Mellitus a All comparisons versus Placebo Metformin Hydrochloride Extended-Release Tablets Placebo 500 mg Once Daily 1,000 mg Once Daily 1,500 mg Once Daily 2,000 mg Once Daily 1,000 mg Twice Daily Hemoglobin A1c (%) Baseline Change at FINAL VISIT p-value a (n=115) (n=115) (n=111) (n=125) (n=112) (n=111) 8.2 8.4 8.3 8.4 8.4 8.4 -0.4 -0.6 -0.9 -0.8 -1.1 0.1 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 - FPG (mg/dL) (n=126) (n=118) (n=120) (n=132) (n=122) (n=113) Baseline 182.7 183.7 178.9 181.0 181.6 179.6 Change at FINAL VISIT -15.2 -19.3 -28.5 -29.9 -33.6 7.6 p-value a < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 - Mean baseline body weight was 193 lbs, 192 lbs, 188 lbs, 196 lbs, 193 lbs and 194 lbs in the metformin hydrochloride extended-release tablets 500 mg, 1,000 mg, 1,500 mg, and 2,000 mg once daily, 1,000 mg twice daily and placebo arms, respectively. Mean change in body weight from baseline to week 16 was -1.3 lbs, -1.3 lbs, -0.7 lbs, -1.5 lbs, -2.2 lbs and -1.8 lbs, respectively. A 24-week, double-blind, randomized study of metformin hydrochloride extended-release tablets, taken once daily with the evening meal, and metformin HCl tablets, taken twice daily (with breakfast and evening meal), was conducted in patients with type 2 diabetes mellitus who had been treated with metformin HCl tablets 500 mg twice daily for at least 8 weeks prior to study entry. The results are shown in Table 8.

taken once daily with the evening meal, and metformin HCl tablets, taken twice daily (with breakfast and evening meal), was conducted in patients with type 2 diabetes mellitus who had been treated with metformin HCl tablets 500 mg twice daily for at least 8 weeks prior to study entry. The results are shown in Table 8. Table 8: Mean Changes from Baseline* in HbA1c and Fasting Plasma Glucose at Week 24 Comparing Metformin Hydrochloride Extended-Release vs Metformin hydrochloride in Patients with Type 2 Diabetes Mellitus †a n=68 Metformin hydrochloride 500 mg Twice Daily Metformin Hydrochloride Extended-Release Tablets 1,000 mg Once Daily 1,500 mg Once Daily Hemoglobin A1c (%) (n=67) (n=72) (n=66) Baseline 7.06 6.99 7.02 Change at FINAL VISIT 0.14 a 0.27 0.13 (95% CI) (–0.04, 0.31) (0.11, 0.43) (–0.02, 0.28) FPG (mg/dL) (n=69) (n=72) (n=70) Baseline 127.2 131.0 131.4 Change at FINAL VISIT 14.0 11.5 7.6 (95% CI) (7.0, 21.0) (4.4, 18.6) (1.0, 14.2) Mean baseline body weight was 210 lbs, 203 lbs and 193 lbs in the metformin HCl tablets 500 mg twice daily, and metformin hydrochloride extended-release tablets 1,000 mg and 1,500 mg once daily arms, respectively. Mean change in body weight from baseline to week 24 was 0.9 lbs, 1.1 lbs and 0.9 lbs, respectively.

<table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 7: Mean Changes from Baseline* in HbA1c and Fasting Plasma Glucose at Week 16 Comparing Metformin Hydrochloride Extended-Release Tablets vs Placebo in Patients with Type 2 Diabetes Mellitus</caption><col width="28.8%"/><col width="11.52%"/><col width="11.52%"/><col width="14.4%"/><col width="11.52%"/><col width="11.52%"/><col width="10.72%"/><tfoot><tr><td colspan="66">^aAll comparisons versus Placebo </td></tr></tfoot><tbody><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"> </td><td colspan="5" align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Metformin</content><content styleCode="bold">Hydrochloride Extended-Release Tablets</content> </td><td rowspan="2" align="center" styleCode="Rrule" valign="middle"><content styleCode="bold">Placebo</content> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">500 mg</content> <content styleCode="bold">Once</content> <content styleCode="bold">Daily</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">1,000 mg</content> <content styleCode="bold">Once</content> <content styleCode="bold">Daily</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">1,500 mg</content> <content styleCode="bold">Once Daily</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">2,000 mg</content> <content styleCode="bold">Once Daily</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">1,000 mg</content> <content styleCode="bold">Twice Daily</content> </td></tr><tr styleCode="Botrule"><td rowspan="4" align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Hemoglobin A1c (%)</content> Baseline <content styleCode="bold"/> Change at FINAL VISIT p-value ^a </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">(n=115)</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">(n=115)</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">(n=111)</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">(n=125)</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">(n=112)</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">(n=111)</content> </td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top">8.2 </td><td align="center" styleCode="Rrule" valign="top">8.4 </td><td align="center" styleCode="Rrule" valign="top">8.3 </td><td align="center" styleCode="Rrule" valign="top">8.4 </td><td align="center" styleCode="Rrule" valign="top">8.4 </td><td align="center" styleCode="Rrule" valign="top">8.4 </td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top">-0.4 </td><td align="center" styleCode="Rrule" valign="top">-0.6 </td><td align="center" styleCode="Rrule" valign="top">-0.9 </td><td align="center" styleCode="Rrule" valign="top">-0.8 </td><td align="center" styleCode="Rrule" valign="top">-1.1 </td><td align="center" styleCode="Rrule" valign="top">0.1 </td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="t

<td align="center" styleCode="Rrule" valign="top">-0.9 </td><td align="center" styleCode="Rrule" valign="top">-0.8 </td><td align="center" styleCode="Rrule" valign="top">-1.1 </td><td align="center" styleCode="Rrule" valign="top">0.1 </td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="t op">&lt; 0.001 </td><td align="center" styleCode="Rrule" valign="top">&lt; 0.001 </td><td align="center" styleCode="Rrule" valign="top">&lt; 0.001 </td><td align="center" styleCode="Rrule" valign="top">&lt; 0.001 </td><td align="center" styleCode="Rrule" valign="top">&lt; 0.001 </td><td align="center" styleCode="Rrule" valign="top">- </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">FPG (mg/dL)</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">(n=126)</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">(n=118)</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">(n=120)</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">(n=132)</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">(n=122)</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">(n=113)</content> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Baseline <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">182.7 </td><td align="center" styleCode="Rrule" valign="top">183.7 </td><td align="center" styleCode="Rrule" valign="top">178.9 </td><td align="center" styleCode="Rrule" valign="top">181.0 </td><td align="center" styleCode="Rrule" valign="top">181.6 </td><td align="center" styleCode="Rrule" valign="top">179.6 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">Change at FINAL VISIT </td><td align="center" styleCode="Rrule" valign="top">-15.2 </td><td align="center" styleCode="Rrule" valign="top">-19.3 </td><td align="center" styleCode="Rrule" valign="top">-28.5 </td><td align="center" styleCode="Rrule" valign="top">-29.9 </td><td align="center" styleCode="Rrule" valign="top">-33.6 </td><td align="center" styleCode="Rrule" valign="top">7.6 </td></tr><tr><td styleCode="Lrule Rrule" valign="top">p-value ^a </td><td align="center" styleCode="Rrule" valign="top">&lt; 0.001 </td><td align="center" styleCode="Rrule" valign="top">&lt; 0.001 </td><td align="center" styleCode="Rrule" valign="top">&lt; 0.001 </td><td align="center" styleCode="Rrule" valign="top">&lt; 0.001 </td><td align="center" styleCode="Rrule" valign="top">&lt; 0.001 </td><td align="center" styleCode="Rrule" valign="top">- </td></tr></tbody></table>

leCode="Rrule" valign="top">&lt; 0.001 </td><td align="center" styleCode="Rrule" valign="top">&lt; 0.001 </td><td align="center" styleCode="Rrule" valign="top">&lt; 0.001 </td><td align="center" styleCode="Rrule" valign="top">&lt; 0.001 </td><td align="center" styleCode="Rrule" valign="top">- </td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 8: Mean Changes from Baseline* in HbA1c and Fasting Plasma Glucose at Week 24 Comparing Metformin Hydrochloride Extended-Release vs Metformin hydrochloride in Patients with Type 2 Diabetes Mellitus</caption><col width="27.86%"/><col width="20.04%"/><col width="32.04%"/><col width="20.06%"/><tfoot><tr><td colspan="38">^&#x2020;an=68 </td></tr></tfoot><tbody><tr styleCode="Botrule"><td rowspan="2" align="justify" styleCode="Lrule Rrule" valign="top"> </td><td rowspan="2" align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Metformin hydrochloride</content> <content styleCode="bold">500 mg Twice Daily</content><content styleCode="bold"/> </td><td colspan="2" align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Metformin</content><content styleCode="bold"> Hydrochloride Extended-Release Tablets</content> </td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">1,000 mg</content> <content styleCode="bold">Once</content> <content styleCode="bold">Daily</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">1,500 mg</content> <content styleCode="bold">Once Daily</content> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Hemoglobin A1c (%)</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">(n=67)</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">(n=72)</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">(n=66)</content> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Baseline </td><td align="center" styleCode="Rrule" valign="top">7.06 </td><td align="center" styleCode="Rrule" valign="top">6.99 </td><td align="center" styleCode="Rrule" valign="top">7.02 </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Change at FINAL VISIT <content styleCode="bold"/> </td><td align="center" styleCode="Rrule" valign="top">0.14 ^a </td><td align="center" styleCode="Rrule" valign="top">0.27 </td><td align="center" styleCode="Rrule" valign="top">0.13 </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">(95% CI) </td><td align="center" styleCode="Rrule" valign="top">(&#x2013;0.04, 0.31) </td><td align="center" styleCode="Rrule" valign="top">(0.11, 0.43) </td><td align="center" styleCode="Rrule" valign="top">(&#x2013;0.02, 0.28) </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">FPG (mg/dL)</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">(n=69)</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">(n=72)</content> </td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">(n=70)</content> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Baseline </td><td align="center" styleCode="Rrule" valign="top">127.2 </td><td align="center" styleCode="Rrule" valign="top">131.0 </td><td align="center" styleCode="Rrule" valign="top">131.4 </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Change at FINAL

Rrule" valign="top">Baseline </td><td align="center" styleCode="Rrule" valign="top">127.2 </td><td align="center" styleCode="Rrule" valign="top">131.0 </td><td align="center" styleCode="Rrule" valign="top">131.4 </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Change at FINAL VISIT </td><td align="center" styleCode="Rrule" valign="top">14.0 </td><td align="center" styleCode="Rrule" valign="top">11.5 </td><td align="center" styleCode="Rrule" valign="top">7.6 </td></tr><tr><td align="justify" styleCode="Lrule Rrule" valign="top">(95% CI) </td><td align="center" styleCode="Rrule" valign="top">(7.0, 21.0) </td><td align="center" styleCode="Rrule" valign="top">(4.4, 18.6) </td><td align="center" styleCode="Rrule" valign="top">(1.0, 14.2) </td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING Metformin hydrochloride extended-release tablets, USP are supplied as: 1,000 mg white to off-white colored, oval shaped, unscored biconvex-shaped, film-coated extended-release tablets imprinted with “ME2” in black ink on one side and plain on the other side. NDC: 70518-4652-00 NDC: 70518-4652-01 PACKAGING: 30 in 1 BOX PACKAGING: 1 in 1 POUCH Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86° F) [see USP Controlled Room Temperature]. Avoid excessive heat and humidity. Keep tightly closed (protect from moisture). Protect from light. . Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Lactic Acidosis: Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development. Advise patients to discontinue metformin hydrochloride extended-release tablets immediately and to promptly notify their healthcare provider if unexplained hyperventilation, myalgias, malaise, unusual somnolence or other nonspecific symptoms occur. Counsel patients against excessive alcohol intake and inform patients about importance of regular testing of renal function while receiving metformin hydrochloride extended-release tablets. Instruct patients to inform their doctor that they are taking metformin hydrochloride extended-release tablets prior to any surgical or radiological procedure, as temporary discontinuation may be required [ see Warnings and Precautions ( 5.1 ) ]. Hypoglycemia: Inform patients that hypoglycemia may occur when metformin hydrochloride extended-release tablets are coadministered with oral sulfonylureas and insulin. Explain to patients receiving concomitant therapy the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development [ see Warnings and Precautions ( 5.3 ) ]. Vitamin B 12 Deficiency: Inform patients about importance of regular hematological parameters while receiving metformin hydrochloride extended-release tablets [ see Warnings and Precautions ( 5.2 ) ]. Females of Reproductive Age: Inform females that treatment with metformin hydrochloride extended-release tablets may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy [ see Use in Specific Populations ( 8.3 ) ]. Administration Information: Inform patients that metformin hydrochloride extended-release tablets must be swallowed whole and not crushed, cut, or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet. Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762 PATIENT INFORMATION Metformin Hydrochloride (met for' min hye'' droe klor' ide) extended-release tablets, USP What is the most important information I should know about metformin hydrochloride extended-release tablets? Metformin hydrochloride extended-release tablets can cause serious side effects including: Lactic Acidosis. Metformin hydrochloride, the medicine in metformin hydrochloride extended-release tablets, can cause a rare, but serious side effect called lactic acidosis (a build-up of lactic acid in the blood) that can cause death. Lactic acidosis is a medical emergency and must be treated in a hospital. Stop taking m etformin hydrochloride extended-release tablets and call your healthcare provider right away if you get any of the following symptoms of lactic acidosis: • feel very weak and tired • have unusual (not normal) muscle pain • have trouble breathing • have unexplained stomach or intestinal problems with nausea and vomiting, or diarrhea • have unusual sleepiness or sleep longer than usual • feel cold, especially in your arms and legs • feel dizzy or lightheaded • have a slow or irregular heartbeat You have a higher chance of getting lactic acidosis if you: have severe kidney problems. See “ Do not take m etformin hydrochloride extended-release tablets if you: ” have liver problems.

eep longer than usual • feel cold, especially in your arms and legs • feel dizzy or lightheaded • have a slow or irregular heartbeat You have a higher chance of getting lactic acidosis if you: have severe kidney problems. See “ Do not take m etformin hydrochloride extended-release tablets if you: ” have liver problems. have congestive heart failure that requires treatment with medicines. drink a lot of alcohol (very often or short-term “binge” drinking). get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever, vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise and do not drink enough fluids. have certain x-ray tests with injectable dyes or contrast agents. have surgery. have a heart attack, severe infection, or stroke. are 65 years of age or older. Tell your healthcare provider if you have any of the problems in the list above. Tell your healthcare provider that you are taking metformin hydrochloride extended-release tablets before you have surgery or x-ray tests. Your healthcare provider may need to stop metformin hydrochloride extended-release tablets for a while if you have surgery or certain x-ray tests). Metformin hydrochloride extended-release tablets can have other serious side effects. See “ What are the possible side effects of metformin hydrochloride extended-release tablets? ” What are m etformin hydrochloride extended-release tablets? Metformin hydrochloride extended-release tablets are prescription medicine that contains metformin hydrochloride. Metformin hydrochloride extended-release tablets is used with diet and exercise to help control high blood sugar (hyperglycemia) in adults with type 2 diabetes. It is not known if metformin hydrochloride extended-release tablets is safe and effective in children under 18 years of age. Do not take metformin hydrochloride extended-release tablets if you: have severe kidney problems are allergic to metformin hydrochloride or any of the ingredients in metformin hydrochloride extended-release tablets. See the end of this Patient Information leaflet for a complete list of ingredients in metformin hydrochloride extended-release tablets. have a condition called metabolic acidosis including diabetic ketoacidosis (high levels of certain acids called “ketones” in your blood or urine). Before taking metformin hydrochloride extended-release tablets, tell your healthcare provider about all your medical conditions, including if you: have a history or risk for diabetic ketoacidosis. See “ Do not take metformin hydrochloride extended-release tablets if you: ” have kidney problems. have liver problems. have heart problems, including congestive heart failure. are 65 years of age or older. drink alcohol very often or drink a lot of alcohol in short-term “binge” drinking. are taking insulin or a sulfonylurea medicine. are pregnant or plan to become pregnant. It is not known if metformin hydrochloride extended-release tablets will harm your unborn baby. If you are pregnant, talk with your healthcare provider about the best way to control your blood sugar while you are pregnant. are a woman who has not gone through menopause (premenopausal) who does not have periods regularly or at all. Metformin hydrochloride extended-release tablets can cause the release of an egg from an ovary in a woman (ovulation). This can increase your chance of getting pregnant. are breastfeeding or plan to breastfeed. Metformin can pass into your breast milk. Talk with your healthcare provider about the best way to feed your baby while you take metformin hydrochloride extended-release tablets. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

an pass into your breast milk. Talk with your healthcare provider about the best way to feed your baby while you take metformin hydrochloride extended-release tablets. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. Metformin hydrochloride extended-release tablets may affect the way other medicines work, and other medicines may affect how metformin hydrochloride extended-release tablets works. How should I take m etformin hydrochloride extended-release tablets? Take metformin hydrochloride extended-release tablets exactly as your healthcare provider tells you. Metformin hydrochloride extended-release tablets should be taken with your evening meals to help decrease an upset stomach. Swallow metformin hydrochloride extended-release tablets whole. Do not crush, cut, or chew the tablets. You may sometimes pass a soft mass in your stools (bowel movement) that looks like metformin hydrochloride extended-release tablets. This is not harmful and will not affect the way metformin hydrochloride extended-release tablets works. When your body is under some types of stress, such as fever, trauma (such as a car accident), infection, or surgery, the amount of diabetes medicine that you need may change. Tell your healthcare provider right away if you have any of these problems. Your healthcare provider should do blood tests to check how well your kidneys are working before and during your treatment with metformin hydrochloride extended-release tablets. Your healthcare provider will check your diabetes with regular blood tests, including your blood sugar levels and your hemoglobin A1C. Low blood sugar (hypoglycemia) can happen more often when metformin hydrochloride extended-release tablets is taken with certain other diabetes medicines. Talk to your healthcare provider about how to prevent, recognize and manage low blood sugar. See “ What are the possible side effects of metformin hydrochloride extended-release tablets? ” Check your blood sugar as your healthcare provider tells you to. Stay on your prescribed diet and exercise program while taking metformin hydrochloride extended-release tablets. If you take too much metformin hydrochloride extended-release tablets, call your healthcare provider or go to the nearest hospital emergency room right away. What should I avoid while taking metformin hydrochloride extended-release tablets? Do not drink a lot of alcoholic drinks while taking metformin hydrochloride extended-release tablets. This means you should not binge drink for short periods, and you should not drink a lot of alcohol on a regular basis. Alcohol can increase the chance of getting lactic acidosis. What are the possible side effects of metformin hydrochloride extended-release tablets? Metformin hydrochloride extended-release tablets may cause serious side effects, including: See “What is the most important information I should know about metformin hydrochloride extended-release tablets?” Low vitamin B 12 (vitamin B 12 deficiency). Using metformin hydrochloride extended-release tablets may cause a decrease in the amount of vitamin B 12 in your blood, especially if you have had low vitamin B 12 levels before. Your healthcare provider may do blood tests to check your vitamin B 12 levels. Low blood sugar (hypoglycemia). If you take metformin hydrochloride extended-release tablets with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin, your risk of getting low blood sugar is higher.

els before. Your healthcare provider may do blood tests to check your vitamin B 12 levels. Low blood sugar (hypoglycemia). If you take metformin hydrochloride extended-release tablets with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take metformin hydrochloride extended-release tablets. Signs and symptoms of low blood sugar may include: o headache o drowsiness o weakness o irritability o hunger o fast heartbeat o confusion o shaking or feeling jittery o dizziness o sweating Common side effects of metformin hydrochloride extended-release tablets include: • diarrhea • nausea and vomiting • gassiness (flatulence) • indigestion • stomach-area (abdominal) pain and swelling • headache • taste disturbance (unpleasant metallic taste) These are not all the possible side effects of metformin hydrochloride extended-release tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store metformin hydrochloride extended-release tablets? Metformin hydrochloride extended-release tablets comes in a child-resistant package. Store metformin hydrochloride extended-release tablets at room temperature between 68°F to 77°F (20°C to 25°C). See insert. Keep bottle tightly closed between each use to protect the metformin hydrochloride extended-release tablets from moisture. Protect from light. Keep metformin hydrochloride extended-release tablets and all medicines out of the reach of children. General information about the safe and effective use of metformin hydrochloride extended-release tablets Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use metformin hydrochloride extended-release tablets for a condition for which it was not prescribed. Do not give metformin hydrochloride extended-release tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about metformin hydrochloride extended-release tablets that is written for health professionals. What are the ingredients in metformin hydrochloride extended-release tablets? Active ingredients : metformin hydrochloride. Inactive ingredients : hypromellose, magnesium stearate, polyethylene glycols (PEG 400), povidone, pregelatinized starch, ethyl cellulose. Imprinting ink contains: shellac, ferrosoferric oxide, propylene glycol and ammonium hydroxide. For more information call Ajanta Pharma USA Inc. at 855-664-7744. This Patient Information has been approved by the U.S. Food and Drug Administration Revised: 11/2025 Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

<table cellspacing="0" cellpadding="0" border="0"><tbody><tr><td styleCode="Lrule Rrule">&#x2022; feel very weak and tired &#x2022; have unusual (not normal) muscle pain &#x2022; have trouble breathing &#x2022; have unexplained stomach or intestinal problems with nausea and vomiting, or diarrhea </td><td styleCode="Rrule">&#x2022; have unusual sleepiness or sleep longer than usual &#x2022; feel cold, especially in your arms and legs &#x2022; feel dizzy or lightheaded &#x2022; have a slow or irregular heartbeat </td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="0"><tbody><tr><td styleCode="Lrule Rrule">o headache o drowsiness o weakness o irritability </td><td styleCode="Rrule">o hunger o fast heartbeat o confusion o shaking or feeling jittery </td><td styleCode="Rrule">o dizziness o sweating </td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="0"><tbody><tr><td styleCode="Lrule Rrule">&#x2022; diarrhea &#x2022; nausea and vomiting &#x2022; gassiness (flatulence) &#x2022; indigestion </td><td styleCode="Rrule">&#x2022; stomach-area (abdominal) pain and swelling &#x2022; headache &#x2022; taste disturbance (unpleasant metallic taste) </td></tr></tbody></table>

Rx only Recommended Dosing Schedule Adults - In general, clinically significant responses are not seen at doses below 1500 mg per day. However, a lower recommended starting dose and gradually increased dosage is advised to minimize gastrointestinal symptoms. The usual starting dose of metformin hydrochloride extended release tablets USP is 500 mg once daily with the evening meal. Dosage increases should be made in increments of 500 mg weekly, up to a maximum of 2000 mg once daily with the evening meal. If glycemic control is not achieved on metformin hydrochloride extended release tablets 2000 mg once daily, a trial of metformin hydrochloride extended release tablets 1000 mg twice daily should be considered. If higher doses of metformin are required, metformin hydrochloride tablets should be used at total daily doses up to 2550 mg administered in divided daily doses, as described above. (See CLINICAL PHARMACOLOGY: Clinical Studies. ) In a randomized trial, patients currently treated with metformin hydrochloride tablets were switched to metformin hydrochloride extended release tablets USP. Results of this trial suggest that patients receiving metformin hydrochloride tablets treatment may be safely switched to metformin hydrochloride extended release tablets USP once daily at the same total daily dose, up to 2000 mg once daily. Following a switch from metformin hydrochloride tablets to metformin hydrochloride extended release tablets USP, glycemic control should be closely monitored and dosage adjustments made accordingly (see CLINICAL PHARMACOLOGY: Clinical Studies ). Pediatrics - Safety and effectiveness of metformin hydrochloride extended release tablets USP in pediatric patients have not been established. Transfer From Other Antidiabetic Therapy When transferring patients from standard oral hypoglycemic agents other than chlorpropamide to metformin hydrochloride extended release tablets USP, no transition period generally is necessary. When transferring patients from chlorpropamide, care should be exercised during the first two weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia.

in hydrochloride extended release tablets USP, no transition period generally is necessary. When transferring patients from chlorpropamide, care should be exercised during the first two weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia. Concomitant Metformin Hydrochloride Extended Release Tablets USP and Oral Sulfonylurea Therapy in Adult Patients If patients have not responded to four weeks of the maximum dose of metformin hydrochloride extended release tablets USP monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing metformin hydrochloride extended release tablets USP at the maximum dose, even if prior primary or secondary failure to a sulfonylurea has occurred. Clinical and pharmacokinetic drug-drug interaction data are currently available only for metformin plus glyburide (glibenclamide). With concomitant metformin hydrochloride extended release tablets USP and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal. With concomitant metformin hydrochloride extended release tablets USP and sulfonylurea therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased. Appropriate precautions should be taken. (See Package Insert of the respective sulfonylurea.) If patients have not satisfactorily responded to one to three months of concomitant therapy with the maximum dose of metformin hydrochloride extended release tablets USP and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without metformin hydrochloride extended release tablets USP. Concomitant Metformin Hydrochloride Extended Release Tablets USP and Insulin Therapy in Adult Patients The current insulin dose should be continued upon initiation of metformin hydrochloride extended release tablets USP therapy. Metformin hydrochloride extended release tablets USP therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of metformin hydrochloride extended release tablets USP should be increased by 500 mg after approximately 1 week and by 500 mg every week thereafter until adequate glycemic control is achieved. The maximum recommended daily dose is 2000 mg for metformin hydrochloride extended release tablets USP. It is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dL in patients receiving concomitant insulin and metformin hydrochloride extended release tablets USP. Further adjustment should be individualized based on glucose-lowering response. Specific Patient Populations Metformin hydrochloride extended release tablets USP is not recommended for use in pregnancy. Metformin hydrochloride extended-release tablets USP is not recommended in pediatric patients (below the age of 17 years). The initial and maintenance dosing of metformin hydrochloride extended release tablets USP should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment should be based on a careful assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of metformin hydrochloride extended release tablets USP. Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly. (See WARNINGS .)

ul assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of metformin hydrochloride extended release tablets USP. Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly. (See WARNINGS .) What are the side effects of metformin hydrochloride extended release tablets USP? Lactic Acidosis. In rare cases, metformin hydrochloride can cause a serious side effect called lactic acidosis. This is caused by a buildup of lactic acid in your blood. This buildup can cause serious damage. Lactic acidosis caused by metformin hydrochloride is rare and has occurred mostly in people whose kidneys were not working normally. Lactic acidosis has been reported in about one in 33,000 patients taking metformin hydrochloride over the course of a year. Although rare, if lactic acidosis does occur, it can be fatal in up to half the people who develop it. It is also important for your liver to be working normally when you take metformin hydrochloride extended release tablets USP. Your liver helps remove lactic acid from your blood. Make sure you tell your doctor before you use metformin hydrochloride extended release tablets USP if you have kidney or liver problems. You should also stop using metformin hydrochloride extended release tablets USP and call your doctor right away if you have signs of lactic acidosis. Lactic acidosis is a medical emergency that must be treated in a hospital. Signs of lactic acidosis are: feeling very weak, tired, or uncomfortable unusual muscle pain trouble breathing unusual or unexpected stomach discomfort feeling cold feeling dizzy or lightheaded suddenly developing a slow or irregular heartbeat If your medical condition suddenly changes, stop taking metformin hydrochloride extended release tablets USP and call your doctor right away. This may be a sign of lactic acidosis or another serious side effect. Other Side Effects. Common side effects of metformin hydrochloride include diarrhea, nausea, and upset stomach. These side effects generally go away after you take the medicine for a while. Taking your medicine with meals can help reduce these side effects. Tell your doctor if the side effects bother you a lot, last for more than a few weeks, come back after they’ve gone away, or start later in therapy. You may need a lower dose or need to stop taking the medicine for a short period or for good. About 3 out of every 100 people who take metformin hydrochloride extended release tablets USP have an unpleasant metallic taste when they start taking the medicine. It lasts for a short time. Metformin hydrochloride extended release tablets USP rarely cause hypoglycemia (low blood sugar) by themselves. However, hypoglycemia can happen if you do not eat enough, if you drink alcohol, or if you take other medicines to lower blood sugar. General advice about prescription medicines If you have questions or problems, talk with your doctor or other healthcare provider. You can ask your doctor or pharmacist for the information about metformin hydrochloride that is written for health care professionals. Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use metformin hydrochloride extended release tablets USP for a condition for which it was not prescribed. Do not share your medicine with other people. Manufactured By: Inventia Healthcare Private Limited Plot No.F1 & F-1/1, Additional Ambernath M.I.D.C., Ambernath (East)-421506, Dist. Thane, Maharashtra, India Distributed by: Ascend Laboratories, LLC Montvale, NJ 07645

DESCRIPTION Metformin hydrochloride extended release tablets USP is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride ( N,N -dimethylimidodicar- bonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. The structural formula is as shown: Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C 4 H 11 N 5 • HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pK a of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. Metformin hydrochloride extended release tablets USP contain 500 mg of metformin hydrochloride USP as the active ingredient. Metformin hydrochloride extended release tablets USP 500 mg contain the inactive ingredients sodium carboxymethyl cellulose, hypromellose and magnesium stearate. Metformin hydrochloride extended release tablets USP 500 mg meets USP dissolution Test 3. System Components and Performance- Metformin hydrochloride extended release tablets USP comprises a swellable matrix system. In the aqueous gastrointestinal (GI) environment, the dosage form swells remarkably thereby increasing in size and geometry from where drug is released slowly by a process of diffusion through the gel matrix that is essentially independent of pH. The hydrated polymer system is not rigid and is expected to be broken up by normal peristalsis in the GI tract. The biologically inert components of the tablet may occasionally remain intact during GI transit and will be eliminated in the feces as a soft, hydrated mass. Structural Formula

Mechanism of Action Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see PRECAUTIONS ) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

Pharmacokinetics Absorption and Bioavailability Following a single oral dose of metformin hydrochloride extended release tablets USP, C max is achieved with a median value of 7 hours and a range of 4 hours to 8 hours. Peak plasma levels are approximately 20% lower compared to the same dose of metformin hydrochloride tablets however, the extent of absorption (as measured by AUC) is similar to metformin hydrochloride tablets. At steady state, the AUC and C max are less than dose proportional for metformin hydrochloride extended release tablets USP within the range of 500 mg to 2000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1, 1.4, and 1.8 μg/mL for 500, 1000, 1500, and 2000 mg once-daily doses, respectively. The extent of metformin absorption (as measured by AUC) from metformin hydrochloride extended release tablets USP at a 2000 mg once-daily dose is similar to the same total daily dose administered as metformin hydrochloride tablets 1000 mg twice daily. After repeated administration of metformin hydrochloride extended release tablets USP, metformin did not accumulate in plasma. Within-subject variability in C max and AUC of metformin from metformin hydrochloride extended release tablets USP is comparable to that with metformin hydrochloride tablets. Although the extent of metformin absorption (as measured by AUC) from the metformin hydrochloride extended release tablet USP increased by approximately 50% when given with food, there was no effect of food on C max and T max of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of metformin hydrochloride extended release tablets USP. Distribution The apparent volume of distribution (V/F) of metformin following single oral doses of metformin hydrochloride 850 mg tablets averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin hydrochloride, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally LESS THAN 1 μg/mL. During controlled clinical trials of metformin hydrochloride tablets, maximum metformin plasma levels did not exceed 5 μg/mL, even at maximum doses. Metabolism and Elimination Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance (see Table 1 ) is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. Special Populations Patients with Type 2 Diabetes In the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see Table 1 ), nor is there any accumulation of metformin in either group at usual clinical doses.

ns Patients with Type 2 Diabetes In the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see Table 1 ), nor is there any accumulation of metformin in either group at usual clinical doses. The pharmacokinetics of metformin hydrochloride extended release tablets USP in patients with type 2 diabetes are comparable to those in healthy normal adults. Renal Insufficiency In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see Table 1 ; also see WARNINGS ). Hepatic Insufficiency No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency. Geriatrics Limited data from controlled pharmacokinetic studies of metformin hydrochloride in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and C max is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 1 ). Metformin hydrochloride treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced (see WARNINGS and DOSAGE AND ADMINISTRATION ). Table 1: Select Mean (±S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin Hydrochloride. Subject Groups : Metformin Hydrochloride dose a ( number of subjects ) C max b ( μg / mL ) T max c ( hrs ) Renal Clearance ( mL / min ) Healthy , nondiabetic adults : 500 mg single dose (24) 850 mg single dose (74) d 850 mg three times daily for 19 doses e (9) 1.03 (±0.33) 1.60 (±0.38) 2.01 (±0.42) 2.75 (±0.81) 2.64 (±0.82) 1.79 (±0.94) 600 (±132) 552 (±139) 642 (±173) Adults with type 2 diabetes : 850 mg single dose (23) 850 mg three times daily for 19 doses e (9) 1.48 (±0.5) 1.90 (±0.62) 3.32 (±1.08) 2.01 (±1.22) 491 (±138) 550 (±160) Elderly f , healthy nondiabetic adults : 850 mg single dose (12) 2.45 (±0.70) 2.71 (±1.05) 412 (±98) Renal - impaired adults : 850 mg single dose Mild (CL c r g 61-90 mL/min) (5) Moderate (CL c r 31-60 mL/min) (4) Severe (CL c r 10-30 mL/min) (6) 1.86 (±0.52) 4.12 (±1.83) 3.93 (±0.92) 3.20 (±0.45) 3.75 (±0.50) 4.01 (±1.10) 384 (±122) 108 (±57) 130 (±90) a All doses given fasting except the first 18 doses of the multiple dose studies b Peak plasma concentration c Time to peak plasma concentration d Combined results (average means) of five studies: mean age 32 years (range 23-59 years) e Kinetic study done following dose 19, given fasting f Elderly subjects, mean age 71 years (range 65-81 years) g CL c r = creatinine clearance normalized to body surface area of 1.73 m 2 Pediatrics After administration of a single oral metformin hydrochloride 500 mg tablet with food, geometric mean metformin C max and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), all with normal renal function. Gender Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males = 19, females = 16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin hydrochloride tablets was comparable in males and females. Race No studies of metformin pharmacokinetic parameters according to race have been performed.

according to gender (males = 19, females = 16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin hydrochloride tablets was comparable in males and females. Race No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin hydrochloride tablets in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).

<table ID="S06" width="99%"><col width="53%"/><col width="16%"/><col width="15%"/><col width="15%"/><thead><tr><td align="left" colspan="4" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold"> Table 1: Select Mean (&#xB1;S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin Hydrochloride.

%"/><col width="16%"/><col width="15%"/><col width="15%"/><thead><tr><td align="left" colspan="4" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold"> Table 1: Select Mean (&#xB1;S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin Hydrochloride. </content></td></tr></thead><tbody><tr><td align="center" colspan="1" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold"> </content><content styleCode="bold">Subject </content><content styleCode="bold">Groups</content><content styleCode="bold">: </content><content styleCode="bold">Metformin </content><content styleCode="bold">Hydrochloride dose ^a</content> <content styleCode="bold">(</content><content styleCode="bold">number </content><content styleCode="bold">of </content><content styleCode="bold">subjects</content><content styleCode="bold">)</content><content styleCode="bold"> </content></td><td align="center" colspan="1" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold"> </content><content styleCode="bold">C _max^b</content><content styleCode="bold"> </content><content styleCode="bold">(</content><content styleCode="bold">&#x3BC;g</content><content styleCode="bold">/</content><content styleCode="bold">mL</content><content styleCode="bold">)</content><content styleCode="bold"> </content></td><td align="center" colspan="1" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold"> </content><content styleCode="bold">T _max^c</content><content styleCode="bold"> </content><content styleCode="bold">(</content><content styleCode="bold">hrs</content><content styleCode="bold">)</content><content styleCode="bold"> </content></td><td align="center" colspan="1" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">Renal </content> <content styleCode="bold">Clearance</content><content styleCode="bold"> </content><content styleCode="bold">(</content><content styleCode="bold">mL</content><content styleCode="bold">/</content><content styleCode="bold">min</content><content styleCode="bold">)</content><content styleCode="bold"> </content></td></tr><tr><td align="justify" styleCode=" Lrule Rrule Botrule Toprule" valign="top"><content styleCode="bold"/><content styleCode="bold"> Healthy</content>, <content styleCode="bold">nondiabetic </content><content styleCode="bold">adults</content><content styleCode="bold">:</content><content styleCode="bold"> </content> 500 mg single dose (24) 850 mg single dose (74) ^d 850 mg three times daily for 19 doses ^e (9) </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="top"> 1.03 (&#xB1;0.33) 1.60 (&#xB1;0.38) 2.01 (&#xB1;0.42) </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="top"> 2.75 (&#xB1;0.81) 2.64 (&#xB1;0.82) 1.79 (&#xB1;0.94) </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="top"> 600 (&#xB1;132) 552 (&#xB1;139) 642 (&#xB1;173) </td></tr><tr><td align="justify" styleCode=" Lrule Rrule Botrule Toprule" valign="top"><content styleCode="bold"/><content styleCode="bold"> Adults </content><content styleCode="bold">with </content><content styleCode="bold">type </content><content styleCode="bold">2 </content><content styleCode="bold">diabetes</content><content styleCode="bold">:</content><content styleCode="bold"> </content> 850 mg single dose (23) 850 mg three times daily for 19 doses ^e (9) <content styleCode="bold"> </content></td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="top"> 1.48 (&#xB1;0.5) 1.90 (&#xB1;0.62) </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="top"> 3.32 (&#xB1;1.08) 2.01 (&#xB1;1.22

850 mg three times daily for 19 doses ^e (9) <content styleCode="bold"> </content></td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="top"> 1.48 (&#xB1;0.5) 1.90 (&#xB1;0.62) </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="top"> 3.32 (&#xB1;1.08) 2.01 (&#xB1;1.22 ) </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="top"> 491 (&#xB1;138) 550 (&#xB1;160) </td></tr><tr><td align="justify" styleCode=" Lrule Rrule Botrule Toprule" valign="top"><content styleCode="bold"> Elderly ^f</content>, <content styleCode="bold">healthy </content><content styleCode="bold">nondiabetic </content><content styleCode="bold">adults</content><content styleCode="bold">:</content><content styleCode="bold"> </content> 850 mg single dose (12) </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="top"> 2.45 (&#xB1;0.70) </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="top"> 2.71 (&#xB1;1.05) </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="top"> 412 (&#xB1;98) </td></tr><tr><td align="justify" styleCode=" Lrule Rrule Botrule Toprule" valign="top"><content styleCode="bold"/><content styleCode="bold"> Renal</content><content styleCode="bold">-</content><content styleCode="bold">impaired </content><content styleCode="bold">adults</content><content styleCode="bold">: </content><content styleCode="bold"> </content><content styleCode="bold"> 850 </content><content styleCode="bold">mg </content><content styleCode="bold">single </content><content styleCode="bold">dose</content><content styleCode="bold"> </content><content styleCode="bold"> Mild </content>(CL _c_r^g 61-90 mL/min) (5) <content styleCode="bold"> Moderate </content>(CL _c_r 31-60 mL/min) (4) <content styleCode="bold"> Severe </content>(CL _c_r 10-30 mL/min) (6) </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="top"> 1.86 (&#xB1;0.52) 4.12 (&#xB1;1.83) 3.93 (&#xB1;0.92) </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="top"> 3.20 (&#xB1;0.45) 3.75 (&#xB1;0.50) 4.01 (&#xB1;1.10) </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="top"> 384 (&#xB1;122) 108 (&#xB1;57) 130 (&#xB1;90) </td></tr><tr><td align="left" colspan="4" valign="top"><paragraph styleCode="Footnote">^aAll doses given fasting except the first 18 doses of the multiple dose studies </paragraph><paragraph styleCode="Footnote">^bPeak plasma concentration </paragraph><paragraph styleCode="Footnote">^cTime to peak plasma concentration </paragraph><paragraph styleCode="Footnote">^dCombined results (average means) of five studies: mean age 32 years (range 23-59 years) </paragraph><paragraph styleCode="Footnote">^eKinetic study done following dose 19, given fasting </paragraph><paragraph styleCode="Footnote">^fElderly subjects, mean age 71 years (range 65-81 years) </paragraph><paragraph styleCode="Footnote">^gCL _c_r = creatinine clearance normalized to body surface area of 1.73 m ² </paragraph></td></tr></tbody></table>

Clinical Studies Metformin Hydrochloride Extended Release Tablets USP A 24-week, double-blind, placebo-controlled study of metformin hydrochloride extended release tablets USP , taken once daily with the evening meal, was conducted in patients with type 2 diabetes who had failed to achieve glycemic control with diet and exercise (HbA 1c 7.0%-10.0%, FPG 126-270 mg/dL). Patients entering the study had a mean baseline HbA 1c of 8.0% and a mean baseline FPG of 176 mg/dL. After 12 weeks treatment, mean HbA 1c had increased from baseline by 0.1% and mean FPG decreased from baseline by 2 mg/dL in the placebo group, compared with a decrease in mean HbA 1c had increased from baseline by 0.1% and mean FPG decreased from baseline by 2 mg/dL in the placebo group, compared with a decrease in mean HbA 1c of 0.6% and a decrease in mean FPG of 23 mg/dL in patients treated with metformin hydrochloride extended release tablets USP 1000 mg once daily. Subsequently, the treatment dose was increased to 1500 mg once daily if HbA 1c was ≥7.0% but <8.0% (patients with HbA 1c ≥8.0% were discontinued from the study). At the final visit (24-week), mean HbA 1c had increased 0.2% from baseline in placebo patients and decreased 0.6% with metformin hydrochloride extended release tablets USP. A 16-week, double-blind, placebo-controlled, dose-response study of metformin hydrochloride extended release tablets USP, taken once daily with the evening meal or twice daily with meals, was conducted in patients with type 2 diabetes who had failed to achieve glycemic control with diet and exercise (HbA 1c 7.0%-11.0%, FPG 126-280 mg/dL). Changes in glycemic control and body weight are shown in Table 6 . Table 6: Summary of Mean Changes from Baseline* in HbA 1c , Fasting Plasma Glucose, and Body Weight at Final Visit (16-week study) Metformin Hydrochloride Extended Release Tablets USP 500 mg Once Daily 1000 mg Once Daily 1500 mg Once Daily 2000 mg Once Daily 1000 mg Twice Daily Placebo Hemoglobin A 1 c (%) Baseline Change at FINAL VISIT p-value a ( n = 115 ) 8.2 -0.4 <0.001 ( n = 115 ) 8.4 -0.6 <0.001 ( n = 111 ) 8.3 -0.9 <0.001 ( n = 125 ) 8.4 -0.8 <0.001 ( n = 112 ) 8.4 -1.1 <0.001 ( n = 111 ) 8.4 0.1 - FPG ( mg / dL ) Baseline Change at FINAL VISIT p-value a ( n = 126 ) 182.7 -15.2 <0.001 ( n = 118 ) 183.7 -19.3 <0.001 ( n = 120 ) 178.9 -28.5 <0.001 ( n = 132 ) 181.0 -29.9 <0.001 ( n = 122 ) 181.6 -33.6 <0.001 ( n = 113 ) 179.6 7.6 - Body Weight ( lbs ) Baseline Change at FINAL VISIT p-value a ( n = 125 ) 192.9 -1.3 NS** ( n = 119 ) 191.8 -1.3 NS** ( n = 117 ) 188.3 -0.7 NS** ( n = 131 ) 195.4 -1.5 NS** ( n = 119 ) 192.5 -2.2 NS** ( n = 113 ) 194.3 -1.8 - * All patients on diet therapy at Baseline a All comparisons versus Placebo ** Not statistically significant Compared with placebo, improvement in glycemic control was seen at all dose levels of metformin hydrochloride extended release tablets USP and treatment was not associated with any significant change in weight (see DOSAGE AND ADMINISTRATION for dosing recommendations for metformin hydrochloride extended release tablets USP). A 24-week, double-blind, randomized study of metformin hydrochloride extended release tablets USP, taken once daily with the evening meal, and metformin hydrochloride tablets, taken twice daily (with breakfast and evening meal), was conducted in patients with type 2 diabetes who had been treated with metformin hydrochloride tablets 500 mg twice daily for at least 8 weeks prior to study entry.

ed release tablets USP, taken once daily with the evening meal, and metformin hydrochloride tablets, taken twice daily (with breakfast and evening meal), was conducted in patients with type 2 diabetes who had been treated with metformin hydrochloride tablets 500 mg twice daily for at least 8 weeks prior to study entry. The metformin hydrochloride tablets dose had not necessarily been titrated to achieve a specific level of glycemic control prior to study entry. Patients qualified for the study if HbA 1c was ≤8.5% and FPG was ≤200 mg/dL. Changes in glycemic control and body weight are shown in Table 7. Table 7: Summary of Mean Changes from Baseline * in HbA 1c , Fasting Plasma Glucose, and Body Weight at Week 12 and at Final Visit (24-week study) Metformin Hydrochloride Tablets Metformin Hydrochloride Extended Release Tablets USP 500 mg Twice Daily 1000 mg Once Daily 1500 mg Once Daily Hemoglobin A 1 c (%) Baseline Change at 12 Weeks (95% CI) Change at FINAL VISIT (95% CI) ( n = 67 ) 7.06 0.14 (-0.03, 0.31) 0.14 a (-0.04, 0.31) ( n = 72 ) 6.99 0.23 (0.10, 0.36) 0.27 (0.11, 0.43) ( n = 66 ) 7.02 0.04 (-0.08, 0.15) 0.13 (-0.02, 0.28) FPG ( mg / dL ) Baseline Change at 12 Weeks (95% CI) Change at FINAL VISIT (95% CI) ( n = 69 ) 127.2 12.9 (6.5, 19.4) 14.0 (7.0, 21.0) ( n = 72 ) 131.0 9.5 (4.4, 14.6) 11.5 (4.4, 18.6) ( n = 70 ) 131.4 3.7 (-0.4, 7.8) 7.6 (1.0, 14.2) Body Weight ( lbs ) Baseline Change at 12 Weeks (95% CI) Change at FINAL VISIT (95% CI) ( n = 71 ) 210.3 0.4 (-0.4, 1.5) 0.9 (-0.4, 2.2) ( n = 74 ) 202.8 0.9 (0.0, 2.0) 1.1 (-0.2, 2.4) ( n = 71 ) 192.7 0.7 (-0.4, 1.8) 0.9 (-0.4, 2.0) * All patients on metformin hydrochloride tablets 500 mg twice daily at Baseline a n=68 After 12 weeks of treatment, there was an increase in mean HbA 1c in all groups; in the metformin hydrochloride extended release tablets USP 1000 mg group, the increase from baseline of 0.23% was statistically significant (see DOSAGE AND ADMINISTRATION ). Changes in lipid parameters in the previously described placebo-controlled dose-response study of metformin hydrochloride extended release tablets USP are shown in Table 8. Table 8: Summary of Mean Percent Changes from Baseline* in Major Lipid Variables at Final Visit (16-week study) Metformin Hydrochloride Extended Release Tablets USP 500 mg Once Daily 1000 mg Once Daily 1500 mg Once Daily 2000 mg Once Daily 1000 mg Twice Daily Placebo Total Cholesterol ( mg / dL ) Baseline Mean % Change at FINAL VISIT ( n = 120 ) 210.3 1.0% ( n = 113 ) 218.1 1.7% ( n = 110 ) 214.6 0.7% ( n = 126 ) 204.4 -1.6% ( n = 117 ) 208.2 -2.6% ( n = 110 ) 208.6 2.6% Total Triglycerides ( mg / dL ) Baseline Mean % Change at FINAL VISIT ( n = 120 ) 220.2 14.5% ( n = 113 ) 211.9 9.4% ( n = 110 ) 198.0 15.1% ( n = 126 ) 194.2 14.9% ( n = 117 ) 179.0 9.4% ( n = 110 ) 211.7 10.9% LDL - Cholesterol ( mg / dL ) Baseline Mean % Change at FINAL VISIT ( n = 119 ) 131.0 -1.4% ( n = 113 ) 134.9 -1.6% ( n = 109 ) 135.8 -3.5% ( n = 126 ) 125.8 -3.3% ( n = 117 ) 131.4 -5.5% ( n = 107 ) 131.9 3.2% HDL - Cholesterol ( mg / dL ) Baseline Mean % Change at FINAL VISIT ( n = 120 ) 40.8 6.2% ( n = 108 ) 41.6 8.6% ( n = 108 ) 40.6 5.5% ( n = 125 ) 40.2 6.1% ( n = 117 ) 42.4 7.1% ( n = 108 ) 39.4 5.8% * All patients on diet therapy at Baseline Changes in lipid parameters in the previously described study of metformin hydrochloride tablets and metformin hydrochloride extended release tablets USP are shown in Table 9.

8 ) 41.6 8.6% ( n = 108 ) 40.6 5.5% ( n = 125 ) 40.2 6.1% ( n = 117 ) 42.4 7.1% ( n = 108 ) 39.4 5.8% * All patients on diet therapy at Baseline Changes in lipid parameters in the previously described study of metformin hydrochloride tablets and metformin hydrochloride extended release tablets USP are shown in Table 9. Table 9: Summary of Mean Percent Changes from Baseline* in Major Lipid Variables at Final Visit (24-week study) Metformin Hydrochloride Tablets Metformin Hydrochloride Extended Release Tablets USP 500 mg Twice Daily 1000 mg Once Daily 1500 mg Once Daily Total Cholesterol ( mg / dL ) Baseline Mean % Change at FINAL VISIT ( n = 68 ) 199.0 0.1% ( n = 70 ) 201.9 1.3% ( n = 66 ) 201.6 0.1% Total Triglycerides ( mg / dL ) Baseline Mean % Change at FINAL VISIT ( n = 68 ) 178.0 6.3% ( n = 70 ) 169.2 25.3% ( n = 66 ) 206.8 33.4% LDL - Cholesterol ( mg / dL ) Baseline Mean %Change at FINAL VISIT ( n = 68 ) 122.1 -1.3% ( n = 70 ) 126.2 -3.3% ( n = 66 ) 115.7 -3.7% HDL - Cholesterol ( mg / dL ) Baseline Mean % Change at FINAL VISIT ( n = 68 ) 41.9 4.8% ( n = 70 ) 41.7 1.0% ( n = 65 ) 44.6 -2.1% * All patients on metformin hydrochloride tablet 500 mg twice daily at Baseline

<table width="99%" ID="i56b1ad06-be88-45e8-8c2e-6f478ebb4f32"><col width="24%"/><col width="12%"/><col width="13%"/><col width="13%"/><col width="12%"/><col width="13%"/><col width="12%"/><thead><tr><td align="center" colspan="7" styleCode=" Lrule Rrule Toprule" valign="middle"><content styleCode="bold"> Table 6: Summary of Mean Changes from Baseline* in HbA _1c, Fasting Plasma Glucose, and Body Weight at Final Visit (16-week study) </content></td></tr></thead><tbody><tr><td align="left" colspan="1" styleCode=" Lrule Rrule Toprule" valign="middle"> <content styleCode="bold"> </content></td><td align="center" colspan="5" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">Metformin </content><content styleCode="bold">Hydrochloride </content><content styleCode="bold">Extended</content> <content styleCode="bold">Release Tablets USP </content></td><td align="center" colspan="1" styleCode=" Lrule Rrule Toprule" valign="middle"><content styleCode="bold"> </content></td></tr><tr><td align="left" colspan="1" styleCode=" Lrule Rrule Botrule" valign="middle"><content styleCode="bold"> </content></td><td align="center" colspan="1" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">500 </content><content styleCode="bold">mg</content><content styleCode="bold"> </content><content styleCode="bold">Once</content> <content styleCode="bold">Daily</content><content styleCode="bold"> </content></td><td align="center" colspan="1" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">1000 </content><content styleCode="bold">mg</content><content styleCode="bold"> </content><content styleCode="bold">Once</content> <content styleCode="bold">Daily</content><content styleCode="bold"> </content></td><td align="center" colspan="1" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">1500 </content><content styleCode="bold">mg</content><content styleCode="bold"> </content><content styleCode="bold">Once</content> <content styleCode="bold">Daily</content><content styleCode="bold"> </content></td><td align="center" colspan="1" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">2000 </content><content styleCode="bold">mg</content><content styleCode="bold"> </content><content styleCode="bold">Once</content> <content styleCode="bold">Daily</content><content styleCode="bold"> </content></td><td align="center" colspan="1" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">1000 </content><content styleCode="bold">mg</content><content styleCode="bold"> </content><content styleCode="bold">Twice</content> <content styleCode="bold">Daily</content><content styleCode="bold"> </content></td><td align="center" colspan="1" styleCode=" Lrule Rrule Botrule" valign="middle"><content styleCode="bold">Placebo</content><content styleCode="bold"> </content></td></tr><tr><td align="left" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">Hemoglobin </content><content styleCode="bold">A ₁_c </content><content styleCode="bold">(%)</content><content styleCode="bold"> </content> Baseline Change at FINAL VISIT p-value ^a</td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">115</con

tent><content styleCode="bold"> </content> Baseline Change at FINAL VISIT p-value ^a</td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">115</con tent><content styleCode="bold">)</content><content styleCode="bold"> </content>8.2 -0.4 &lt;0.001 </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">115</content><content styleCode="bold">)</content><content styleCode="bold"> </content>8.4 -0.6 &lt;0.001 </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">111</content><content styleCode="bold">)</content><content styleCode="bold"> </content>8.3 -0.9 &lt;0.001 </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">125</content><content styleCode="bold">)</content><content styleCode="bold"> </content>8.4 -0.8 &lt;0.001 </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">112</content><content styleCode="bold">)</content><content styleCode="bold"> </content>8.4 -1.1 &lt;0.001 </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">111</content><content styleCode="bold">)</content><content styleCode="bold"> </content>8.4 0.1 - </td></tr><tr><td align="left" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">FPG </content><content styleCode="bold">(</content><content styleCode="bold">mg</content><content styleCode="bold">/</content><content styleCode="bold">dL</content><content styleCode="bold">)</content><content styleCode="bold"> </content> Baseline Change at FINAL VISIT p-value ^a </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">126</content><content styleCode="bold">)</content><content styleCode="bold"> </content>182.7 -15.2 &lt;0.001 </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">118</content><content styleCode="bold">)</content><content styleCode="bold"> </content>183.7 -19.3 &lt;0.001 </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">120</content><content styleCode="bold">)</content><content styleCode="bold"> </content>178.9 -28.5 &lt;0.001 </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">132</content><content styleCode="bold">)</content><content styleCode="bold"> </content>181.0 -29.9 &lt;0.001 </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middl

tent styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">132</content><content styleCode="bold">)</content><content styleCode="bold"> </content>181.0 -29.9 &lt;0.001 </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middl e"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">122</content><content styleCode="bold">)</content><content styleCode="bold"> </content>181.6 -33.6 &lt;0.001 </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">113</content><content styleCode="bold">)</content><content styleCode="bold"> </content>179.6 7.6 - </td></tr><tr><td align="left" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">Body </content><content styleCode="bold">Weight</content><content styleCode="bold">(</content><content styleCode="bold">lbs</content><content styleCode="bold">)</content><content styleCode="bold"> </content> Baseline Change at FINAL VISIT p-value ^a </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">125</content><content styleCode="bold">)</content><content styleCode="bold"> </content>192.9 -1.3 NS** </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">119</content><content styleCode="bold">)</content><content styleCode="bold"> </content>191.8 -1.3 NS** </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">117</content><content styleCode="bold">)</content><content styleCode="bold"> </content>188.3 -0.7 NS** </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">131</content><content styleCode="bold">)</content><content styleCode="bold"> </content>195.4 -1.5 NS** </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">119</content><content styleCode="bold">)</content><content styleCode="bold"> </content>192.5 -2.2 NS** </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">113</content><content styleCode="bold">)</content><content styleCode="bold"> </content>194.3 -1.8 - </td></tr><tr><td align="left" colspan="7"><paragraph styleCode="Footnote">* All patients on diet therapy at Baseline </paragraph><paragraph styleCode="Footnote">^a<sup/>All comparisons versus Placebo </paragraph><paragraph styleCode="Footnote">** Not statistically significant </paragraph></td></tr></tbody></table>

/tr><tr><td align="left" colspan="7"><paragraph styleCode="Footnote">* All patients on diet therapy at Baseline </paragraph><paragraph styleCode="Footnote">^a<sup/>All comparisons versus Placebo </paragraph><paragraph styleCode="Footnote">** Not statistically significant </paragraph></td></tr></tbody></table> <table width="101%" ID="idf1f67f9-ca7f-41ac-80ce-f814fbd64805"><col width="26%"/><col width="29%"/><col width="22%"/><col width="22%"/><thead><tr><td align="center" colspan="4" styleCode=" Lrule Rrule Toprule" valign="middle"><content styleCode="bold"> Table 7: Summary of Mean Changes from Baseline ^* in HbA _1c, Fasting Plasma Glucose, and Body Weight at Week 12 and at Final Visit (24-week study) </content></td></tr></thead><tbody><tr><td align="left" colspan="1" styleCode=" Lrule Rrule Toprule" valign="middle"><content styleCode="bold"> </content></td><td align="center" colspan="1" styleCode=" Lrule Rrule Toprule" valign="middle"><content styleCode="bold">Metformin </content> <content styleCode="bold">Hydrochloride </content><content styleCode="bold">Tablets</content><content styleCode="bold"> </content></td><td align="center" colspan="2" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">Metformin </content><content styleCode="bold">Hydrochloride </content><content styleCode="bold">Extended</content> <content styleCode="bold">Release </content><content styleCode="bold">Tablets </content><content styleCode="bold">USP</content><content styleCode="bold"> </content></td></tr><tr><td align="left" colspan="1" styleCode=" Lrule Rrule Botrule" valign="middle"><content styleCode="bold"> </content></td><td align="center" colspan="1" styleCode=" Lrule Rrule Botrule" valign="middle"><content styleCode="bold">500 </content><content styleCode="bold">mg</content><content styleCode="bold"> </content><content styleCode="bold">Twice </content><content styleCode="bold">Daily</content><content styleCode="bold"> </content></td><td align="center" colspan="1" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">1000 </content><content styleCode="bold">mg</content><content styleCode="bold"> </content><content styleCode="bold">Once </content><content styleCode="bold">Daily</content><content styleCode="bold"> </content></td><td align="center" colspan="1" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">1500 </content><content styleCode="bold">mg</content><content styleCode="bold"> </content><content styleCode="bold">Once </content><content styleCode="bold">Daily</content><content styleCode="bold"> </content></td></tr><tr><td align="left" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">Hemoglobin </content><content styleCode="bold">A ₁_c </content><content styleCode="bold">(%)</content><content styleCode="bold"> </content> Baseline Change at 12 Weeks (95% CI) Change at FINAL VISIT (95% CI) </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">67</content><content styleCode="bold">)</content><content styleCode="bold"> </content>7.06 0.14 (-0.03, 0.31) 0.14 ^a (-0.04, 0.31) </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">72</content><content styleCode="bold">)</content><content styleCode="bold"> </content>6.99 0.23 (0.10, 0.36) 0.27 (0.11, 0.43) </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</co

"bold">n</content><content styleCode="bold">=</content><content styleCode="bold">72</content><content styleCode="bold">)</content><content styleCode="bold"> </content>6.99 0.23 (0.10, 0.36) 0.27 (0.11, 0.43) </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</co ntent><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">66</content><content styleCode="bold">)</content><content styleCode="bold"> </content>7.02 0.04 (-0.08, 0.15) 0.13 (-0.02, 0.28) </td></tr><tr><td align="left" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">FPG </content><content styleCode="bold">(</content><content styleCode="bold">mg</content><content styleCode="bold">/</content><content styleCode="bold">dL</content><content styleCode="bold">)</content><content styleCode="bold"> </content> Baseline Change at 12 Weeks (95% CI) Change at FINAL VISIT (95% CI) <content styleCode="bold"> </content></td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">69</content><content styleCode="bold">)</content><content styleCode="bold"> </content>127.2 12.9 (6.5, 19.4) 14.0 (7.0, 21.0) </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">72</content><content styleCode="bold">)</content><content styleCode="bold"> </content>131.0 9.5 (4.4, 14.6) 11.5 (4.4, 18.6) </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">70</content><content styleCode="bold">)</content><content styleCode="bold"> </content>131.4 3.7 (-0.4, 7.8) 7.6 (1.0, 14.2) </td></tr><tr><td align="left" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">Body </content><content styleCode="bold">Weight</content><content styleCode="bold">(</content><content styleCode="bold">lbs</content><content styleCode="bold">)</content><content styleCode="bold"> </content> Baseline Change at 12 Weeks (95% CI) Change at FINAL VISIT (95% CI) </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">71</content><content styleCode="bold">)</content><content styleCode="bold"> </content>210.3 0.4 (-0.4, 1.5) 0.9 (-0.4, 2.2) </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">74</content><content styleCode="bold">)</content><content styleCode="bold"> </content>202.8 0.9 (0.0, 2.0) 1.1 (-0.2, 2.4) </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">71</content><content styleCode="bold">)</content><content styleCode="bold"> </content>192.7 0.7 (-0.4, 1.8) 0.9 (-0.4, 2.0) </td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">^* All patients on metformin hydrochloride tablets 500 mg twice daily at Baseline </paragraph><paragraph styleCode="Footnote">^a n=68 </paragraph></td></tr></tbody></table>

ld"> </content>192.7 0.7 (-0.4, 1.8) 0.9 (-0.4, 2.0) </td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">^* All patients on metformin hydrochloride tablets 500 mg twice daily at Baseline </paragraph><paragraph styleCode="Footnote">^a n=68 </paragraph></td></tr></tbody></table> <table width="100%" ID="i539b903e-5e48-4d73-8757-324200b653a5"><col width="30%"/><col width="12%"/><col width="12%"/><col width="12%"/><col width="12%"/><col width="12%"/><col width="10%"/><thead><tr><td align="center" colspan="7" styleCode=" Lrule Rrule Toprule" valign="middle"><content styleCode="bold"> Table 8: Summary of Mean Percent Changes from Baseline* in Major Lipid Variables at Final Visit (16-week study) </content> </td></tr></thead><tbody><tr><td align="left" colspan="1" styleCode=" Lrule Rrule Toprule" valign="middle"><content styleCode="bold"> </content></td><td align="center" colspan="5" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">Metformin </content><content styleCode="bold">Hydrochloride </content><content styleCode="bold">Extended</content> <content styleCode="bold">Release </content><content styleCode="bold">Tablets </content><content styleCode="bold">USP</content><content styleCode="bold"> </content></td><td align="center" colspan="1" styleCode=" Lrule Rrule Toprule" valign="middle"><content styleCode="bold"> </content></td></tr><tr><td align="left" colspan="1" styleCode=" Lrule Rrule Botrule" valign="middle"><content styleCode="bold"> </content></td><td align="center" colspan="1" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">500 </content><content styleCode="bold">mg</content><content styleCode="bold"> </content><content styleCode="bold">Once </content><content styleCode="bold">Daily</content><content styleCode="bold"> </content></td><td align="center" colspan="1" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">1000 </content><content styleCode="bold">mg</content><content styleCode="bold"> </content><content styleCode="bold">Once </content><content styleCode="bold">Daily</content><content styleCode="bold"> </content></td><td align="center" colspan="1" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">1500 </content><content styleCode="bold">mg</content><content styleCode="bold"> </content><content styleCode="bold">Once </content><content styleCode="bold">Daily</content><content styleCode="bold"> </content></td><td align="center" colspan="1" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">2000 </content><content styleCode="bold">mg</content><content styleCode="bold"> </content><content styleCode="bold">Once </content><content styleCode="bold">Daily</content><content styleCode="bold"> </content></td><td align="center" colspan="1" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">1000 </content><content styleCode="bold">mg</content><content styleCode="bold"> </content><content styleCode="bold">Twice </content><content styleCode="bold">Daily</content><content styleCode="bold"> </content></td><td align="center" colspan="1" styleCode=" Lrule Rrule Botrule" valign="middle"><content styleCode="bold">Placebo</content><content styleCode="bold"> </content></td></tr><tr><td align="left" styleCode=" Lrule Rrule Botrule Toprule" valign="top"><content styleCode="bold"> Total </content><content styleCode="bold">Cholesterol </content> <content styleCode="bold">(</content><content styleCode="bold">mg</content><content styleCode="bold">/</content><content styleCode="bold">dL</content><content styleCode="bold">)</content><content styleCode="bold"> </content> Baseline Mean % Change at FINAL VISIT </td><td align="center" styleCod

">Cholesterol </content> <content styleCode="bold">(</content><content styleCode="bold">mg</content><content styleCode="bold">/</content><content styleCode="bold">dL</content><content styleCode="bold">)</content><content styleCode="bold"> </content> Baseline Mean % Change at FINAL VISIT </td><td align="center" styleCod e=" Lrule Rrule Botrule Toprule" valign="top"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">120</content><content styleCode="bold">)</content><content styleCode="bold"> </content>210.3 1.0% </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="top"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">113</content><content styleCode="bold">)</content><content styleCode="bold"> </content>218.1 1.7% </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="top"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">110</content><content styleCode="bold">)</content><content styleCode="bold"> </content>214.6 0.7% </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="top"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">126</content><content styleCode="bold">)</content><content styleCode="bold"> </content>204.4 -1.6% </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="top"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">117</content><content styleCode="bold">)</content><content styleCode="bold"> </content>208.2 -2.6% </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="top"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">110</content><content styleCode="bold">)</content><content styleCode="bold"> </content>208.6 2.6% </td></tr><tr><td align="left" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold"> Total </content><content styleCode="bold">Triglycerides </content> <content styleCode="bold">(</content><content styleCode="bold">mg</content><content styleCode="bold">/</content><content styleCode="bold">dL</content><content styleCode="bold">)</content><content styleCode="bold"> </content> Baseline Mean % Change at FINAL VISIT </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">120</content><content styleCode="bold">)</content><content styleCode="bold"> </content>220.2 14.5% </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">113</content><content styleCode="bold">)</content><content styleCode="bold"> </content>211.9 9.4% </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">110</content><content styleCode="bold">)</content><content styleCode="bold"> </content>198.0 15.1% </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">126</content><content styleCode="bold">

d">)</content><content styleCode="bold"> </content>198.0 15.1% </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">126</content><content styleCode="bold"> )</content><content styleCode="bold"> </content>194.2 14.9% </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">117</content><content styleCode="bold">)</content><content styleCode="bold"> </content>179.0 9.4% </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">110</content><content styleCode="bold">)</content><content styleCode="bold"> </content>211.7 10.9% </td></tr><tr><td align="left" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold"> LDL</content><content styleCode="bold">-</content><content styleCode="bold">Cholesterol </content> <content styleCode="bold">(</content><content styleCode="bold">mg</content><content styleCode="bold">/</content><content styleCode="bold">dL</content><content styleCode="bold">)</content><content styleCode="bold"> </content> Baseline Mean % Change at FINAL VISIT </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">119</content><content styleCode="bold">)</content><content styleCode="bold"> </content>131.0 -1.4% </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">113</content><content styleCode="bold">)</content><content styleCode="bold"> </content>134.9 -1.6% </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">109</content><content styleCode="bold">)</content><content styleCode="bold"> </content>135.8 -3.5% </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">126</content><content styleCode="bold">)</content><content styleCode="bold"> </content>125.8 -3.3% </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">117</content><content styleCode="bold">)</content><content styleCode="bold"> </content>131.4 -5.5% </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">107</content><content styleCode="bold">)</content><content styleCode="bold"> </content>131.9 3.2% </td></tr><tr><td align="left" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold"> HDL</content><content styleCode="bold">-</content><content styleCode="bold">Cholesterol </content> <content styleCode="bold">(</content><content styleCode="bold">mg</content><content styleCode="bold">/</content><content styleCode="bold">dL</content><content styleCode="bold">)</content><content styleCode="bold"> <

old"> HDL</content><content styleCode="bold">-</content><content styleCode="bold">Cholesterol </content> <content styleCode="bold">(</content><content styleCode="bold">mg</content><content styleCode="bold">/</content><content styleCode="bold">dL</content><content styleCode="bold">)</content><content styleCode="bold"> < /content> Baseline Mean % Change at FINAL VISIT </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">120</content><content styleCode="bold">)</content><content styleCode="bold"> </content>40.8 6.2% <content styleCode="bold"> </content></td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">108</content><content styleCode="bold">)</content><content styleCode="bold"> </content>41.6 8.6% <content styleCode="bold"> </content></td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">108</content><content styleCode="bold">)</content><content styleCode="bold"> </content>40.6 5.5% <content styleCode="bold"> </content></td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">125</content><content styleCode="bold">)</content><content styleCode="bold"> </content>40.2 6.1% </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">117</content><content styleCode="bold">)</content><content styleCode="bold"> </content>42.4 7.1% <content styleCode="bold"> </content></td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">108</content><content styleCode="bold">)</content><content styleCode="bold"> </content>39.4 5.8% <content styleCode="bold"> </content></td></tr><tr><td align="left" colspan="7"><paragraph styleCode="Footnote">^*All patients on diet therapy at Baseline </paragraph></td></tr></tbody></table>

nt styleCode="bold">108</content><content styleCode="bold">)</content><content styleCode="bold"> </content>39.4 5.8% <content styleCode="bold"> </content></td></tr><tr><td align="left" colspan="7"><paragraph styleCode="Footnote">^*All patients on diet therapy at Baseline </paragraph></td></tr></tbody></table> <table width="100%" ID="i263f7661-42a9-4f2c-824e-be3ada39a3e7"><col width="32%"/><col width="28%"/><col width="20%"/><col width="20%"/><thead><tr><td align="center" colspan="4" styleCode=" Lrule Rrule Toprule" valign="middle"><content styleCode="bold"> Table 9: Summary of Mean Percent Changes from Baseline* in Major Lipid Variables at Final Visit (24-week study) </content> </td></tr></thead><tbody><tr><td align="left" colspan="1" styleCode=" Lrule Rrule Toprule" valign="middle"><content styleCode="bold"> </content></td><td align="center" colspan="1" styleCode=" Lrule Rrule Toprule" valign="middle"><content styleCode="bold">Metformin </content><content styleCode="bold">Hydrochloride </content> <content styleCode="bold">Tablets</content><content styleCode="bold"> </content></td><td align="center" colspan="2" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">Metformin </content><content styleCode="bold">Hydrochloride </content><content styleCode="bold">Extended</content> <content styleCode="bold">Release </content> <content styleCode="bold">Tablets </content><content styleCode="bold">USP</content><content styleCode="bold"> </content></td></tr><tr><td align="left" colspan="1" styleCode=" Lrule Rrule Botrule" valign="middle"><content styleCode="bold"> </content></td><td align="center" colspan="1" styleCode=" Lrule Rrule Botrule" valign="middle"><content styleCode="bold">500 mg </content><content styleCode="bold">Twice Daily </content></td><td align="center" colspan="1" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">1000 </content><content styleCode="bold">mg</content><content styleCode="bold"> </content><content styleCode="bold">Once </content><content styleCode="bold">Daily</content><content styleCode="bold"> </content></td><td align="center" colspan="1" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">1500 </content><content styleCode="bold">mg</content><content styleCode="bold"> </content><content styleCode="bold">Once </content><content styleCode="bold">Daily</content><content styleCode="bold"> </content></td></tr><tr><td align="left" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold"> Total </content><content styleCode="bold">Cholesterol </content><content styleCode="bold">(</content><content styleCode="bold">mg</content><content styleCode="bold">/</content><content styleCode="bold">dL</content><content styleCode="bold">)</content><content styleCode="bold"> </content> Baseline Mean % Change at FINAL VISIT </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">68</content><content styleCode="bold">)</content><content styleCode="bold"> </content>199.0 0.1% </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">70</content><content styleCode="bold">)</content><content styleCode="bold"> </content>201.9 1.3% </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">66</content><content styleCode="bold">)</content><content styleCode=

Code="bold"> </content>201.9 1.3% </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">66</content><content styleCode="bold">)</content><content styleCode= "bold"> </content>201.6 0.1% </td></tr><tr><td align="left" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold"> Total </content><content styleCode="bold">Triglycerides </content><content styleCode="bold">(</content><content styleCode="bold">mg</content><content styleCode="bold">/</content><content styleCode="bold">dL</content><content styleCode="bold">)</content><content styleCode="bold"> </content> Baseline Mean % Change at FINAL VISIT </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">68</content><content styleCode="bold">)</content><content styleCode="bold"> </content>178.0 6.3% </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">70</content><content styleCode="bold">)</content><content styleCode="bold"> </content>169.2 25.3% </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">66</content><content styleCode="bold">)</content><content styleCode="bold"> </content>206.8 33.4% </td></tr><tr><td align="left" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold"> LDL</content><content styleCode="bold">-</content><content styleCode="bold">Cholesterol </content><content styleCode="bold">(</content><content styleCode="bold">mg</content><content styleCode="bold">/</content><content styleCode="bold">dL</content><content styleCode="bold">)</content><content styleCode="bold"> </content> Baseline Mean %Change at FINAL VISIT </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">68</content><content styleCode="bold">)</content><content styleCode="bold"> </content>122.1 -1.3% <content styleCode="bold"> </content></td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">70</content><content styleCode="bold">)</content><content styleCode="bold"> </content>126.2 -3.3% <content styleCode="bold"> </content></td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">66</content><content styleCode="bold">)</content><content styleCode="bold"> </content>115.7 -3.7% <content styleCode="bold"> </content></td></tr><tr><td align="left" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold"> HDL</content><content styleCode="bold">-</content><content styleCode="bold">Cholesterol </content><content styleCode="bold">(</content><content styleCode="bold">mg</content><content styleCode="bold">/</content><content styleCode="bold">dL</content><content styleCode="bold">)</content><content styleCode="bold"> </content> Baseline Mean % Change at FINAL VISIT </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valig

eCode="bold">(</content><content styleCode="bold">mg</content><content styleCode="bold">/</content><content styleCode="bold">dL</content><content styleCode="bold">)</content><content styleCode="bold"> </content> Baseline Mean % Change at FINAL VISIT </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valig n="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">68</content><content styleCode="bold">)</content><content styleCode="bold"> </content>41.9 4.8% </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">70</content><content styleCode="bold">)</content><content styleCode="bold"> </content>41.7 1.0% </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">65</content><content styleCode="bold">)</content><content styleCode="bold"> </content>44.6 -2.1% </td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">^*All patients on metformin hydrochloride tablet 500 mg twice daily at Baseline </paragraph></td></tr></tbody></table>

CONTRAINDICATIONS Metformin hydrochloride are contraindicated in patients with: Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females] or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia (see WARNINGS and PRECAUTIONS ). Known hypersensitivity to metformin hydrochloride. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin. Metformin hydrochloride should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function. (See also PRECAUTIONS. )

Lactic Acidosis: Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with metformin hydrochloride extended release tablets USP when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 μg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin hydrochloride extended release tablets USP and by use of the minimum effective dose of metformin hydrochloride extended release tablets USP. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin hydrochloride extended release tablets USP treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, metformin hydrochloride should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, metformin hydrochloride should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking metformin hydrochloride extended release tablets USP, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, metformin hydrochloride should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see also PRECAUTIONS ). The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis.

RECAUTIONS ). The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur (see also PRECAUTIONS ). Metformin hydrochloride should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of metformin hydrochloride extended release tablets USP, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease. Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking metformin hydrochloride extended release tablets USP do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling. (See also PRECAUTIONS ). Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia). Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking metformin hydrochloride extended release tablets USP, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery. (See also CONTRAINDICATIONS and PRECAUTIONS ).

General Macrovascular Outcomes - There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with metformin hydrochloride extended release tablets USP or any other anti-diabetic drug. Monitoring of renal function - Metformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive metformin hydrochloride extended release tablets USP. In patients with advanced age, metformin hydrochloride should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those ≥80 years of age, renal function should be monitored regularly and, generally, metformin hydrochloride should not be titrated to the maximum dose (see WARNINGS and DOSAGE AND ADMINISTRATION ). Before initiation of metformin hydrochloride extended release tablets USP tablets therapy and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and metformin hydrochloride extended release tablets USP discontinued if evidence of renal impairment is present. Use of concomitant medications that may affect renal function or metformin disposition - Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion (see PRECAUTIONS: Drug Interactions ), should be used with caution. Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials) - Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin (see CONTRAINDICATIONS ). Therefore, in patients in whom any such study is planned, metformin hydrochloride extended release tablets USP should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal. Hypoxic states - Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on metformin hydrochloride extended release tablets USP therapy, the drug should be promptly discontinued. Surgical procedures - Metformin hydrochloride extended release tablets USP therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal. Alcohol intake - Alcohol is known to potentiate the effect of metformin on lactate metabolism.

ny surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal. Alcohol intake - Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving metformin hydrochloride extended release tablets USP. Impaired hepatic function - Since impaired hepatic function has been associated with some cases of lactic acidosis, metformin hydrochloride should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Vitamin B 12 levels - In controlled clinical trials of metformin hydrochloride tablets of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin hydrochloride tablets or vitamin B 12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on metformin hydrochloride extended release tablets USP and any apparent abnormalities should be appropriately investigated and managed (see PRECAUTIONS: Laboratory Tests ). Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. In these patients, routine serum vitamin B 12 measurements at two- to three year intervals may be useful. Change in clinical status of patients with previously controlled type 2 diabetes - A patient with type 2 diabetes previously well controlled on metformin hydrochloride extended release tablets USP who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, metformin hydrochloride extended release tablets USP must be stopped immediately and other appropriate corrective measures initiated (see also WARNINGS ). Hypoglycemia - Hypoglycemia does not occur in patients receiving metformin hydrochloride extended release tablets USP alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs. Loss of control of blood glucose - When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold metformin hydrochloride extended release tablets USP and temporarily administer insulin. Metformin hydrochloride extended release tablets USP may be reinstituted after the acute episode is resolved. The effectiveness of oral antidiabetic drugs in lowering blood glucose to a targeted level decreases in many patients over a period of time.

ride extended release tablets USP and temporarily administer insulin. Metformin hydrochloride extended release tablets USP may be reinstituted after the acute episode is resolved. The effectiveness of oral antidiabetic drugs in lowering blood glucose to a targeted level decreases in many patients over a period of time. This phenomenon, which may be due to progression of the underlying disease or to diminished responsiveness to the drug, is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective during initial therapy. Should secondary failure occur with either metformin hydrochloride extended release tablets USP or sulfonylurea monotherapy, combined therapy with metformin hydrochloride extended release tablets USP and sulfonylurea may result in a response. Should secondary failure occur with combined metformin hydrochloride extended release tablets USP /sulfonylurea therapy, it may be necessary to consider therapeutic alternatives including initiation of insulin therapy.

Information for Patients Patients should be informed of the potential risks and benefits of metformin hydrochloride extended release tablets USP and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose, glycosylated hemoglobin, renal function, and hematologic parameters. The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in the WARNINGS and PRECAUTIONS sections, should be explained to patients. Patients should be advised to discontinue metformin hydrochloride extended release tablets USP immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of metformin hydrochloride extended release tablets USP, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease. Patients should be counselled against excessive alcohol intake, either acute or chronic, while receiving metformin hydrochloride extended release tablets USP. Metformin hydrochloride extended release tablets USP alone does not usually cause hypoglycemia, although it may occur when metformin hydrochloride extended release tablets USP is used in conjunction with oral sulfonylureas and insulin. When initiating combination therapy, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. (See Patient Information printed below.) Patients should be informed that metformin hydrochloride extended release tablets USP must be swallowed whole and not crushed or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.

Laboratory Tests Response to all diabetic therapies should be monitored by periodic measurements of fasting blood glucose and glycosylated hemoglobin levels, with a goal of decreasing these levels toward the normal range. During initial dose titration, fasting glucose can be used to determine the therapeutic response. Thereafter, both glucose and glycosylated hemoglobin should be monitored. Measurements of glycosylated hemoglobin may be especially useful for evaluating long-term control (see also DOSAGE AND ADMINISTRATION ). Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with metformin hydrochloride therapy, if this is suspected, vitamin B 12 deficiency should be excluded.

Drug Interactions (Clinical Evaluation of Drug Interactions Conducted with Metformin Hydrochloride Tablets) Glyburide - In a single-dose interaction study in type 2 diabetes patients, coadministration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and C max were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain (see DOSAGE AND ADMINISTRATION: Concomitant Metformin Hydrochloride Extended Release Tablets USP and Oral Sulfonylurea Therapy in Adult Patients ). Furosemide - A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration. Furosemide increased the metformin plasma and blood C max by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the C max and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when coadministered chronically. Nifedipine - A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration of nifedipine increased plasma metformin C max and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. T max and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine. Cationic drugs - Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of metformin hydrochloride extended release tablets USP and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system. Other - Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving metformin hydrochloride extended release tablets USP, the patient should be closely observed for loss of blood glucose control.

id products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving metformin hydrochloride extended release tablets USP, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin hydrochloride extended release tablets USP, the patient should be observed closely for hypoglycemia. In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when coadministered in single-dose interaction studies. Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.

Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately four times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day. There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test ( S. typhimurium ), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative. Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons.

Pregnancy Teratogenic Effects: Pregnancy Category B Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Because animal reproduction studies are not always predictive of human response, metformin hydrochloride should not be used during pregnancy unless clearly needed. There are no adequate and well-controlled studies in pregnant women with metformin hydrochloride extended release tablets USP. Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about two and six times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

Nursing Mothers Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If metformin hydrochloride extended release tablets USP is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

Geriatric Use Controlled clinical studies of metformin hydrochloride did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, metformin hydrochloride should only be used in patients with normal renal function (see CONTRAINDICATIONS, WARNINGS , and CLINICAL PHARMACOLOGY: Pharmacokinetics ). Because aging is associated with reduced renal function, metformin hydrochloride extended release tablets USP should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of metformin hydrochloride extended release tablets USP (see also WARNINGS and DOSAGE AND ADMINISTRATION ).

ADVERSE REACTIONS In worldwide clinical trials over 900 patients with type 2 diabetes have been treated with metformin hydrochloride extended release tablets USP in placebo- and active-controlled studies. In placebo-controlled trials, 781 patients were administered metformin hydrochloride extended release tablets USP and 195 patients received placebo. Adverse reactions reported in greater than 5% of the metformin hydrochloride extended release tablets USP patients, and that were more common in metformin hydrochloride extended release tablets USP - than placebo-treated patients, are listed in Table 12. Table 12: Most Common Adverse Reactions (>5.0 Percent) in Placebo-Controlled Studies of Metformin Hydrochloride Extended Release Tablets USP* Metformin Hydrochloride Extended Release Tablets USP ( n = 781 ) Placebo ( n = 195 ) Adverse Reaction % of Patients Diarrhea 9.6 2.6 Nausea/Vomiting 6.5 1.5 * Reactions that were more common in metformin hydrochloride extended release tablets USP - than placebo-treated patients. Diarrhea led to discontinuation of study medication in 0.6% of patients treated with metformin hydrochloride extended release tablets USP. Additionally, the following adverse reactions were reported in ≥1.0% - ≤5.0% of metformin hydrochloride extended release tablets USP patients and were more commonly reported with metformin hydrochloride extended release tablets USP than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance.

<table width="100%" ID="i8d484981-cfcb-45a4-84b2-1c7fd60a63c6"><col width="26%"/><col width="32%"/><col width="32%"/><thead><tr><td align="center" colspan="3" styleCode=" Lrule Rrule Toprule" valign="middle"><content styleCode="bold"> Table 12: Most Common Adverse Reactions (&gt;5.0 Percent) in Placebo-Controlled Studies of Metformin Hydrochloride Extended Release Tablets USP* </content> </td></tr></thead><tbody><tr><td align="center" colspan="1" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold"> </content></td><td align="center" colspan="1" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">Metformin </content><content styleCode="bold">Hydrochloride </content> <content styleCode="bold">Extended</content> <content styleCode="bold">Release </content><content styleCode="bold">Tablets </content><content styleCode="bold">USP</content><content styleCode="bold"> </content><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">781</content><content styleCode="bold">)</content><content styleCode="bold"> </content></td><td align="center" colspan="1" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">Placebo</content><content styleCode="bold"> </content><content styleCode="bold"> </content><content styleCode="bold">(</content><content styleCode="bold">n</content><content styleCode="bold">=</content><content styleCode="bold">195</content><content styleCode="bold">)</content><content styleCode="bold"> </content></td></tr><tr><td align="center" colspan="1" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">Adverse </content><content styleCode="bold">Reaction</content><content styleCode="bold"> </content></td><td align="center" colspan="2" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"><content styleCode="bold">% </content><content styleCode="bold">of </content><content styleCode="bold">Patients</content><content styleCode="bold"> </content></td></tr><tr><td align="justify" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"> Diarrhea </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle">9.6 </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle">2.6 </td></tr><tr><td align="justify" styleCode=" Lrule Rrule Botrule Toprule" valign="middle"> Nausea/Vomiting </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle">6.5 </td><td align="center" styleCode=" Lrule Rrule Botrule Toprule" valign="middle">1.5 </td></tr><tr><td align="left" colspan="3"><paragraph styleCode="Footnote">^*Reactions that were more common in metformin hydrochloride extended release tablets USP - than placebo-treated patients. </paragraph></td></tr></tbody></table>

OVERDOSAGE Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see WARNINGS ). Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

DOSAGE AND ADMINISTRATION There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with metformin hydrochloride extended release tablets USP or any other pharmacologic agent. Dosage of metformin hydrochloride extended release tablets USP must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily doses. The maximum recommended daily dose of metformin hydrochloride extended release tablets USP in adults is 2000 mg. Metformin hydrochloride extended release tablets USP should generally be given once daily with the evening meal. Metformin hydrochloride extended release tablets USP should be started at a low dose, with gradual dose escalation, both to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control of the patient. During treatment initiation and dose titration (see Recommended Dosing Schedule ), fasting plasma glucose should be used to determine the therapeutic response to metformin hydrochloride extended release tablets USP and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately three months. The therapeutic goal should be to decrease both fasting plasma glucose and glycosylated hemoglobin levels to normal or near normal by using the lowest effective dose of metformin hydrochloride extended release tablets USP, either when used as monotherapy or in combination with sulfonylurea or insulin. Monitoring of blood glucose and glycosylated hemoglobin will also permit detection of primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication, and secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness. Short-term administration of metformin hydrochloride extended release tablets USP may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone. Metformin hydrochloride extended release tablets USP must be swallowed whole and never crushed or chewed. Occasionally, the inactive ingredients of metformin hydrochloride extended release tablets USP will be eliminated in the feces as a soft, hydrated mass. (See Patient Information printed below.)

HOW SUPPLIED Metformin Hydrochloride Extended Release Tablets USP Bottles of 20 NDC 68071-1419-2 Bottles of 30 NDC 68071-1419-3 Bottles of 60 NDC 68071-1419-6 Bottles of 90 NDC 68071-1419-9 Bottles of 180 NDC 68071-1419-8 Metformin hydrochloride extended release tablets USP 500 mg are white to off-white, capsule shaped, biconvex, beveled edge tablet, with occasionally mottled appearance, debossed with " ˥L 001" on one side and plain on other side. Storage Store at 20° to 25° C (68° to 77° F); excursions permitted to 15° to 30° C (59° to 86° F). (See USP Controlled Room Temperature.) Dispense in light-resistant containers. Manufactured By: Inventia Healthcare Private Limited Plot No.F1 & F-1/1, Additional Ambernath M.I.D.C., Ambernath (East)-421506, Dist. Thane, Maharashtra, India Distributed by: Ascend Laboratories, LLC Montvale, NJ 07645 PT 1977

PATIENT INFORMATION Metformin Hydrochloride Extended Release Tablets USP Rx only Read this information carefully before you start taking this medicine and each time you refill your prescription. There may be new information. This information does not take the place of your doctor’s advice. Ask your doctor or pharmacist if you do not understand some of this information or if you want to know more about this medicine. What are metformin hydrochloride extended release tablets USP? Metformin hydrochloride is used to treat type 2 diabetes. This is also known as non-insulin-dependent diabetes mellitus. People with type 2 diabetes are not able to make enough insulin or respond normally to the insulin their bodies make. When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems including kidney damage, amputations, and blindness. Diabetes is also closely linked to heart disease. The main goal of treating diabetes is to lower your blood sugar to a normal level. High blood sugar can be lowered by diet and exercise, by a number of medicines taken by mouth, and by insulin shots. Before you take metformin hydrochloride extended release tablets USP, try to control your diabetes by exercise and weight loss. While you take your diabetes medicine, continue to exercise and follow the diet advised for your diabetes. No matter what your recommended diabetes management plan is, studies have shown that maintaining good blood sugar control can prevent or delay complications of diabetes, such as blindness. Metformin hydrochloride extended release tablets USP works longer in your body. Both of these medicines help control your blood sugar in a number of ways. These include helping your body respond better to the insulin it makes naturally, decreasing the amount of sugar your liver makes, and decreasing the amount of sugar your intestines absorb. Metformin hydrochloride extended release tablets USP do not cause your body to make more insulin. Because of this, when taken alone, they rarely cause hypoglycemia (low blood sugar), and usually do not cause weight gain. However, when they are taken with a sulfonylurea or with insulin, hypoglycemia is more likely to occur, as is weight gain. WARNING: A small number of people who have metformin hydrochloride have developed a serious condition called lactic acidosis. Lactic acidosis is caused by a buildup of lactic acid in the blood. This happen more often in people with kidney problems. Most people with kidney problems should not take metformin hydrochloride extended release tablets USP. (See " What are the side effects of metformin hydrochloride extended release tablets USP? ") Who should not take metformin hydrochloride extended release tablets USP? Some conditions increase your chance of getting lactic acidosis, or cause other problems if you take either of these medicines. Most of the conditions listed below can increase your chance of getting lactic acidosis. Do not take metformin hydrochloride extended release tablets USP if you: have kidney problems have liver problems have heart failure that is treated with medicines, such as Lanoxin ® (digoxin) or Lasix ® (furosemide) drink a lot of alcohol.

he conditions listed below can increase your chance of getting lactic acidosis. Do not take metformin hydrochloride extended release tablets USP if you: have kidney problems have liver problems have heart failure that is treated with medicines, such as Lanoxin ® (digoxin) or Lasix ® (furosemide) drink a lot of alcohol. This means you binge drink for short periods or drink all the time are seriously dehydrated (have lost a lot of water from your body) are going to have an x-ray procedure with injection of dyes (contrast agents) are going to have surgery develop a serious condition, such as heart attack, severe infection, or a stroke are 80 years or older and you have NOT had your kidney function tested Tell your doctor if you are pregnant or plan to become pregnant. Metformin hydrochloride extended release tablets USP may not be right for you. Talk with your doctor about your choices. You should also discuss your choices with your doctor if you are nursing a child. Can metformin hydrochloride extended release tablets USP be used in children? Metformin hydrochloride extended release tablets USP have not been studied in children. How should I take metformin hydrochloride extended release tablets USP? Your doctor will tell you how much medicine to take and when to take it. You will probably start out with a low dose of the medicine. Your doctor may slowly increase your dose until your blood sugar is better controlled. You should take metformin hydrochloride extended release tablets USP with meals. Your doctor may have you take other medicines along with metformin hydrochloride extended release tablets USP to control your blood sugar. These medicines may include insulin shots. Taking metformin hydrochloride extended release tablets USP with insulin may help you better control your blood sugar while reducing the insulin dose. Continue your exercise and diet program and test your blood sugar regularly while taking metformin hydrochloride extended release tablets USP. Your doctor will monitor your diabetes and may perform blood tests on you from time to time to make sure your kidneys and your liver are functioning normally. There is no evidence that metformin hydrochloride extended release tablets USP causes harm to the liver or kidneys. Tell your doctor if you: have an illness that causes severe vomiting, diarrhea or fever, or if you drink a much lower amount of liquid than normal. These conditions can lead to severe dehydration (loss of water in your body).You may need to stop taking metformin hydrochloride extended release tablets USP for a short time. plan to have surgery or an x-ray procedure with injection of dye (contrast agent). You may need to stop taking metformin hydrochloride extended release tablets USP for a short time. start to take other medicines or change how you take a medicine. Metformin hydrochloride can affect how well other drugs work, and some drugs can affect how well metformin hydrochloride work. Some medicines may cause high blood sugar. Metformin hydrochloride extended release tablets USP must be swallowed whole and never crushed or chewed. Occasionally, the inactive ingredients of metformin hydrochloride extended release tablets USP may be eliminated as a soft mass in your stool that may look like the original tablet; this is not harmful and will not affect the way metformin hydrochloride extended release tablets USP works to control your diabetes. What should I avoid while taking metformin hydrochloride extended release tablets USP? Do not drink a lot of alcoholic drinks while taking metformin hydrochloride extended release tablets USP. This means you should not binge drink for short periods, and you should not drink a lot of alcohol on a regular basis. Alcohol can increase the chance of getting lactic acidosis.