Metformin Hydrochloride

6 ADVERSE REACTIONS The incidence and type of adverse reactions reported by greater than 5% of patients for the combined metformin hydrochloride extended-release tablets group versus placebo group are hypoglycemia, diarrhea, and nausea. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-800-272-5525 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience The following adverse reactions are discussed in more detail in other sections of the labeling: Lactic acidosis [see Warnings and Precautions ( 5.1 )] Vitamin B 12 Levels [see Warnings and Precautions ( 5.2 )] Hypoglycemia [see Warnings and Precautions ( 5.3 )] 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 clinical practice. In clinical trials conducted in the U.S., over 1000 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 24-week monotherapy trial comparing metformin hydrochloride extended-release tablets to immediate-release metformin, serious adverse reactions were reported in 3.6% (19/528) of the metformin hydrochloride extended-release tablets-treated patients compared to 2.9% (5/174) of the patients treated with immediate-release metformin. 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. A serious adverse reaction was reported in 2.1% (9/431) of the metformin hydrochloride extended-release tablets and glyburide-treated patients compared to 1.4% (2/144) of the placebo and glyburide-treated patients. When the data from the monotherapy and add-on to sulfonylurea clinical trials were combined, the most frequently (incidence greater than or equal to 0.5 %) reported serious adverse reactions classified by system organ class were gastrointestinal disorders (1.0% of metformin hydrochloride extended-release tablets-treated patients compared to 0% of patients not treated with metformin hydrochloride extended-release tablets) and cardiac disorders (0.4% of metformin hydrochloride extended-release tablets-treated patients compared to 0.5% of patients not treated with metformin hydrochloride extended-release tablets). Only 2 serious adverse reactions (unstable angina [n=2] and pancreatitis [n=2]) were reported in more than one metformin hydrochloride extended-release tablets-treated patient. 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: Treatment-Emergent Adverse Reactions Reported By Greater Than 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 13.7% 4.9% Diarrhea 12.5% 5.6% Nausea 6.7% 4.2% * ARs that were more common in the metformin hydrochloride extended-release tablets-treated than in the placebo-treated patients. Laboratory Tests Vitamin B 12 concentrations Metformin may lower serum vitamin B 12 concentrations. Measurement of hematologic parameters on an annual basis is advised in patients on metformin hydrochloride extended-release tablets and any apparent abnormalities should be appropriately investigated and managed. [See Warnings and Precautions (5.2)] 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cholestatic, hepatocellular, and mixed hepatocellular liver injury

4 CONTRAINDICATIONS Metformin hydrochloride extended-release tablets are contraindicated in patients with: Severe renal impairment (eGFR below 30mL/min/1.73 m 2 ) [See Warnings and Precautions ( 5.1 )] . Known hypersensitivity to metformin hydrochloride. Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin. Severe renal impairment; (eGFR below 30mL/min/1.73 m 2 ) ( 4 ) Known hypersensitivity to metformin hydrochloride ( 4 ) Metabolic acidosis, including diabetic ketoacidosis ( 4 )

11 DESCRIPTION Metformin hydrochloride extended-release tablet is an oral antihyperglycemic medication used in the management of type 2 diabetes. Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. The structural formula of metformin hydrochloride (metformin HCl) is as shown: Metformin HCl, USP 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 HCl, USP is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. Metformin hydrochloride extended-release tablets, USP are modified release dosage forms that contain 500 mg or 1,000 mg of metformin HCl. Each 500 mg tablet contains cellulose acetate, hydroxypropyl cellulose, FD&C blue #2, hypromellose, iron oxide black, lecithin, magnesium stearate, povidone, polyethylene glycol, polyvinyl alcohol, propylene glycol, sodium lauryl sulfate, talc, titanium dioxide, xanthan gum. Each 1,000 mg tablet contains cellulose acetate, hydroxypropyl cellulose, hypromellose, iron oxide black, lecithin, magnesium stearate, povidone, polyethylene glycol, polyvinyl alcohol, propylene glycol, sodium lauryl sulfate, talc, titanium dioxide, xanthan gum. Metformin hydrochloride extended-release tablets USP, 500 mg and 1,000 mg tablets are formulated to gradually release metformin to the upper gastrointestinal (GI) tract. structural formula

2 DOSAGE AND ADMINISTRATION Starting dose is 500 mg daily with evening meal ( 2.1 ) Individualize dose based on effectiveness and tolerability, while not exceeding the maximum recommended daily dose of 2,000 mg. ( 2.1 ) 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 Metformin hydrochloride extended-release tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures ( 2.4 ) Swallow whole. Never split, crush or chew. ( 2.5 ) 2.1 Recommended Dosage The starting dose of metformin hydrochloride extended-release tablets in patients who are not currently taking metformin is 500 mg orally, once daily with the evening meal. Increase the dose in 500 mg increments every 1 to 2 weeks if a higher dose of metformin hydrochloride extended-release tablets is needed and there are no gastrointestinal adverse reactions. The dosage of metformin hydrochloride extended-release tablets must be individualized on the basis of both effectiveness and tolerability, while not exceeding the maximum recommended daily dose of 2,000 mg. 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/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 Switching from Immediate-Release Metformin to Metformin Hydrochloride Extended-Release Tablets If switching from immediate-release metformin to metformin hydrochloride extended-release tablets, initiate metformin hydrochloride extended-release tablets once daily at the same total dose, up to 2,000 mg once daily. 2.4 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/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 [See Warnings and Precautions ( 5.1 )] . 2.5 Important Administration Instructions Administer metformin hydrochloride extended-release tablets orally, once daily with the evening meal. Metformin hydrochloride extended-release tablets must be swallowed whole and never split, crushed or chewed. If a dose of metformin hydrochloride extended-release tablets 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 [See Patient Counseling Information ( 17 )].

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. Important Limitations of Use Metformin hydrochloride extended-release tablets should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. 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 ) Important limitations of use: Not for treatment of type 1 diabetes or diabetic ketoacidosis. ( 1 )

10 OVERDOSAGE No cases of overdose were reported during metformin hydrochloride extended-release tablets clinical trials. It would be expected that adverse reactions of a more intense character including epigastric discomfort, nausea, and vomiting followed by diarrhea, drowsiness, weakness, dizziness, malaise and headache might be seen. Should those symptoms persist, lactic acidosis should be excluded. 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 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.

7 DRUG INTERACTIONS Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring. ( 7.1 ) 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. ( 7.2 ) Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake. ( 7.3 ) 7.1 Carbonic Anhydrase Inhibitors Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) 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. Consider more frequent monitoring of these patients. 7.2 Drugs that Reduce Metformin Clearance 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 such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology ( 12.3 )] . Consider the benefits and risks of concomitant use. 7.3 Alcohol Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving metformin hydrochloride extended-release tablets. 7.4 Insulin Secretagogues or Insulin Co-administration of metformin hydrochloride extended-release tablets with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia. 7.5 Drugs Affecting Glycemic Control 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 blockers, and isoniazid. When such drugs are administered to a patient receiving metformin hydrochloride extended-release tablets, 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, the patient should be observed closely for hypoglycemia.

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. Metformin does not produce hypoglycemia in patients with type 2 diabetes or in healthy subjects except in special circumstances, [see Warnings and Precautions ( 5 )] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and daylong plasma insulin response may actually 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. Metformin hydrochloride extended-release tablets must be administered immediately after a meal to maximize therapeutic benefit. 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. 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. In a two-way, single-dose crossover study in healthy volunteers, the 1,000 mg tablet was found to be bioequivalent to two 500 mg tablets under fed conditions based on equivalent C max and AUCs for the two formulations. Distribution The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg immediate release metformin hydrochloride averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. 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 less than 1 mcg/mL. During controlled clinical trials, which served as the basis of approval for metformin, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses. 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. Metabolism studies with extended-release metformin tablets have not been conducted. 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 )] Geriatrics: Limited data from controlled pharmacokinetic studies of metformin hydrochloride 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 Warnings and Precautions ( 5.1 ) and Dosage and Administration ( 2 )] 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. The gender differences for C max are unlikely to be clinically important. 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: There were no definitive conclusions on the differences between the races with respect to the pharmacokinetics of metformin because of the imbalance in the respective sizes of the racial groups. However, the data suggest a trend towards 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 hydrochloride in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n = 249), blacks (n = 51) and Hispanics (n = 24). Pediatrics: No pharmacokinetic data from studies of metformin hydrochloride extended-release tablets in pediatric subjects are available. Drug Interactions: 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. Table 2: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure Coadministered Drug Dose of Coadministered Drug 1 Dose of Metformin 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 mg 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 Drugs that are eliminated by renal tubular secretion may increase the accumulation of metformin: [ See Warnings and Precautions (5) 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) and Drug Interactions (7)] Topiramate 100 mg 5 500 mg 5 1.25 5 1.17 1. All metformin and coadministered drugs were given as single doses 2. AUC = AUC 0–∞ 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 0-12h Table 3: Effect of Metformin on Coadministered Drug Systemic Exposure Coadministered Drug Dose of Coadministered Drug 1 Dose of Metformin 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 mg 850 mg 0.87 3 0.69 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 5 Cimetidine 400 mg 850 mg 0.95 4 1.01 1. All metformin and coadministered drugs were given as single doses 2. AUC = AUC 0–∞ 3. Ratio of arithmetic means, p-value of difference <0.05 4. AUC 0-24 hr 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. Metformin does not produce hypoglycemia in patients with type 2 diabetes or in healthy subjects except in special circumstances, [see Warnings and Precautions ( 5 )] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and daylong plasma insulin response may actually 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. Metformin hydrochloride extended-release tablets must be administered immediately after a meal to maximize therapeutic benefit. 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. 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. In a two-way, single-dose crossover study in healthy volunteers, the 1,000 mg tablet was found to be bioequivalent to two 500 mg tablets under fed conditions based on equivalent C max and AUCs for the two formulations. Distribution The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg immediate release metformin hydrochloride averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. 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 less than 1 mcg/mL. During controlled clinical trials, which served as the basis of approval for metformin, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses. 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. Metabolism studies with extended-release metformin tablets have not been conducted. 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 )] Geriatrics: Limited data from controlled pharmacokinetic studies of metformin hydrochloride 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 Warnings and Precautions ( 5.1 ) and Dosage and Administration ( 2 )] 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. The gender differences for C max are unlikely to be clinically important. 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: There were no definitive conclusions on the differences between the races with respect to the pharmacokinetics of metformin because of the imbalance in the respective sizes of the racial groups. However, the data suggest a trend towards 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 hydrochloride in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n = 249), blacks (n = 51) and Hispanics (n = 24). Pediatrics: No pharmacokinetic data from studies of metformin hydrochloride extended-release tablets in pediatric subjects are available. Drug Interactions: 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. Table 2: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure Coadministered Drug Dose of Coadministered Drug 1 Dose of Metformin 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 mg 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 Drugs that are eliminated by renal tubular secretion may increase the accumulation of metformin: [ See Warnings and Precautions (5) 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) and Drug Interactions (7)] Topiramate 100 mg 5 500 mg 5 1.25 5 1.17 1. All metformin and coadministered drugs were given as single doses 2. AUC = AUC 0–∞ 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 0-12h Table 3: Effect of Metformin on Coadministered Drug Systemic Exposure Coadministered Drug Dose of Coadministered Drug 1 Dose of Metformin 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 mg 850 mg 0.87 3 0.69 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 5 Cimetidine 400 mg 850 mg 0.95 4 1.01 1. All metformin and coadministered drugs were given as single doses 2. AUC = AUC 0–∞ 3. Ratio of arithmetic means, p-value of difference <0.05 4. AUC 0-24 hr reported 5. Ratio of arithmetic means

20170430

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3 DOSAGE FORMS AND STRENGTHS Metformin hydrochloride extended-release tablets USP, 500 mg are available as blue, round, biconvex, film coated tablets, an orifice on both sides, imprinted with “ WPI ” on the top and “ 500 ” on the bottom of one side, and plain on the other. Metformin hydrochloride extended-release tablets USP, 1,000 mg are available as white to off-white, round, biconvex, film coated tablets, an orifice on both sides, imprinted with “ WPI ” on the top and “ 1000 ” on the bottom of one side, and plain on the other. Extended Release Tablets, 500 mg and 1,000 mg ( 3 )

Metformin Hydrochloride Metformin Hydrochloride METFORMIN HYDROCHLORIDE METFORMIN CELLULOSE ACETATE HYDROXYPROPYL CELLULOSE, UNSPECIFIED FD&C BLUE NO. 2 HYPROMELLOSE 2910 (6 MPA.S) FERROSOFERRIC OXIDE LECITHIN, SOYBEAN MAGNESIUM STEARATE POVIDONE K90 POLYETHYLENE GLYCOL 400 POLYETHYLENE GLYCOL 3350 POLYETHYLENE GLYCOL 8000 POLYVINYL ALCOHOL, UNSPECIFIED PROPYLENE GLYCOL SODIUM LAURYL SULFATE TALC TITANIUM DIOXIDE XANTHAN GUM WPI;500 Metformin Hydrochloride Metformin Hydrochloride METFORMIN HYDROCHLORIDE METFORMIN CELLULOSE ACETATE HYDROXYPROPYL CELLULOSE, UNSPECIFIED HYPROMELLOSE 2910 (6 MPA.S) FERROSOFERRIC OXIDE LECITHIN, SOYBEAN MAGNESIUM STEARATE POVIDONE K90 POLYETHYLENE GLYCOL 400 POLYETHYLENE GLYCOL 3350 POLYETHYLENE GLYCOL 8000 POLYVINYL ALCOHOL, UNSPECIFIED PROPYLENE GLYCOL SODIUM LAURYL SULFATE TALC TITANIUM DIOXIDE XANTHAN GUM white to off-white WPI;1000

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 dose up to 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose based on body surface area comparisons.

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 dose up to 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose based on body surface area comparisons.

ANDA203755

Metformin Hydrochloride

Metformin Hydrochloride

0591-2411

HUMAN PRESCRIPTION DRUG

ORAL

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cholestatic, hepatocellular, and mixed hepatocellular liver injury

PRINCIPAL DISPLAY PANEL NDC 0591-2411-30 Once-Daily Metformin Hydrochloride Extended-Release Tablets, USP 500 mg Actavis 30 Tablets Rx Only 1

RECENT MAJOR CHANGES Boxed Warning 04/2017 Dosage and Administration ( 2 ) 04/2016 Contraindications ( 4 ) 04/2016 Warnings and Precautions ( 5.1 ) 04/2017

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Information for Patients Patients should be informed of the potential risks and benefits of metformin hydrochloride extended-release tablets 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, and hemoglobin A1c. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be advised to seek medical advice promptly. The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in the metformin hydrochloride extended-release tablets sections, should be explained to patients. Patients should be advised to discontinue metformin hydrochloride extended-release tablets 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, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to recur. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease. Patients should be advised to notify their health practitioner or call the Poison Control Center immediately in case of metformin hydrochloride extended-release tablets overdose. Patients should be informed about the importance of regular testing of renal function and hematological parameters when receiving treatment with 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 of metformin hydrochloride extended-release tablets may be required until renal function has been confirmed to be normal [see Warnings and Precautions ( 5.1 )]. Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving metformin hydrochloride extended-release tablets. Metformin hydrochloride extended-release tablets alone do not usually cause hypoglycemia, although it may occur when metformin hydrochloride extended-release tablets are used in conjunction with insulin secretagogues, such as sulfonylureas and insulin. Patients should be informed that metformin hydrochloride extended-release tablets must be swallowed whole and not crushed or chewed, and that the membrane coating remains intact during the transit of the dosage form through the gastrointestinal tract and is excreted in the feces. Manufactured by: Actavis Laboratories, FL Inc. Fort Lauderdale, FL 33314 USA Distributed by: Actavis Pharma, Inc. Parsippany, NJ 07054 USA Revised: April 2017 234056-1

14 CLINICAL STUDIES Metformin hydrochloride extended-release tablets have been studied as monotherapy and in combination with a sulfonylurea and insulin. Other formulations of metformin have been studied with other classes of antihyperglycemic agents, either as immediate or as extended release tablets. Double-Blind, Randomized, Parallel Group Clinical Trial to Compare the Efficacy, Safety, and Tolerability of Metformin ER (M-ER) Tablets and Metformin Immediate Release (M-IR) Tablets in the Treatment of Type 2 Diabetes Mellitus In a multicenter, randomized, double-blind, active-controlled, dose-ranging, parallel group trial 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 1,500 mg per day in divided doses (500 mg in the morning and 1,000 mg in the evening). This trial enrolled patients (n = 338) who were newly diagnosed with diabetes, patients treated only with diet and exercise, patients treated with a single anti-diabetic medication (sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, or meglitinides), and patients (n = 368) receiving metformin 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 anti-diabetic 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. For HbA 1c and fasting plasma glucose, each of the metformin hydrochloride extended-release tablets regimens was at least as effective as immediate-release metformin. Additionally, once daily dosing of metformin hydrochloride extended-release tablets was as effective as twice daily dosing of the immediate release metformin formulation. Table 4: Mean±SE Changes from Baseline to Final Visit in HbA1c, Fasting Plasma Glucose and Body Weight for the Metformin Extended-Release Tablets and Metformin Immediate-Release Treatment Groups (First 24-Week Study) Parameter Metformin Hydrochloride Extended-Release Tablets Metformin Immediate-Release 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 ± 0.3 8.5 ± 0.2 8.3 ± 0.2 8.7 ± 0.3 Mean Change ± SE at Final Visit -0.7 ± 0.1 -0.7 ± 0.1 -1.1 ± 0.1 -0.7 ± 0.1 Mean Difference ± SE from Metformin IR 0 ± 0.1 0 ± 0.1 -0.4 ± 0.1 N/A 98.4% CI for Difference (-0.3, 0.3) (-0.3, 0.3) (-0.7, -0.1) Fasting Plasma Glucose (mg/dL) N 175 179 170 172 Baseline 190 ± 10 192.3 ± 10 184 ± 10 197 ± 11 Mean Change ± SE at Final Visit -39 ± 4 -32 ± 4 -42 ± 5 -32 ± 5 Mean Difference ± SE from Metformin IR -6 ± 4 0 ± 4 -10 ± 4 N/A 95% CI for Difference (-15, 2) (-8, 9) (-19, -1) Body Weight (kg) N 176 180 171 173 Baseline 88.2 ± 3.7 90.5 ± 3.7 87.7 ± 3.7 88.7 ± 3.9 Mean Change ± SE at Final Visit -0.9 ± 0.4 -0.7 ± 0.4 -1.1 ± 0.4 -0.9 ± 0.4 Mean Difference ± SE from Metformin IR -0.1 ± 0.4 0.2 ± 0.4 -0.3 ± 0.4 N/A 95% CI for Difference (-0.9, 0.7) (-0.6, 0.9) (-1.0, 0.5) A Double-Blind, Randomized, Parallel-Group Study to Compare the Safety, Efficacy, and Tolerability of Metformin Extended Release (M-ER) Tablets in Combination with a Sulfonylurea (SU) and SU Alone in the Management of Patients with Type 2 Diabetes Mellitus In a double-blind, randomized, placebo-controlled (glyburide add-on) multicenter trial, 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/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) were enrolled. 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 phase was followed by a 21-week maintenance treatment phase. Use of insulin and oral hypoglycemic agents other than the study drugs were prohibited. The difference in the change from Baseline in HbA1c levels between the combined metformin hydrochloride extended-release tablets + glyburide groups and the glyburide only group was statistically significant at week 24 (p˂0.001). The changes in glycemic control across the three metformin hydrochloride extended-release tablets +glyburide groups were comparable. Table 5: Mean±SE Changes from Baseline to Final Visit in HbA1c, Fasting Plasma Glucose and Body Weight for the Metformin Hydrochloride Extended-Release Tablets/Glyburide Groups and Placebo/Glyburide Treatment Group (Second 24-Week Study) Parameter Metformin Hydrochloride Extended-Release Tablets + Glyburide* Placebo/ Glyburide* (n = 144) 1,500 mg QD (n = 144) 1,000 mg BID (n = 141) 2,000 mg QD (n = 146) HbA 1c (%) N 136 136 144 141 Baseline 7.9 ± 0.1 7.8 ± 0.1 7.7 ± 0.1 8.1 ± 0.1 Mean Change ± SE at Final Visit -0.7 ± 0.1 -0.8 ± 0.1 -0.7 ± 0.1 -0.1 ± 0.1 Mean Difference ± SE from Glyburide Alone -0.8 ± 0.1 -0.9 ± 0.1 -0.8 ± 0.1 N/A 95% CI for Difference (-1.0, -0.6) (-1.1, -0.7) (-1.0, -0.6) p-value for pairwise comparison < 0.001 < 0.001 < 0.001 Fasting Plasma Glucose (mg/dL) N 143 141 145 144 Baseline 163 ± 5 163 ± 5 159 ± 5 164 ± 5 Mean Change ± SE at Final Visit -14 ± 4 -16 ± 4 -9 ± 4 16 ± 4 Mean Difference ± SE from Glyburide Alone -29.2 ± 4.9 -31.2 ± 40.9 -24.9 ± 4.9 N/A 95% CI for Difference (-39, -20) (-41, -22) (-35, -15) p-value for pairwise comparison < 0.001 < 0.001 < 0.001 Body Weight (kg) N 143 141 146 144 Baseline 89.4 ± 11.2 103.7 ± 11.2 102.9 ± 11.2 95.6 ± 8.0 Mean Change ± SE at Final Visit 0.3 ± 1.1 0.1 ± 1.1 0 ± 1.1 0.7 ± 1.0 Mean Difference ± SE from Glyburide Alone -0.4 ± 0.5 -0.6 ± 0.5 -0.7 ± 0.5 N/A 95% CI for Difference (-1.5, 0.6) (-1.7, 0.4) (-1.8, 0.3) p-value for pairwise comparison 0.410 0.230 0.156 * - Glyburide was administered as 10 mg at breakfast and 5 mg at dinner. A 24-week, double-blind, placebo-controlled trial of immediate release metformin plus insulin versus insulin plus placebo was conducted in patients with type 2 diabetes who failed to achieve adequate glycemic control on insulin alone. Patients randomized to receive metformin plus insulin achieved a mean reduction in HbA 1c of 2.10%, compared to a 1.56% reduction in HbA 1c achieved by insulin plus placebo. The improvement in glycemic control was achieved at the final study visit with 16% less insulin, 93.0 U/day vs. 110.6 U/day, metformin plus insulin versus insulin plus placebo, respectively, p=0.04. A second double-blind, placebo-controlled study (n=51), with 16 weeks of randomized treatment, demonstrated that in patients with type 2 diabetes controlled on insulin for 8 weeks with an average HbA 1c of 7.46 ± 0.97%, the addition of metformin maintained similar glycemic control (HbA 1c 7.15 ± 0.61 versus 6.97 ± 0.62 for metformin plus insulin and placebo plus insulin, respectively) with 19% less insulin versus baseline (reduction of 23.68 ± 30.22 versus an increase of 0.43 ± 25.20 units for metformin plus insulin and placebo plus insulin, p˂0.01). In addition, this study demonstrated that the combination of metformin plus insulin resulted in reduction in body weight of 3.11 ± 4.30 lbs, compared to an increase of 1.30 ± 6.08 lbs for placebo plus insulin, p=0.01.

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. Other reported clinical experience has not identified differences in responses between the elderly and 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 ) and Dosage and Administration ( 2.2 )]

8.2 Labor and Delivery The safety and effectiveness of metformin hydrochloride extended-release tablets used during labor and delivery has not been evaluated in human studies.

8.3 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. Thus, the potential for hypoglycemia in nursing infants after metformin HCl oral solution may exist.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Metformin hydrochloride extended-release tablets are not recommended in pediatric patients below the age of 18 years.

8.1 Pregnancy Teratogenic Effects: Pregnancy Category B Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day, which represent 3 and 6 times the maximum recommended human daily dose of 2,000 mg based on body surface area comparison for rats and rabbits, respectively. However, because animal reproduction studies are not always predictive of human response, Metformin HCl should not be used during pregnancy unless clearly needed.

8 USE IN SPECIFIC POPULATIONS Pediatric Use: Safety and effectiveness in children younger than 18 years of age have not been established. ( 8.4 ) Geriatric Use: Assess renal function more frequently. ( 8.5 ) Hepatic Impairment: Avoid use in patients with hepatic impairment. ( 8.7 ) 8.1 Pregnancy Teratogenic Effects: Pregnancy Category B Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day, which represent 3 and 6 times the maximum recommended human daily dose of 2,000 mg based on body surface area comparison for rats and rabbits, respectively. However, because animal reproduction studies are not always predictive of human response, Metformin HCl should not be used during pregnancy unless clearly needed. 8.2 Labor and Delivery The safety and effectiveness of metformin hydrochloride extended-release tablets used during labor and delivery has not been evaluated in human studies. 8.3 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. Thus, the potential for hypoglycemia in nursing infants after metformin HCl oral solution may exist. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Metformin hydrochloride extended-release tablets are not recommended in pediatric patients below the age of 18 years. 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. Other reported clinical experience has not identified differences in responses between the elderly and 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 ) and Dosage and Administration ( 2.2 )] 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 )]

16 HOW SUPPLIED/STORAGE AND HANDLING Metformin hydrochloride extended-release tablets USP, 500 mg are available as blue, round, biconvex, film-coated tablets, an orifice on both sides, imprinted with “ WPI ” on the top and “ 500 ” on the bottom of one side, and plain on the other. Metformin hydrochloride extended-release tablets USP, 1,000 mg are available as white to off-white, round, biconvex, film-coated tablets, an orifice on both sides, imprinted with “ WPI ” on the top and “ 1000 ” on the bottom of one side, and plain on the other. They are supplied as follows: Package Strength NDC Code Bottles of 30 500 mg 0591-2411-30 Bottles of 100 500 mg 0591-2411-01 Bottles of 1,000 500 mg 0591-2411-10 Bottles of 30 1,000 mg 0591-2412-30 Bottles of 90 1,000 mg 0591-2412-19 Bottles of 1,000 1,000 mg 0591-2412-10 Store at 20º to 25ºC (68º to 77ºF) [See USP Controlled Room Temperature].

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 ), Drug Interactions ( 7 ), and Use in Specific Populations ( 8.6 , 8.7 )]. 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 P ostmarketing 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 ) R i s k 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 )