Metformin hydrochloride

6 ADVERSE REACTIONS The following adverse reactions are also discussed elsewhere in the labeling: • Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1) ] • Vitamin B 12 Deficiency [see Warnings and Precautions (5.2) ] • Hypoglycemia [see Warnings and Precautions (5.3) ] For metformin hydrochloride tablets, the most common adverse reactions (>5.0%) are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Granules Pharmaceuticals Inc. at 1-877-770-3183 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Metformin Hydrochloride Tablets In a U.S. clinical trial of metformin hydrochloride tablets in patients with type 2 diabetes mellitus, a total of 141 patients received metformin hydrochloride tablets up to 2550 mg per day. Adverse reactions reported in greater than 5% of metformin hydrochloride tablets treated patients and that were more common than in placebo-treated patients, are listed in Table 1. Table 1: Adverse Reactions from a Clinical Trial of Metformin Hydrochloride Tablets Occurring >5% and More Common than Placebo in Patients with Type 2 Diabetes Mellitus Diarrhea led to discontinuation of metformin hydrochloride tablets in 6% of patients. Additionally, the following adverse reactions were reported in ≥ 1% to ≤ 5% of metformin hydrochloride tablets treated patients and were more commonly reported with metformin hydrochloride tablets than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation. In metformin hydrochloride tablets clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients. Pediatric Patients In clinical trials with metformin hydrochloride tablets in pediatric patients with type 2 diabetes mellitus, the profile of adverse reactions was similar to that observed in adults. Table 1 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.

4 CONTRAINDICATIONS Metformin hydrochloride tablets are contraindicated in patients with: • Severe renal impairment (eGFR below 30 mL/min/1.73 m2) [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)

11 DESCRIPTION Metformin hydrochloride tablets, USP contain the antihyperglycemic agent metformin, which is a biguanide, in the form of monohydrochloride. The chemical name of metformin hydrochloride is N,N dimethylimidodicarbonimidic diamide hydrochloride. The structural formula is as shown below: Metformin hydrochloride, USP is a white to off-white crystalline compound with a molecular formula of C H N • HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water, slightly 4 11 5 soluble in alcohol, practically insoluble in acetone and in methylene chloride. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. Metformin hydrochloride tablets, USP contain 500 mg, 850 mg, or 1000 mg of metformin hydrochloride. Each tablet contains the inactive ingredients povidone (K-30), povidone (K-90), pregelatinized starch, and magnesium stearate. In addition, the coating for the tablets contains artificial blackberry flavor, hypromellose, macrogol and titanium dioxide. Formula

2 DOSAGE AND ADMINISTRATION Adult Dosage for metformin hydrochloride Tablets: • Starting dose: 500 mg orally twice a day or 850 mg once a day, with meals (2.1) • Increase the dose in increments of 500 mg weekly or 850 mg every 2 weeks, up to a maximum dose of 2550 mg per day, given in divided doses (2.1) • Doses above 2000 mg may be better tolerated given 3 times a day with meals (2.1) Pediatric Dosage for metformin hydrochloride Tablets: • Starting dose: 500 mg orally twice a day, with meals (2.2) • Increase dosage in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses twice daily (2.2) Renal Impairment: • Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) (2.3) o Do not use in patients with eGFR below 30 mL/minute/1.73 m2 (2.3) o Initiation is not recommended in patients with eGFR between 30 to 45 mL/minute/1.73 m2 (2.3) o Assess risk/benefit of continuing if eGFR falls below 45 mL/minute/1.73 m2 (2.3) o Discontinue if eGFR falls below 30 mL/minute/1.73 m2 (2.3) 2.1 Adult Dosage Metformin Hydrochloride Tablets • The recommended starting dose of metformin hydrochloride tablets are 500 mg orally twice a day or 850 mg once a day, given with meals. • Increase the dose in increments of 500 mg weekly or 850 mg every 2 weeks on the basis of glycemic control and tolerability, up to a maximum dose of 2550 mg per day, given in divided doses. • Doses above 2000 mg may be better tolerated given 3 times a day with meals. 2.2 Pediatric Dosage for Metformin Hydrochloride Tablets • The recommended starting dose of metformin hydrochloride tablets for pediatric patients 10 years of age and older is 500 mg orally twice a day, given with meals. • Increase dosage in increments of 500 mg weekly on the basis of glycemic control and tolerability, up to a maximum of 2000 mg per day, given in divided doses twice daily. 2.3 Recommendations for Use in Renal Impairment • Assess renal function prior to initiation of metformin hydrochloride tablets and periodically thereafter. • Metformin hydrochloride tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m 2 . • Initiation of metformin hydrochloride tablets in patients with an eGFR between 30 to 45 mL/minute/ 1.73 m 2 is not recommended. • In patients taking metformin hydrochloride tablets whose eGFR later falls below 45 mL/min/1.73 m 2 , assess the benefit risk of continuing therapy. • Discontinue metformin hydrochloride tablets if the patient’s eGFR later falls below 30 mL/ minute/ 1.73 m 2 [see Warnings and Precautions (5.1) ]. 2.4 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue metformin hydrochloride 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 tablets if renal function is stable.

1 INDICATIONS AND USAGE Metformin hydrochloride tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients 10 years of age and older with type 2 diabetes mellitus. Metformin hydrochloride tablets are biguanide indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients 10 years of age and older with type 2 diabetes mellitus. (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.

7 DRUG INTERACTIONS Table 3 presents clinically significant drug interactions with metformin hydrochloride tablets. Table 3: Clinically Significant Drug Interactions with Metformin Hydrochloride Tablets • 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 3

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 The absolute bioavailability of a metformin hydrochloride tablets 500 mg given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin hydrochloride tablets 500 to 1500 mg and 850 to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. At usual clinical doses and dosing schedules of metformin hydrochloride tablets, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 μg/mL. Following a single oral dose of metformin hydrochloride extended-release tablets, C max is achieved with a median value of 7 hours and a range of 4 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 comparable to metformin hydrochloride tablets. At steady state, the AUC and C max are less than dose proportional for metformin hydrochloride extended-release tablets within the range of 500 to 2000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1, 1.4 and 1.8 mcg/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 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, metformin did not accumulate in plasma. Effect of food: Food decreases the extent of absorption and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (C max ), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (T max ) following administration of a single 850 mg tablet of metformin hydrochloride tablets with food, compared to the same tablet strength administered fasting. Distribution The apparent volume of distribution (V/F) of metformin following single oral doses of metformin hydrochloride tablets 850 mg 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 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 3) [see Dosage and Administration (2.3), Contraindications (4), 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) ]. Limited data from controlled pharmacokinetic studies of metformin hydrochloride 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 Hydrochloride 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 to 59 years) e Kinetic study done following dose 19, given fasting f Elderly subjects, mean age 71 years (range 65 to 81 years) g CL cr = 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 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 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 Table 6: Effect of Metformin on Coadministered Drug Systemic Exposure * All metformin 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 Table 4 Table 5 Table 6

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 The absolute bioavailability of a metformin hydrochloride tablets 500 mg given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin hydrochloride tablets 500 to 1500 mg and 850 to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. At usual clinical doses and dosing schedules of metformin hydrochloride tablets, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 μg/mL. Following a single oral dose of metformin hydrochloride extended-release tablets, C max is achieved with a median value of 7 hours and a range of 4 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 comparable to metformin hydrochloride tablets. At steady state, the AUC and C max are less than dose proportional for metformin hydrochloride extended-release tablets within the range of 500 to 2000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1, 1.4 and 1.8 mcg/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 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, metformin did not accumulate in plasma. Effect of food: Food decreases the extent of absorption and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (C max ), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (T max ) following administration of a single 850 mg tablet of metformin hydrochloride tablets with food, compared to the same tablet strength administered fasting. Distribution The apparent volume of distribution (V/F) of metformin following single oral doses of metformin hydrochloride tablets 850 mg 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 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 3) [see Dosage and Administration (2.3), Contraindications (4), 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) ]. Limited data from controlled pharmacokinetic studies of metformin hydrochloride 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 Hydrochloride 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 to 59 years) e Kinetic study done following dose 19, given fasting f Elderly subjects, mean age 71 years (range 65 to 81 years) g CL cr = 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 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 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 Table 6: Effect of Metformin on Coadministered Drug Systemic Exposure * All metformin 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 Table 4 Table 5 Table 6

20231023

11

3 DOSAGE FORMS AND STRENGTHS Metformin Hydrochloride Tablets, USP are available as: • Tablets: 500 mg - White to off-white, round, biconvex, film coated tablets debossed with G over 10 on one side and plain on the other side. • Tablets: 850 mg - White to off-white, round, biconvex, film coated tablets debossed with G over 11 on one side and plain on the other side. • Tablets: 1000 mg - White to off-white, oval, biconvex, scored, film coated tablets debossed with G and 12 on either side of the scoreline on one side and plain on the other side. Metformin Hydrochloride Tablets : 500 mg, 850 mg, and 1000 mg (3)

Metformin hydrochloride Metformin hydrochloride POVIDONE K30 POVIDONE K90 STARCH, CORN MAGNESIUM STEARATE BLACKBERRY POLYETHYLENE GLYCOL 400 HYPROMELLOSE 2910 (6 MPA.S) TITANIUM DIOXIDE METFORMIN HYDROCHLORIDE METFORMIN white to off-white Artificial G;10 biconvex Metformin hydrochloride Metformin hydrochloride POVIDONE K30 POVIDONE K90 STARCH, CORN MAGNESIUM STEARATE BLACKBERRY POLYETHYLENE GLYCOL 400 HYPROMELLOSE 2910 (6 MPA.S) TITANIUM DIOXIDE METFORMIN HYDROCHLORIDE METFORMIN white to off-white Artificial G;11 biconvex Metformin hydrochloride Metformin hydrochloride POVIDONE K30 POVIDONE K90 STARCH, CORN MAGNESIUM STEARATE BLACKBERRY POLYETHYLENE GLYCOL 400 HYPROMELLOSE 2910 (6 MPA.S) TITANIUM DIOXIDE METFORMIN HYDROCHLORIDE METFORMIN white to off-white Artificial G;12 biconvex

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 1500 mg/kg/day, espectively. These doses are both approximately 3 times the maximum recommended human daily dose f 2550 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was ound in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin n male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats reated 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 2550 mg based on body surface area comparisons.

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 1500 mg/kg/day, espectively. These doses are both approximately 3 times the maximum recommended human daily dose f 2550 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was ound in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin n male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats reated 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 2550 mg based on body surface area comparisons.

ANDA090564

Metformin hydrochloride

Metformin hydrochloride

68645-583

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Metformin Hydrochloride Tablets, USP 500mg Metformin Hydrochloride Tablets, USP 850mg Metformin Hydrochloride Tablets, USP 1000mg PACKAGE LABEL.PRINCIPAL DISPLAY PANEL PACKAGE LABEL.PRINCIPAL DISPLAY PANEL PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

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 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 tablets. Instruct patients to inform their doctor that they are taking metformin hydrochloride 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 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 tablets [see Warnings and Precautions (5.2) ]. Females of Reproductive Age: Inform females that treatment with metformin hydrochloride tablets may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy [see Use in Specific Populations (8.3) ]. Manufactured by: Granules India Limited Hyderabad-500 081, India MADE IN INDIA Manufactured for: Granules Pharmaceuticals Inc. Chantilly, VA 20151 Distributed by: Wal-Mart Bentonville, AR 72716 Packaged by: Legacy Pharmaceutical Packaging, LLC Earth City, MO 63045 Revision date: 08/2023

14 CLINICAL STUDIES 14.1 Metformin Hydrochloride Tablets Adult Clinical Studies A double-blind, placebo-controlled, multicenter US clinical trial involving obese patients with type 2 diabetes mellitus whose hyperglycemia was not adequately controlled with dietary management alone (baseline fasting plasma glucose [FPG] of approximately 240 mg/dL) was conducted. Patients were treated with metformin hydrochloride tablets (up to 2550 mg/day) or placebo for 29 weeks. The results are presented in Table 7. Table 7: Mean Change in Fasting Plasma Glucose and HbA1c at Week 29 Comparing Metformin Hydrochloride Tablets vs Placebo in Patients with Type 2 Diabetes Mellitus Metformin Hydrochloride Tablets (n=141) Placebo (n=145) p-Value FPG (mg/dL) Baseline 241.5 237.7 NS* Change at FINAL VISIT –53.0 6.3 0.001 Hemoglobin A1c (%) Baseline 8.4 8.2 NS* Change at FINAL VISIT –1.4 0.4 0.001 *Not statistically significant Mean baseline body weight was 201 lbs and 206 lbs in the metformin hydrochloride tablets and placebo arms, respectively. Mean change in body weight from baseline to week 29 was -1.4 lbs and -2.4 lbs in the metformin hydrochloride tablets and placebo arms, respectively. A 29-week, double-blind, placebo-controlled study of metformin hydrochloride tablets and glyburide, alone and in combination, was conducted in obese patients with type 2 diabetes mellitus who had failed to achieve adequate glycemic control while on maximum doses of glyburide (baseline FPG of approximately 250 mg/dL). Patients randomized to the combination arm started therapy with metformin hydrochloride tablets 500 mg and glyburide 20 mg. At the end of each week of the first 4 weeks of the trial, these patients had their dosages of metformin hydrochloride tablets increased by 500 mg if they had failed to reach target fasting plasma glucose. After week 4, such dosage adjustments were made monthly, although no patient was allowed to exceed metformin hydrochloride tablets 2500 mg. Patients in the metformin hydrochloride tablets only arm (metformin plus placebo) discontinued glyburide and followed the same titration schedule. Patients in the glyburide arm continued the same dose of glyburide. At the end of the trial, approximately 70% of the patients in the combination group were taking metformin hydrochloride tablets 2000 mg/glyburide 20 mg or metformin hydrochloride tablets 2500 mg/glyburide 20 mg. The results are displayed in Table 8. Table 8: Mean Change in Fasting Plasma Glucose and HbA1c at Week 29 Comparing Metformin Hydrochloride Tablets /Glyburide (Comb) vs Glyburide (Glyb) vs Metformin Hydrochloride Tablets (MET): in Patients with Type 2 Diabetes Mellitus with Inadequate Glycemic Control on Glyburide MET (n=210) p-Values Comb (n=213) Glyb (n=209) Glyb vs Comb MET vs Comb MET vs Glyb Fasting Plasma Glucose (mg/dL) Baseline 250.5 247.5 253.9 NS* NS* NS* Change at FINAL VISIT –63.5 13.7 -0.9 0.001 0.001 0.025 Hemoglobin A1c (%) Baseline 8.8 8.5 8.9 NS* NS* 0.007 Change at FINAL VISIT -1.7 0.2 -0.4 0.001 0.001 0.001 *Not statistically significant Mean baseline body weight was 202 lbs, 203 lbs, and 204 lbs in the metformin hydrochloride tablets /glyburide, glyburide, and metformin hydrochloride tablets arms, respectively. Mean change in body weight from baseline to week 29 was 0.9 lbs, -0.7 lbs, and -8.4 lbs in the metformin hydrochloride tablets/glyburide, glyburide, and metformin hydrochloride tablets arms, respectively. Pediatric Clinical Studies A double-blind, placebo-controlled study in pediatric patients aged 10 to 16 years with type 2 diabetes mellitus (mean FPG 182.2 mg/dL), treatment with metformin hydrochloride tablets (up to 2000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks) was conducted. The results are displayed in Table 9. Table 9: Mean Change in Fasting Plasma Glucose at Week 16 Comparing Metformin Hydrochloride Tablets vs Placebo in Pediatric Patients a with Type 2 Diabetes Mellitus Metformin Hydrochloride Tablets Placebo p-Value FPG (mg/dL) (n=37) (n=36) Baseline 162.4 192.3 Change at FINAL VISIT -42.9 21.4 <0.001 a Pediatric patients mean age 13.8 years (range 10 to 16 years) Mean baseline body weight was 205 lbs and 189 lbs in the metformin hydrochloride tablets and placebo arms, respectively. Mean change in body weight from baseline to week 16 was -3.3 lbs and -2.0 lbs in the metformin hydrochloride tablets and placebo arms, respectively. 14.2 Metformin Hydrochloride Extended-Release Tablets A 24-week, double-blind, randomized study of metformin hydrochloride extended-release tablets, 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 mellitus who had been treated with metformin hydrochloride tablets 500 mg twice daily for at least 8 weeks prior to study entry. The results are shown in Table 11. Table 11: Mean Changes from Baseline* in HbA1c and Fasting Plasma Glucose at Week 24 comparing Metformin Hydrochloride Tablets vs Metformin Hydrochloride Extended-Release Tablets in Patients with Type 2 Diabetes Mellitus Metformin Hydrochloride Tablets 500 mg Twice Daily Metformin Hydrochloride Extended – release Tablets 1000 mg Once Daily 1500 mg Once Daily Hemoglobin A 1c (%) Baseline Change at FINAL VISIT (95% CI) (n=67) (n=72) (n=66) 7.06 6.99 7.02 0.14a 0.27 0.13 (–0.04, 0.31) (0.11, 0.43) (–0.02, 0.28) FPG(mg/dL) Baseline Change at FINAL VISIT (95% CI) (n=69) (n=72) (n=70) 127.2 131.0 131.4 14.0 11.5 7.6 (7.0, 21.0) (4.4, 18.6) (1.0, 14.2) †a n=68 Mean baseline body weight was 210 lbs, 203 lbs and 193 lbs in the metformin hydrochloride tablets 500 mg twice daily, and metformin hydrochloride extended-release tablets 1000 mg and 1500 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.

8.5 Geriatric Use Controlled clinical studies of metformin hydrochloride 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) ].

8.2 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 tablets and any potential adverse effects on the breastfed child from metformin hydrochloride 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 tablets may result in ovulation in some anovulatory women.

8.4 Pediatric Use Metformin Hydrochloride Tablets The safety and effectiveness of metformin hydrochloride tablets for the treatment of type 2 diabetes mellitus have been established in pediatric patients 10 to 16 years old. Safety and effectiveness of metformin hydrochloride tablets have not been established in pediatric patients less than 10 years old. Use of metformin hydrochloride tablets in pediatric patients 10 to 16 years old for the treatment of type 2 diabetes mellitus is supported by evidence from adequate and well-controlled studies of metformin hydrochloride tablets in adults with additional data from a controlled clinical study in pediatric patients 10 to 16 years old with type 2 diabetes mellitus, which demonstrated a similar response in glycemic control to that seen in adults [see Clinical Studies (14.1) ]. In this study, adverse reactions were similar to those described in adults. A maximum daily dose of 2000 mg of metformin hydrochloride tablets is recommended. [see Dosage and Administration (2.2). ]

8.1 Pregnancy Risk Summary Limited data with metformin hydrochloride 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 2550 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 2550 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 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) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling 8.1 Pregnancy Risk Summary Limited data with metformin hydrochloride 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 2550 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 2550 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 tablets and any potential adverse effects on the breastfed child from metformin hydrochloride 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 tablets may result in ovulation in some anovulatory women. 8.4 Pediatric Use Metformin Hydrochloride Tablets The safety and effectiveness of metformin hydrochloride tablets for the treatment of type 2 diabetes mellitus have been established in pediatric patients 10 to 16 years old. Safety and effectiveness of metformin hydrochloride tablets have not been established in pediatric patients less than 10 years old. Use of metformin hydrochloride tablets in pediatric patients 10 to 16 years old for the treatment of type 2 diabetes mellitus is supported by evidence from adequate and well-controlled studies of metformin hydrochloride tablets in adults with additional data from a controlled clinical study in pediatric patients 10 to 16 years old with type 2 diabetes mellitus, which demonstrated a similar response in glycemic control to that seen in adults [see Clinical Studies (14.1) ]. In this study, adverse reactions were similar to those described in adults. A maximum daily dose of 2000 mg of metformin hydrochloride tablets is recommended. [see Dosage and Administration (2.2). ] 8.5 Geriatric Use Controlled clinical studies of metformin hydrochloride 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 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 (2.3), 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 tablets are not recommended in patients with hepatic impairment. [ see Warnings and Precautions (5.1) ].

16 HOW SUPPLIED 16.1 How Supplied Metformin Hydrochloride Tablets, USP 500 mg - White to off-white, round, biconvex, film coated tablets debossed with G over 10 on one side and plain on the other side. Unit of Use Bottles of 60 - 500mg - NDC 68645-582-59 850 mg - White to off-white, round, biconvex, film coated tablets debossed with G over 11 on one side and plain on the other side. Unit of Use Bottles of 60 - 850mg - NDC 68645-583-59 1000 mg - White to off-white, oval, biconvex, scored, film coated tablets debossed with G and 12 on either side of the scoreline on one side and plain on the other side. Unit of Use Bottles of 60 - 1000mg - NDC 68645-584-59 16.2 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 tight, light-resistant containers with child-resistant closure.

16.2 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 tight, light-resistant containers with child-resistant closure.

BOXED WARNING WARNING: LACTIC ACIDOSIS Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions (5.1) ]. Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g. carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided [see Dosage and Administration (2.3), (2.7), Contraindications (4), Warnings and Precautions (5.1) ]. If metformin-associated lactic acidosis is suspected, immediately discontinue metformin hydrochloride tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see 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 tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. (5.1)