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/metformin hydrochloride extended-release 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 Macleods Pharma USA, Inc. at 1-888-943-3210 or 1-855-926-3384 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 Metformin hydrochloride tablets (n=141) Placebo (n=145) Diarrhea 53% 12% Nausea/Vomiting 26% 8% Flatulence 12% 6% Asthenia 9% 6% Indigestion 7% 4% Abdominal Discomfort 6% 5% Headache 6% 5% Diarrhea led to discontinuation of metformin hydrochloride 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. Metformin hydrochloride extended-release tablets In placebo-controlled trials, 781 patients were administered metformin hydrochloride extended-release tablets. Adverse reactions reported in greater than 5% of the metformin hydrochloride extended-release tablets patients, and that were more common in metformin hydrochloride extended-release tablets -than placebo-treated patients, are listed in Table 2. Table 2: Adverse Reactions from Clinical Trials of Metformin Hydrochloride Extended-Release Tablets Occurring >5% and More Common than Placebo in Patients with Type 2 Diabetes Mellitus Metformin hydrochloride extended-release Tablets (n=781) Placebo (n=195) Diarrhea 10% 3% Nausea/Vomiting 7% 2% Diarrhea led to discontinuation of metformin hydrochloride extended-release tablets in 0.6% of patients. Additionally, the following adverse reactions were reported in ≥1.0% to ≤5.0% of metformin hydrochloride extended-release tablets patients and were more commonly reported with metformin hydrochloride extended-release tablets than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance. 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 and metformin hydrochloride extended-release tablets are contraindicated in patients with: • Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) [see Warnings and Precautions ( 5.1 ) ]. • Hypersensitivity to metformin. • Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. • Severe renal impairment (eGFR below 30 mL/min/1.73 m2) ( 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/ metformin hydrochloride extended-release 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 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. It is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pK a of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. Metformin hydrochloride tablets,USP contain 500 mg, 850 mg, or 1000 mg of metformin hydrochloride, USP. Each tablet contains the inactive ingredients povidone, microcrystalline cellulose, sodium starch glycolate and magnesium stearate. In addition, the coating for the tablets contains hypromellose and polyethylene glycol. Metformin hydrochloride extended-release tablets,USP contain 500 mg or 750 mg of metformin hydrochloride, USP as the active ingredient. Each tablet contains the inactive ingredients carbomer homopolymer type A, magnesium trisilicate, dibasic calcium phosphate anhydrous, hydroxyl propyl cellulose, xanthan gum, microcrystalline cellulose, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc. Metformin hydrochloride extended-release tablets 750 mg also contain iron oxide red. Metformin hydrochloride extended-release tablets: USP Dissolution test is pending. metformin hydrochloride structure

2 DOSAGE & ADMINISTRATION Adult Dosage for Metformin Hydrochloride Tablet : • 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 ) Adult Dosage for Metformin Hydrochloride Extended-Release tablet : • Swallow metformin hydrochloride extended-release tablets whole and never crush, cut or chew ( 2.1 ) • Starting dose: 500 mg orally once daily with the evening meal ( 2.1 ) • Increase the dose in increments of 500 mg weekly, up to a maximum of 2000 mg once daily with the evening meal ( 2.1 ) • Patients receiving metformin hydrochloride tablets may be switched to metformin hydrochloride extended-release tablets once daily at the same total daily dose, up to 2000 mg once daily ( 2.1 ) Pediatric Dosage for Metformin Hydrochloride Tablet : • 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 30-45 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 ) Discontinuation for Iodinated Contrast Imaging Procedures : • Metformin hydrochloride tablets /metformin hydrochloride extended-release tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures ( 2.4 ) 2.1 Adult Dosage Metformin hydrochloride tablets • The recommended starting dose of metformin hydrochloride tablets is 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. Metformin hydrochloride extended-release tablets •Swallow metformin hydrochloride extended-release tablets whole and never crush, cut or chew. •The recommended starting dose of metformin hydrochloride extended-release tablets is 500 mg orally once daily with the evening meal. •Increase the dose in increments of 500 mg weekly on the basis of glycemic control and tolerability, up to a maximum of 2000 mg once daily with the evening meal. •If glycemic control is not achieved with metformin hydrochloride extended-release tablets 2000 mg once daily, consider a trial of metformin hydrochloride extended-release tablets 1000 mg twice daily. If higher doses are required, switch to metformin hydrochloride tablets at total daily doses up to 2550 mg administered in divided daily doses, as described above. •Patients receiving metformin hydrochloride tablets may be switched to metformin hydrochloride extended-release tablets once daily at the same total daily dose, up to 2000 mg once daily. 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 /metformin hydrochloride extended-release tablets and periodically thereafter. • Metformin hydrochloride tablets/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 tablets, /metformin hydrochloride extended-release tablets in patients with an eGFR between 30- 45 mL/minute/1.73 m 2 is not recommended. • In patients taking metformin hydrochloride tablets /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 tablets/metformin hydrochloride extended-release tablets if the patient’s eGFR later falls below 30 mL/minute/1.73m 2 [see Warnings and Precautions ( 5.1 )]. 2.4 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue metformin hydrochloride tablets/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 tablets/metformin hydrochloride extended-release tablets if renal function is stable.

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

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 / metformin hydrochloride extended-release tablets. Table 3: Clinically Significant Drug Interactions with Metformin Hydrochloride Tablets / Metformin Hydrochloride Extended-Release Tablets Carbonic Anhydrase Inhibitors Clinical Impact: Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with metformin hydrochloride tablets / metformin hydrochloride extended-release tablets may increase the risk for lactic acidosis. Intervention: Consider more frequent monitoring of these patients. Examples: Topiramate, zonisamide, acetazolamide or dichlorphenamide. Drugs that Reduce Metformin Hydrochloride Tablets / Metformin Hydrochloride Extended-Release Tablets Clearance Clinical Impact: Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology ( 12.3 )]. Intervention: Consider the benefits and risks of concomitant use with metformin hydrochloride tablets / metformin hydrochloride extended-release tablets. Examples: Ranolazine, vandetanib, dolutegravir, and cimetidine. Alcohol Clinical Impact: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Intervention: Warn patients against excessive alcohol intake while receiving metformin hydrochloride tablets / metformin hydrochloride extended-release tablets. Insulin Secretagogues or Insulin Clinical Impact: Coadministration of metformin hydrochloride tablets / metformin hydrochloride extended-release tablets with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia. Intervention: Patients receiving an insulin secretagogue or insulin may require lower doses of the insulin secretagogue or insulin. Drugs Affecting Glycemic Control Clinical Impact: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. Intervention: When such drugs are administered to a patient receiving metformin hydrochloride tablets / metformin hydrochloride extended-release tablets, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin hydrochloride tablets / metformin hydrochloride extended-release tablets, observe the patient closely for hypoglycemia. Examples: Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. • Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring ( 7 ) • Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin. Consider the benefits and risks of concomitant use ( 7 ) • Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake ( 7 )

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 tablet 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 tablets1000 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. Although the extent of metformin absorption (as measured by AUC) from the metformin hydrochloride extended-release tablets increased by approximately 50% when given with food, there was no effect of food on C max and T max of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of metformin hydrochloride extended-release tablets. 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 )]. Geriatrics 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 Subject Groups: Metformin Hydrochloride Tablets dose a (number of subjects) C max b (mcg/mL) T max c (hrs) Renal Clearance (mL/min) Healthy, nondiabetic adults: 500 mg single dose (24) 850 mg single dose (74) d 850 mg three times daily for 19 doses e (9) 1.03 (±0.33) 1.60 (±0.38) 2.01 (±0.42) 2.75 (±0.81) 2.64 (±0.82) 1.79 (±0.94) 600 (±132) 552 (±139) 642 (±173) Adults with type 2 diabetes mellitus: 850 mg single dose (23) 850 mg three times daily for 19 doses e (9) 1.48 (±0.5) 1.90 (±0.62) 3.32 (±1.08) 2.01 (±1.22) 491 (±138) 550 (±160) Elderly f , healthy nondiabetic adults: 850 mg single dose (12) 2.45 (±0.70) 2.71 (±1.05) 412 (±98) Renal-impaired adults: 850 mg single dose Mild (CLcr g 61-90 mL/min) (5) Moderate (CLcr 31-60 mL/min) (4) Severe (CLcr 10-30 mL/min) (6) 1.86 (±0.52) 4.12 (±1.83) 3.93 (±0.92) 3.20 (±0.45) 3.75 (±0.50) 4.01 (±1.10) 384 (±122) 108 (±57) 130 (±90 a All doses given fasting except the first 18 doses of the multiple dose studies b Peak plasma concentration c Time to peak plasma concentration d Combined results (average means) of five studies: mean age 32 years (range 23 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 CLcr = creatinine clearance normalized to body surface area of 1.73 m 2 Pediatrics After administration of a single oral metformin hydrochloride tablets 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 Coadministered Drug Dose of Coadministered Drug * Dose of Metformin * Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00 AUC † C max No dosing adjustments required for the following: Glyburide 5 mg 850 mg metformin 0.91 ‡ 0.93 ‡ Furosemide 40 mg 850 mg metformin 1.09 ‡ 1.22 ‡ Nifedipine 10 mg 850 mg metformin 1.16 1.21 Propranolol 40 mg 850 mg metformin 0.90 0.94 Ibuprofen 400 mg 850 mg metformin 1.05 ‡ 1.07 ‡ Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination [See Warnings and Precautions (5.9) and Drug Interactions (7.2). ] Cimetidine 400 mg 850 mg metformin 1.40 1.61 Carbonic anhydrase inhibitors may cause metabolic acidosis [See Warnings and Precautions (5.1) and Drug Interactions (7.1). ] Topiramate 100 mg § 500 mg § metformin 1.25 § 1.17 * 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 Coadministered Drug Dose of Coadministered Drug* Dose of Metformin* Geometric Mean Ratio (ratio with/without metformin) No Effect = 1.00 AUC † C max No dosing adjustments required for the following: Glyburide 5 mg 850 mg glyburide 0.78 ‡ 0.63 ‡ Furosemide 40 mg 850 mg furosemide 0.87 ‡ 0.69 ‡ Nifedipine 10 mg 850 mg nifedipine 1.10 § 1.08 Propranolol 40 mg 850 mg propranolol 1.01 § 1.02 Ibuprofen 400 mg 850 mg ibuprofen 0.97 ¶ 1.01 ¶ Cimetidine 400 mg 850 mg cimetidine 0.95 § 1.01 * 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

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 tablet 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 tablets1000 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. Although the extent of metformin absorption (as measured by AUC) from the metformin hydrochloride extended-release tablets increased by approximately 50% when given with food, there was no effect of food on C max and T max of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of metformin hydrochloride extended-release tablets. 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 )]. Geriatrics 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 Subject Groups: Metformin Hydrochloride Tablets dose a (number of subjects) C max b (mcg/mL) T max c (hrs) Renal Clearance (mL/min) Healthy, nondiabetic adults: 500 mg single dose (24) 850 mg single dose (74) d 850 mg three times daily for 19 doses e (9) 1.03 (±0.33) 1.60 (±0.38) 2.01 (±0.42) 2.75 (±0.81) 2.64 (±0.82) 1.79 (±0.94) 600 (±132) 552 (±139) 642 (±173) Adults with type 2 diabetes mellitus: 850 mg single dose (23) 850 mg three times daily for 19 doses e (9) 1.48 (±0.5) 1.90 (±0.62) 3.32 (±1.08) 2.01 (±1.22) 491 (±138) 550 (±160) Elderly f , healthy nondiabetic adults: 850 mg single dose (12) 2.45 (±0.70) 2.71 (±1.05) 412 (±98) Renal-impaired adults: 850 mg single dose Mild (CLcr g 61-90 mL/min) (5) Moderate (CLcr 31-60 mL/min) (4) Severe (CLcr 10-30 mL/min) (6) 1.86 (±0.52) 4.12 (±1.83) 3.93 (±0.92) 3.20 (±0.45) 3.75 (±0.50) 4.01 (±1.10) 384 (±122) 108 (±57) 130 (±90 a All doses given fasting except the first 18 doses of the multiple dose studies b Peak plasma concentration c Time to peak plasma concentration d Combined results (average means) of five studies: mean age 32 years (range 23 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 CLcr = creatinine clearance normalized to body surface area of 1.73 m 2 Pediatrics After administration of a single oral metformin hydrochloride tablets 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 Coadministered Drug Dose of Coadministered Drug * Dose of Metformin * Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00 AUC † C max No dosing adjustments required for the following: Glyburide 5 mg 850 mg metformin 0.91 ‡ 0.93 ‡ Furosemide 40 mg 850 mg metformin 1.09 ‡ 1.22 ‡ Nifedipine 10 mg 850 mg metformin 1.16 1.21 Propranolol 40 mg 850 mg metformin 0.90 0.94 Ibuprofen 400 mg 850 mg metformin 1.05 ‡ 1.07 ‡ Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination [See Warnings and Precautions (5.9) and Drug Interactions (7.2). ] Cimetidine 400 mg 850 mg metformin 1.40 1.61 Carbonic anhydrase inhibitors may cause metabolic acidosis [See Warnings and Precautions (5.1) and Drug Interactions (7.1). ] Topiramate 100 mg § 500 mg § metformin 1.25 § 1.17 * 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 Coadministered Drug Dose of Coadministered Drug* Dose of Metformin* Geometric Mean Ratio (ratio with/without metformin) No Effect = 1.00 AUC † C max No dosing adjustments required for the following: Glyburide 5 mg 850 mg glyburide 0.78 ‡ 0.63 ‡ Furosemide 40 mg 850 mg furosemide 0.87 ‡ 0.69 ‡ Nifedipine 10 mg 850 mg nifedipine 1.10 § 1.08 Propranolol 40 mg 850 mg propranolol 1.01 § 1.02 Ibuprofen 400 mg 850 mg ibuprofen 0.97 ¶ 1.01 ¶ Cimetidine 400 mg 850 mg cimetidine 0.95 § 1.01 * 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

20230118

6

3 DOSAGE FORMS & STRENGTHS Metformin hydrochloride tablets,USP: • Metformin hydrochloride tablets, USP 500 mg are white to off white,circular, biconvex, film coated, beveled edge tablets, debossed with "C74" on one side and plain on other side. • Metformin hydrochloride tablets, USP 850 mg are white to off white,circular, biconvex, film coated, beveled edge tablets, debossed with "C75" on one side and plain on other side. • Metformin hydrochloride tablets, USP 1000 mg are white to off white, oval shaped, biconvex, film coated tablet, debossed with "C" and "76" separated by breakline on both sides (functional scoring). Metformin hydrochloride extended-release tablets,USP: • Metformin hydrochloride extended-release tablets, USP 500 mg are white to off white, capsule shaped, biconvex, film coated tablets debossed with "ML30" on one side and plain on the other side. • Metformin hydrochloride extended-release tablets, USP 750 mg are pink capsule shaped, biconvex, film coated tablets debossed with "ML31" on one side and plain on the other side. • Metformin hydrochloride tablets: 500 mg, 850 mg, and 1000 mg ( 3 ) • Metformin hydrochloride extended-release tablets: 500 mg and 750 mg ( 3 )

Metformin hydrochloride Metformin hydrochloride METFORMIN HYDROCHLORIDE METFORMIN POVIDONE CELLULOSE, MICROCRYSTALLINE SODIUM STARCH GLYCOLATE TYPE A POTATO MAGNESIUM STEARATE HYPROMELLOSES POLYETHYLENE GLYCOL, UNSPECIFIED White to off white circular, biconvex C74 Metformin hydrochloride Metformin hydrochloride METFORMIN HYDROCHLORIDE METFORMIN POVIDONE CELLULOSE, MICROCRYSTALLINE SODIUM STARCH GLYCOLATE TYPE A POTATO MAGNESIUM STEARATE HYPROMELLOSES POLYETHYLENE GLYCOL, UNSPECIFIED White to off white circular, biconvex C75 Metformin hydrochloride Metformin hydrochloride METFORMIN HYDROCHLORIDE METFORMIN POVIDONE CELLULOSE, MICROCRYSTALLINE SODIUM STARCH GLYCOLATE TYPE A POTATO MAGNESIUM STEARATE HYPROMELLOSES POLYETHYLENE GLYCOL, UNSPECIFIED White to off white oval shaped, biconvex C76 Metformin hydrochloride Metformin hydrochloride METFORMIN HYDROCHLORIDE METFORMIN MAGNESIUM TRISILICATE CALCIUM PHOSPHATE, DIBASIC, ANHYDROUS HYDROXYPROPYL CELLULOSE, UNSPECIFIED CELLULOSE, MICROCRYSTALLINE MAGNESIUM STEARATE POLYVINYL ALCOHOL TITANIUM DIOXIDE POLYETHYLENE GLYCOL, UNSPECIFIED TALC CARBOMER HOMOPOLYMER TYPE C (ALLYL PENTAERYTHRITOL CROSSLINKED) XANTHAN GUM White to off white Capsule shaped, biconvex ML;30 Metformin hydrochloride Metformin hydrochloride METFORMIN HYDROCHLORIDE METFORMIN MAGNESIUM TRISILICATE CALCIUM PHOSPHATE, DIBASIC, ANHYDROUS HYDROXYPROPYL CELLULOSE, UNSPECIFIED CELLULOSE, MICROCRYSTALLINE MAGNESIUM STEARATE POLYVINYL ALCOHOL TITANIUM DIOXIDE POLYETHYLENE GLYCOL, UNSPECIFIED TALC CARBOMER HOMOPOLYMER TYPE C (ALLYL PENTAERYTHRITOL CROSSLINKED) XANTHAN GUM FERRIC OXIDE RED Pink Capsule shaped, biconvex ML;31

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, respectively. These doses are both approximately 3 times the maximum recommended human daily dose of 2550 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day. There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test ( S. typhimurium ), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative. Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately 2 times the maximum recommended human daily dose of 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, respectively. These doses are both approximately 3 times the maximum recommended human daily dose of 2550 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day. There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test ( S. typhimurium ), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative. Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately 2 times the maximum recommended human daily dose of 2550 mg based on body surface area comparisons.

ANDA206955

Metformin hydrochloride

Metformin hydrochloride

33342-240

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL PRINCIPLE DISPLAY PANEL Metformin hydrochloride tablets 500mg Pack Count-100s NDC 33342-141-11 Metformin hydrochloride tablets 850mg Pack Count-100s NDC 33342-142-11 Metformin hydrochloride tablets 1000mg Pack Count-100s NDC 33342-143-11 Metformin hydrochloride extended-release tablets 500mg Pack Count-100s NDC 33342-239-11 Metformin hydrochloride extended-release tablets 750mg Pack Count-100s NDC 33342-240-11 123 776 998 556 884

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 /metformin hydrochloride extended-release tablets immediately and to promptly notify their healthcare provider if unexplained hyperventilation, myalgias, malaise, unusual somnolence or other nonspecific symptoms occur. Counsel patients against excessive alcohol intake and inform patients about importance of regular testing of renal function while receiving metformin hydrochloride tablets /metformin hydrochloride extended-release tablets. Instruct patients to inform their doctor that they are taking metformin hydrochloride tablets /metformin hydrochloride extended-release tablets prior to any surgical or radiological procedure, as temporary discontinuation may be required [ see Warnings and Precautions ( 5.1 ) ]. Hypoglycemia: Inform patients that hypoglycemia may occur when metformin hydrochloride tablets /metformin hydrochloride extended-release tablets is 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 B12 Deficiency: Inform patients about importance of regular hematological parameters while receiving metformin hydrochloride tablets /metformin hydrochloride extended-release tablets [ see Warnings and Precautions ( 5.2 )]. Females of Reproductive Age: Inform females that treatment with metformin hydrochloride tablets /metformin hydrochloride extended-release tablets may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy [ see Use in Specific Populations ( 8.3 )]. Metformin Hydrochloride Extended-Release Tablets Administration Information: Inform patients that metformin hydrochloride extended-release tablets must be swallowed whole and not crushed, cut, or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet. Manufactured for : Macleods Pharma USA, Inc. Princeton, NJ 08540 Manufactured by : Macleods Pharmaceuticals Ltd . Baddi, Himachal Pradesh, INDIA Revised: January 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 Change at FINAL VISIT 241.5 –53.0 237.7 6.3 NS* 0.001 Hemoglobin A 1c (%) Baseline Change at FINAL VISIT 8.4 –1.4 8.2 0.4 NS* 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 (GLU): in Patients with Type 2 Diabetes Mellitus with Inadequate Glycemic Control on Glyburide Comb (n=213) Glyb (n=209 ) Metformin Hydrochloride Tablets (n=210) p-Values Glyb vs Comb Metformin Hydrochloride Tablets vs Comb Metformin Hydrochloride Tablets vs Glyb Fasting Plasma Glucose (mg/dL) Baseline Change at FINAL VISIT 250.5 –63.5 47.5 13.7 253.9 –0.9 NS* 0.001 NS* 0.001 NS* 0.025 Hemoglobin A1c (%) Baseline Change at FINAL VISIT 8.8 –1.7 8.5 0.2 8.9 –0.4 NS* 0.001 NS* 0.001 0.007 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 10-16 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, placebo-controlled study of metformin hydrochloride extended-release tablets, taken once daily with the evening meal, was conducted in patients with type 2 diabetes mellitus who had failed to achieve glycemic control with diet and exercise. Patients entering the study had a mean baseline HbA 1c of 8.0% and a mean baseline FPG of 176 mg/dL. The treatment dose was increased to 1500 mg once daily if at Week 12 HbA 1c was ≥7.0% but <8.0% (patients with HbA 1c ≥8.0% were discontinued from the study). At the final visit (24-week), mean HbA 1c had increased 0.2% from baseline in placebo patients and decreased 0.6% with metformin hydrochloride extended-release tablets. A 16-week, double-blind, placebo-controlled, dose-response study of metformin hydrochloride extended-release tablets, taken once daily with the evening meal or twice daily with meals, was conducted in patients with type 2 diabetes mellitus who had failed to achieve glycemic control with diet and exercise. The results are shown in Table 10. Table 10: Mean Changes from Baseline* in HbA 1c and Fasting Plasma Glucose at Week 16 Comparing Metformin Hydrochloride Extended-Release Tablets vs Placebo in Patients with Type 2 Diabetes Mellitus Metformin hydrochloride extended-release tablets Placebo 500 mg Once Daily 1000 mg Once Daily 1500 mg Once Daily 2000 mg Once Daily 1000 mg Twice Daily Hemoglobin A1c (%) Baseline Change at FINAL VISIT p-value a (n=115) 8.2 –0.4 <0.001 (n=115) 8.4 –0.6 <0.001 (n=111) 8.3 –0.9 <0.001 (n=125) 8.4 –0.8 <0.001 (n=112) 8.4 –1.1 <0.001 (n=111) 8.4 0.1 – FPG (mg/dL) Baseline Change at FINAL VISIT p-value a (n=126) 182.7 –15.2 <0.001 (n=118) 183.7 –19.3 <0.001 (n=120) 178.9 –28.5 <0.001 (n=132) 181.0 –29.9 <0.001 (n=122) 181.6 –33.6 <0.001 (n=113) 179.6 7.6 – a All comparisons versus Placebo Mean baseline body weight was 193 lbs, 192 lbs, 188 lbs, 196 lbs, 193 lbs and 194 lbs in the metformin hydrochloride extended-release tablets 500 mg , 1000 mg, 1500 mg, and 2000 mg once daily, 1000 mg twice daily and placebo arms, respectively. Mean change in body weight from baseline to week 16 was -1.3 lbs, -1.3 lbs, -0.7 lbs, -1.5 lbs, -2.2 lbs and -1.8 lbs, respectively. A 24-week, double-blind, randomized study of metformin hydrochloride extended-release tablets, taken once daily with the evening meal, and metformin 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 Extended-Release Tablets vs Metformin Hydrochloride Tablets in Patients with Type 2 Diabetes Mellitus Metformin hydrochloride extended-release tablets Metformin hydrochloride tablets 500 mg Twice Daily 1000 mg Once Daily 1500 mg Once Daily Hemoglobin A1c (%) Baseline Change at FINAL VISIT (95% CI) (n=67) 7.06 0.14 a (–0.04, 0.31) (n=72) 6.99 0.27 (0.11, 0.43) (n=66) 7.02 0.13 (–0.02, 0.28) FPG (mg/dL) Baseline Change at FINAL VISIT (95% CI) (n=69) 127.2 14.0 (7.0, 21.0) (n=72) 131.0 11.5 (4.4, 18.6) (n=70) 131.4 7.6 (1.0, 14.2) †a n=68 Mean baseline body weight was 210lbs, 203 lbs and 193 lbs in the metformin hydrochloride tablets 500mg twice daily, and metformin hydrochloride extended-release tablets 1000mg and 1500mg 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 / metformin hydrochloride extended-release tablets did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [see Warnings and Precautions ( 5.1 )].

8.4 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 ) ] Metformin hydrochloride extended-release tablets Safety and effectiveness of metformin hydrochloride extended-release tablets in pediatric patients have not been established.

8.1 Pregnancy Risk Summary Limited data with metformin hydrochloride tablets / metformin hydrochloride extended-release tablets in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [ see Data ]. There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy [ see Clinical Considerations ]. No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2-and 5-times, respectively, a 2550 mg clinical dose, based on body surface area [ see Data ]. The estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes mellitus with an HbA1C >7 and has been reported to be as high as 20–25% 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 2–4% and 15–20%, 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 ) 8.1 Pregnancy Risk Summary Limited data with metformin hydrochloride tablets / metformin hydrochloride extended-release tablets in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [ see Data ]. There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy [ see Clinical Considerations ]. No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2-and 5-times, respectively, a 2550 mg clinical dose, based on body surface area [ see Data ]. The estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes mellitus with an HbA1C >7 and has been reported to be as high as 20–25% 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 2–4% and 15–20%, 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 / metformin hydrochloride extended-release tablets and any potential adverse effects on the breastfed child from metformin hydrochloride tablets / metformin hydrochloride extended-release tablets or from the underlying maternal condition. Data Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants. 8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin hydrochloride tablets / metformin hydrochloride extended-release 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 ) ] Metformin hydrochloride extended-release tablets Safety and effectiveness of metformin hydrochloride extended-release tablets in pediatric patients have not been established. 8.5 Geriatric Use Controlled clinical studies of metformin hydrochloride tablets / metformin hydrochloride extended-release tablets did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [see Warnings and Precautions ( 5.1 )]. 8.6 Renal Impairment Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Metformin hydrochloride tablets / metformin hydrochloride extended-release tablets are contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73m 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 / 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 16.1 How supplied Metformin hydrochloride tablets USP and metformin hydrochloride extended-release tablets USP Available Strengths, Units, and Appearance Metformin Hydrochloride Tablets,USP 500mg tablet: White to off white, circular, biconvex, film coated, beveled edge tablets, debossed with "C74" on one side and plain on other side. Bottles of 90's NDC 33342-141-10 Bottles of 100's NDC 33342-141-11 Bottles of 1000's NDC 33342-141-44 850mg tablet: White to off white, circular, biconvex, film coated, beveled edge tablets, debossed with "C75" on one side and plain on other side. Bottles of 90's NDC 33342-142-10 Bottles of 100's NDC 33342-142-11 Bottles of 1000's NDC 33342-142-44 1000mg tablet: White to off white, oval shaped, biconvex, film coated tablet, debossed with "C" and "76"separated by breakline on both sides (functional scoring). Bottles of 90's NDC 33342-143-10 Bottles of 100's NDC 33342-143-11 Bottles of 1000's NDC 33342-143-44 Metformin Hydrochloride Extended-Release Tablets,USP 500mg tablet: White to off white, capsule shaped, biconvex, film coated tablets debossed with 'ML 30' on one side and plain on the other side. Bottles of 100's NDC 33342-239-11 750mg tablet: Pink capsule shaped, biconvex, film coated tablets debossed with 'ML 31' on one side and plain on the other side. Bottles of 100's NDC 33342-240-11 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 light-resistant containers.

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 or metformin hydrochloride extended-release tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions ( 5.1 ) ]. 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/ metformin hydrochloride extended-release tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. ( 5.1 )