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) ] The most common adverse reactions are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact VistaPharm, Inc. at 1-888-655-1505 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In a U.S. clinical trial of metformin HCl tablets in patients with type 2 diabetes mellitus, a total of 141 patients received metformin HCl tablets up to 2,550 mg per day. Adverse reactions reported in greater than 5% of patients treated with metformin HCl tablets 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 HCl Tablets Occurring >5% and More Common than Placebo in Patients with Type 2 Diabetes Mellitus Metformin HCl 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 HCl tablets in 6% of patients. Additionally, the following adverse reactions were reported in ≥ 1% to ≤ 5% of patients treated with metformin HCl tablets and were more commonly reported than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation. Pediatric Patients In clinical trials with metformin HCl tablets in pediatric patients with type 2 diabetes mellitus, the profile of adverse reactions was similar to that observed in adults. Laboratory Tests Vitamin B 12 Concentrations In clinical trials of 29-week duration with metformin HCl tablets, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of metformin. 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 oral solution is contraindicated in patients with: Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) [see Warnings and Precautions (5.1) ]. Hypersensitivity to metformin. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) ( 4 , 5.1 ) Hypersensitivity to metformin ( 4 ) Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. ( 4 )

11 DESCRIPTION Metformin hydrochloride oral solution contains the biguanidine antihyperglycemic agent metformin in the form of monohydrochloride salt. Metformin hydrochloride, is N , N -dimethylimidodicarbonimidic diamide hydrochloride. The structural formula is as shown: Metformin hydrochloride, is a white crystalline powder with a molecular formula of C 4 H 11 N 5 •HCl and a molecular weight of 165.62. Metformin hydrochloride, USP 2.0 g is soluble in 20 mL of water. The pK a of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. It is freely soluble in water; slightly soluble in alcohol; practically insoluble in acetone and in methylene chloride. Metformin hydrochloride oral solution (Cherry Flavor) contains 500 mg of metformin hydrochloride (the equivalent of 389.93 mg metformin) per 5 mL and the following inactive ingredients: Artificial wild cherry flavor, hydrochloric acid, purified water, sodium hydroxide, sucralose, and xylitol. structural formula

2 DOSAGE AND ADMINISTRATION Adult Dosage for Metformin Hydrochloride Oral Solution : Starting dose: 500 mg (5 mL) orally twice a day or 850 mg (8.5 mL) once a day, with meals. ( 2.1 ) Increase the dose in increments of 500 mg (5 mL) weekly or 850 mg (8.5 mL) every 2 weeks, up to a maximum dose of 2,550 mg (25.5 mL) per day, given in divided doses. ( 2.1 ) Doses above 2,000 mg (20 mL) may be better tolerated given in divided doses 3 times a day with meals. ( 2.1 ) Pediatric Dosage for Metformin Hydrochloride Oral Solution : Starting dose: 500 mg (5 mL) orally twice a day, with meals. ( 2.2 ) Increase dosage in increments of 500 mg (5 mL) weekly up to a maximum of 2,000 mg (20 mL) 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 ) Do not use in patients with eGFR below 30 mL/minute/1.73 m 2 . ( 2.3 ) Initiation is not recommended in patients with eGFR between 30 to 45 mL/minute/1.73 m 2 . ( 2.3 ) Assess risk/benefit of continuing metformin hydrochloride if eGFR falls below 45 mL/minute/1.73 m 2 . ( 2.3 ) Discontinue if eGFR falls below 30 mL/minute/1.73 m 2 . ( 2.3 ) Discontinuation for Iodinated Contrast Imaging Procedures : Metformin hydrochloride may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. ( 2.4 ) 2.1 Adult Dosage Measure the metformin hydrochloride oral solution dose in the metformin hydrochloride oral solution specific dosing cup. The recommended starting dose of metformin hydrochloride oral solution is 500 mg (5 mL) orally twice a day or 850 mg (8.5 mL) once a day, given with meals. Increase the dose in increments of 500 mg (5 mL) weekly or 850 mg (8.5 mL) every 2 weeks on the basis of glycemic control and tolerability, up to a maximum dose of 2,550 mg (25.5 mL) per day, given in divided doses. Doses above 2,000 mg (20 mL) may be better tolerated given in divided doses 3 times a day with meals. 2.2 Pediatric Dosage Measure the metformin hydrochloride oral solution dose in the metformin hydrochloride oral solution specific dosing cup. The recommended starting dose of metformin hydrochloride oral solution for pediatric patients 10 years of age and older is 500 mg (5 mL) orally twice a day, given with meals. Increase dosage in increments of 500 mg (5 mL) weekly on the basis of glycemic control and tolerability, up to a maximum of 2,000 mg (20 mL) 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 oral solution and periodically thereafter. Metformin hydrochloride oral solution is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m 2 . Initiation of metformin hydrochloride oral solution in patients with an eGFR between 30 to 45 mL/minute/1.73 m 2 is not recommended. In patients taking metformin hydrochloride oral solution whose eGFR later falls below 45 mL/min/1.73 m 2 , assess the benefit risk of continuing therapy. Discontinue metformin hydrochloride oral solution 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 oral solution 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 oral solution if renal function is stable.

1 INDICATIONS AND USAGE Metformin hydrochloride oral solution is 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 is 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 )

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 2 presents clinically significant drug interactions with metformin hydrochloride. Table 2: Clinically Significant Drug Interactions with Metformin Hydrochloride 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 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 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 [OCT 2 ] / 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. 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. Insulin Secretagogues or Insulin Clinical Impact: Coadministration of metformin hydrochloride 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, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin hydrochloride, 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 Two pharmacokinetic studies performed in healthy volunteers to evaluate the bioavailability of metformin hydrochloride oral solution in comparison with metformin HCl tablets under fasting and fed conditions showed that the rate and extent of absorption of metformin hydrochloride oral solution was found to be comparable to that of metformin HCl tablets under fasting or fed conditions (see Table 3). Table 3. Select Mean ( ± S.D.) Pharmacokinetic Parameters Following Single Oral Doses of 1000 mg Metformin hydrochloride oral solution and Metformin HCl tablets in healthy, nondiabetic adults (n = 36) under fed and fasting conditions Formulation C max (ng/mL) AUC 0- ∞ (ng.h/mL) t max (h) Study 1- Fasting state Metformin Hydrochloride Oral Solution 1540.1 ± 451.1 9069.6 ± 2593.6 2.2 ± 0.5 Metformin HCl Tablets 1885.1 ± 498.5 11100.1 ± 2733.1 2.5 ± 0.6 T/R Ratio X 100 (90% confidence interval) 81.2 (76.3 - 86.4) 81.2 (76.9 - 85.6) - Study 2- Fed State Metformin Hydrochloride Oral Solution 1253.5 ± 177.7 8950.1 ± 1381.2 4.1 ± 0.8 Metformin HCl Tablets 1361 ± 298.8 9307.7 ± 1839.8 3.7 ± 0.8 T/R Ratio X 100 (90% Confidence interval) 91.8 (87.4 - 96.5) 97.0 (92.9 - 101.2) - T-test product (metformin hydrochloride oral solution) R-reference product (immediate release metformin HCl tablets) Studies using single oral doses of metformin HCl tablets 500 mg to 1,500 mg, and 850 mg to 2,550 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, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally < 1 mcg/mL. Effect of food: The food-effect study assessed the effects of a high fat/high calorie meal and a low fat/low calorie meal on the bioavailability of metformin hydrochloride oral solution in comparison with administration in the fasted state, in healthy volunteers. The extent of absorption was increased by approximately 16% and 13% with the low fat/low calorie meal and the high fat/high calorie meal, respectively, compared with the administration in the fasted state. The rate and extent of absorption with high fat/high calorie and low fat/ low calorie meal were similar. The mean t max was 2.5 hours under fasting conditions as compared to 3.9 hours with both low fat/ low calorie meal and high fat/high calorie meals (see Table 4). Table 4. Select Mean ( ± S .D.) Metformin Pharmacokinetic Parameters Following Single Oral Doses of 1000 mg Metformin hydrochloride oral solution i n h ealthy, nondiabetic adults (n = 33) under fed (high fat/high calorie meal and low fat/low calorie meal) and fasting conditions (study 3) Meal type C m ax (ng/mL) AUC 0- ∞ (ng.h/mL) t m ax (h) F asting (F) 1641.5 ± 551.8 9982.9 ± 2544.5 2.5 ± 0.9 Low fat/ low calorie meal (L) 1525.8 ± 396.7 11542.0 ± 2947.5 3.9 ± 0.6 High f at/high calorie meal (H) 1432.5 ± 346.8 11184.5 ± 2446.1 3.9 ± 0.8 L/F Ratio X 100 (90% confidence interval) 94.6 (84.0 - 106.5) 115.6 (103.6 - 128.9) - H/F R atio X 100 (90% confidence interval) 89.4 (79.4 - 100.6) 112.6 (100.9 - 125.6) - L/H Ratio X 100 (90% confidence interval) 105.8 (94.0 - 119.2) 102.7 (92.0 - 114.6) - Distribution The apparent volume of distribution (V/F) of metformin following single oral doses of metformin HCl 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 5) 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 5) [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 HCl tablets in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and C max is increased, compared to healthy young subjects. It appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 5). [see Warnings and Precautions (5.1) and Use in Specific Populations (8.5) ]. Table 5: Select Mean (±S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin HCl Tablets Subject Groups: Metformin HCl 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) Renally-­impaired adults: 850 mg single dose Mild (CL cr g 61 to 90 mL/min) (5) Moderate (CL cr 31 to 60 mL/min) (4) Severe (CL cr 10 to 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 CL cr = creatinine clearance normalized to body surface area of 1.73 m 2 P e diatrics After administration of a single oral metformin HCl 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 6: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure Coadministered Drug Dose of Coadministered Drug * Dose of Metformin HCl * Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00 AUC † C max No dosing adjustments required for the following: Glyburide 5 mg 850 mg metformin 0.91 ‡ 0.93 ‡ Furosemide 40 mg 850 mg metformin 1.09 ‡ 1.22 ‡ Nifedipine 10 mg 850 mg metformin 1.16 1.21 Propranolol 40 mg 850 mg metformin 0.90 0.94 Ibuprofen 400 mg 850 mg metformin 1.05 ‡ 1.07 ‡ Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination [see Warnings and Precautions (5.1) and Drug Interactions (7) . ] Cimetidine 400 mg 850 mg metformin 1.40 1.61 Carbonic anhydrase inhibitors may cause metabolic acidosis [see Warnings and Precautions (5.1) and Drug Interactions (7) . ] Topiramate 100 mg § 500 mg § metformin 125 § 1.17 * All metformin HCl 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 7: Effect of Metformin on Coadministered Drug Systemic Exposure Coadministered Drug Dose of Coadministered Drug * Dose of Metformin HCl * 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 HCl 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 Two pharmacokinetic studies performed in healthy volunteers to evaluate the bioavailability of metformin hydrochloride oral solution in comparison with metformin HCl tablets under fasting and fed conditions showed that the rate and extent of absorption of metformin hydrochloride oral solution was found to be comparable to that of metformin HCl tablets under fasting or fed conditions (see Table 3). Table 3. Select Mean ( ± S.D.) Pharmacokinetic Parameters Following Single Oral Doses of 1000 mg Metformin hydrochloride oral solution and Metformin HCl tablets in healthy, nondiabetic adults (n = 36) under fed and fasting conditions Formulation C max (ng/mL) AUC 0- ∞ (ng.h/mL) t max (h) Study 1- Fasting state Metformin Hydrochloride Oral Solution 1540.1 ± 451.1 9069.6 ± 2593.6 2.2 ± 0.5 Metformin HCl Tablets 1885.1 ± 498.5 11100.1 ± 2733.1 2.5 ± 0.6 T/R Ratio X 100 (90% confidence interval) 81.2 (76.3 - 86.4) 81.2 (76.9 - 85.6) - Study 2- Fed State Metformin Hydrochloride Oral Solution 1253.5 ± 177.7 8950.1 ± 1381.2 4.1 ± 0.8 Metformin HCl Tablets 1361 ± 298.8 9307.7 ± 1839.8 3.7 ± 0.8 T/R Ratio X 100 (90% Confidence interval) 91.8 (87.4 - 96.5) 97.0 (92.9 - 101.2) - T-test product (metformin hydrochloride oral solution) R-reference product (immediate release metformin HCl tablets) Studies using single oral doses of metformin HCl tablets 500 mg to 1,500 mg, and 850 mg to 2,550 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, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally < 1 mcg/mL. Effect of food: The food-effect study assessed the effects of a high fat/high calorie meal and a low fat/low calorie meal on the bioavailability of metformin hydrochloride oral solution in comparison with administration in the fasted state, in healthy volunteers. The extent of absorption was increased by approximately 16% and 13% with the low fat/low calorie meal and the high fat/high calorie meal, respectively, compared with the administration in the fasted state. The rate and extent of absorption with high fat/high calorie and low fat/ low calorie meal were similar. The mean t max was 2.5 hours under fasting conditions as compared to 3.9 hours with both low fat/ low calorie meal and high fat/high calorie meals (see Table 4). Table 4. Select Mean ( ± S .D.) Metformin Pharmacokinetic Parameters Following Single Oral Doses of 1000 mg Metformin hydrochloride oral solution i n h ealthy, nondiabetic adults (n = 33) under fed (high fat/high calorie meal and low fat/low calorie meal) and fasting conditions (study 3) Meal type C m ax (ng/mL) AUC 0- ∞ (ng.h/mL) t m ax (h) F asting (F) 1641.5 ± 551.8 9982.9 ± 2544.5 2.5 ± 0.9 Low fat/ low calorie meal (L) 1525.8 ± 396.7 11542.0 ± 2947.5 3.9 ± 0.6 High f at/high calorie meal (H) 1432.5 ± 346.8 11184.5 ± 2446.1 3.9 ± 0.8 L/F Ratio X 100 (90% confidence interval) 94.6 (84.0 - 106.5) 115.6 (103.6 - 128.9) - H/F R atio X 100 (90% confidence interval) 89.4 (79.4 - 100.6) 112.6 (100.9 - 125.6) - L/H Ratio X 100 (90% confidence interval) 105.8 (94.0 - 119.2) 102.7 (92.0 - 114.6) - Distribution The apparent volume of distribution (V/F) of metformin following single oral doses of metformin HCl 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 5) 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 5) [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 HCl tablets in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and C max is increased, compared to healthy young subjects. It appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 5). [see Warnings and Precautions (5.1) and Use in Specific Populations (8.5) ]. Table 5: Select Mean (±S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin HCl Tablets Subject Groups: Metformin HCl 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) Renally-­impaired adults: 850 mg single dose Mild (CL cr g 61 to 90 mL/min) (5) Moderate (CL cr 31 to 60 mL/min) (4) Severe (CL cr 10 to 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 CL cr = creatinine clearance normalized to body surface area of 1.73 m 2 P e diatrics After administration of a single oral metformin HCl 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 6: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure Coadministered Drug Dose of Coadministered Drug * Dose of Metformin HCl * Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00 AUC † C max No dosing adjustments required for the following: Glyburide 5 mg 850 mg metformin 0.91 ‡ 0.93 ‡ Furosemide 40 mg 850 mg metformin 1.09 ‡ 1.22 ‡ Nifedipine 10 mg 850 mg metformin 1.16 1.21 Propranolol 40 mg 850 mg metformin 0.90 0.94 Ibuprofen 400 mg 850 mg metformin 1.05 ‡ 1.07 ‡ Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination [see Warnings and Precautions (5.1) and Drug Interactions (7) . ] Cimetidine 400 mg 850 mg metformin 1.40 1.61 Carbonic anhydrase inhibitors may cause metabolic acidosis [see Warnings and Precautions (5.1) and Drug Interactions (7) . ] Topiramate 100 mg § 500 mg § metformin 125 § 1.17 * All metformin HCl 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 7: Effect of Metformin on Coadministered Drug Systemic Exposure Coadministered Drug Dose of Coadministered Drug * Dose of Metformin HCl * 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 HCl 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

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3 DOSAGE FORMS AND STRENGTHS Oral solution: 500 mg per 5 mL (100 mg/mL) clear to light yellow solution in cherry flavor Oral Solution: 500 mg per 5 mL (100 mg/mL) in cherry flavor ( 3 )

Metformin Hydrochloride Metformin Hydrochloride METFORMIN HYDROCHLORIDE METFORMIN HYDROCHLORIC ACID WATER SODIUM HYDROXIDE SUCRALOSE XYLITOL Artificial Wild Cherry

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

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

ANDA212677

Metformin Hydrochloride

Metformin Hydrochloride

66689-318

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL - 16 fl. oz. (473 mL) BOTTLE NDC 66689-318-16 Metformin Hydrochloride Oral Solution 500 mg per 5 mL (Cherry Flavored) 16 fl. oz. (473 mL) Rx only VistaPharm ® Bottle Label

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Administration: Instruct patients or caregivers to use the supplied dosing cup to measure the prescribed amount of medication. Inform patients that additional metformin hydrochloride oral solution dosing cups or oral dosing syringes may be obtained from their pharmacy. Lactic Acidosis: Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development. Advise patients to discontinue metformin hydrochloride 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. Instruct patients to inform their doctor that they are taking metformin hydrochloride 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 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 B 12 Deficiency: Inform patients about importance of regular hematological parameters while receiving metformin hydrochloride [see Warnings and Precautions (5.2) ]. Females of Reproductive Age: Inform females that treatment with metformin hydrochloride may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy [see Use in Specific Populations (8.3) ]. Manufactured and Distributed by: VistaPharm, Inc. Largo, FL 33771, USA VP2245 02/2019

14 CLINICAL STUDIES 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 HCl tablets (up to 2,550 mg/day) or placebo for 29 weeks. The results are presented in Table 8. Table 8: Mean Change in Fasting Plasma Glucose and HbA1c at Week 29 Comparing Metformin HCl Tablets vs Placebo in Patients with Type 2 Diabetes Mellitus Metformin HCl Tablets (n = 141) P lacebo (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 HCl tablet 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 HCl tablet and placebo arms, respectively. A 29-week, double-blind, placebo-controlled study of metformin HCl tablet 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 HCl tablet 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 HCl 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 HCl 2,500 mg. Patients in the metformin only arm (metformin HCl 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 HCl 2,000 mg/glyburide 20 mg or metformin HCl 2,500 mg/glyburide 20 mg. The results are displayed in Table 9. Table 9: Mean Change in Fasting Plasma Glucose and HbA1c at Week 29 Comparing Metformin HCl Tablets/Glyburide (Comb) vs Glyburide (Glyb) vs Metformin HCl Tablets (GLU): in Patients with Type 2 Diabetes Mellitus with Inadequate Glycemic Control on Glyburide Comb (n = 213) Glyb (n = 209) GLU (n = 210) p-values Glyb vs Comb GLU vs Comb GLU vs Glyb Fasting Plasma Glucose (mg/dL) Baseline Change at FINAL VISIT 250.5 -63.5 247.5 13.7 253.9 -0.9 NS* 0.001 NS* 0.001 NS* 0.025 Hemoglobin A 1c (%) 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 HCl tablet/glyburide, glyburide, and metformin HCl tablet 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 HCl tablet/glyburide, glyburide, and metformin HCl tablet arms, respectively. Pediatric Clinical Studies A double-blind, placebo-controlled study was conducted in pediatric patients aged 10 to 16 years with type 2 diabetes mellitus (mean FPG 182.2 mg/dL), where patients were treated with metformin HCl tablets (up to 2,000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks). The results are displayed in Table 10. Table 10: Mean Change in Fasting Plasma Glucose at Week 16 Comparing Metformin HCl Tablets vs Placebo in Pediatric Patients a with Type 2 Diabetes Mellitus Metformin HCl Tablets Placebo p-value FPG (mg/dL) Baseline Change at FINAL VISIT (n = 37) 162.4 -42.9 (n = 36) 192.3 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 HCl tablet 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 HCl tablet and placebo arms, respectively.

8.5 Geriatric Use Controlled clinical studies of metformin HCl 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 and any potential adverse effects on the breastfed child from metformin hydrochloride 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 may result in ovulation in some anovulatory women.

8.4 Pediatric Use The safety and effectiveness of metformin hydrochloride 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 have not been established in pediatric patients less than 10 years old. Use of metformin hydrochloride 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 HCl tablets in adults with additional data from a controlled clinical study of metformin HCl tablets 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) ]. In this study, adverse reactions were similar to those described in adults. A maximum daily dose of 2,000 mg of metformin hydrochloride is recommended. [see Dosage and Administration (2.2) .]

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

8 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 in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see Data ]. There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy [see Clinical Considerations ]. No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- and 5- times, respectively, a 2,550 mg clinical dose, based on body surface area [see Data ] . The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes mellitus with an HbA1C >7 and has been reported to be as high as 20 to 25% in women with a HbA1C >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly-controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Human Data Published data from post-marketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. Animal Data Metformin hydrochloride did not adversely affect development outcomes when administered to pregnant rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 5 times a 2,550 mg clinical dose based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin. 8.2 Lactation Risk Summary Limited published studies report that metformin is present in human milk [see Data ]. However, there is insufficient information to determine the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for metformin hydrochloride and any potential adverse effects on the breastfed child from metformin hydrochloride 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 may result in ovulation in some anovulatory women. 8.4 Pediatric Use The safety and effectiveness of metformin hydrochloride 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 have not been established in pediatric patients less than 10 years old. Use of metformin hydrochloride 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 HCl tablets in adults with additional data from a controlled clinical study of metformin HCl tablets 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) ]. In this study, adverse reactions were similar to those described in adults. A maximum daily dose of 2,000 mg of metformin hydrochloride is recommended. [see Dosage and Administration (2.2) .] 8.5 Geriatric Use Controlled clinical studies of metformin HCl 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 is 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 is not recommended in patients with hepatic impairment. [see Warnings and Precautions (5.1) ].

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Metformin hydrochloride oral solution 500 mg per 5 mL (100 mg/mL) is supplied in bottles with child-resistant caps and a dosing cup as follows: Flavor Appearance Size NDC Cherry clear, colorless to light yellow solution 16 ounce (473 mL) 66689-318-16 Storage Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature].

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