Glumetza

6 ADVERSE REACTIONS Adverse reactions occurring >5% in GLUMETZA clinical trials: hypoglycemia, diarrhea, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Salix Pharmaceuticals at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience The following adverse reactions are discussed in more detail in other sections of the labeling: • Lactic Acidosis [see 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 )] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials conducted in the U.S., over 1,000 patients with type 2 diabetes mellitus have been treated with GLUMETZA 1,500 to 2,000 mg/day in active-controlled and placebo-controlled studies with the 500 mg dosage form. In the add-on to sulfonylurea study, patients receiving background glyburide therapy were randomized to receive add-on treatment of either one of three different regimens of GLUMETZA or placebo. In total, 431 patients received GLUMETZA and glyburide and 144 patients received placebo and glyburide. Adverse reactions reported in greater than 5% of patients treated with GLUMETZA that were more common in the combined GLUMETZA and glyburide group than in the placebo and glyburide group are shown in Table 1. In 0.7% of patients treated with GLUMETZA and glyburide, diarrhea was responsible for discontinuation of study medication compared to no patients in the placebo and glyburide group. Table 1: Adverse Reactions Reported by >5%* of Patients for the Combined GLUMETZA Groups Versus Placebo Group Adverse Reaction GLUMETZA + Glyburide (n=431) Placebo + Glyburide (n=144) Hypoglycemia 14% 5% Diarrhea 13% 6% Nausea 7% 4% Laboratory Tests Vitamin B 12 Concentrations In clinical trials of 29-week duration with metformin HCl tablets, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of GLUMETZA. 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 GLUMETZA is contraindicated in patients with: • Severe renal impairment (eGFR below 30 mL/minute/1.73 m2) [see Warnings and Precautions ( 5.1 )] . • Known hypersensitivity to metformin. • Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. • Severe renal impairment: (eGFR below 30 mL/minute/1.73 m 2 ) ( 4 , 5.1 ) • Known hypersensitivity to metformin ( 4 ) • Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma ( 4 )

11 DESCRIPTION GLUMETZA contains the biguanide antihyperglycemic agent metformin in the form of monohydrochloride salt. The chemical name of metformin hydrochloride is N,N-dimethylimidodicarbonimidic diamide hydrochloride. The structural formula is as shown: Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C4H11N5•HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. GLUMETZA tablets contain 500 mg or 1,000 mg of metformin hydrochloride, which is equivalent to 389.93 mg or 779.86 mg metformin, respectively. Each 500 mg tablet contains coloring, hypromellose, magnesium stearate, microcrystalline cellulose and polyethylene oxide. Each 1,000 mg tablet contains colloidal silicon dioxide, polyvinyl alcohol, crospovidone, glyceryl behenate, polyacrylate dispersion, hypromellose, talc, polyethylene glycol, eudragit, titanium dioxide, simethicone emulsion, polysorbate and coloring. Chemical Structure-Glumetza

2 DOSAGE AND ADMINISTRATION • Starting dose: 500 mg orally once daily with the evening meal ( 2.1 ) • Increase the dose in increments of 500 mg every 1 to 2 weeks, up to a maximum of 2,000 mg once daily with the evening meal. ( 2.1 ) • Patients receiving metformin hydrochloride (HCl) tablets may be switched to GLUMETZA once daily at the same total daily dose, up to 2,000 mg once daily. ( 2.1 ) • Swallow GLUMETZA tablets whole and never crush, cut or chew. ( 2.1 ) Renal Impairment: • Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR). ( 2.2 ) • Do not use in patients with eGFR below 30 mL/minute/1.73 m 2 . • Initiation is not recommended in patients with eGFR between 30 to 45 mL/minute/1.73 m 2 . • Assess risk/benefit of continuing GLUMETZA if eGFR falls below 45 mL/minute/1.73 m 2 . • Discontinue if eGFR falls below 30 mL/minute/1.73 m 2 . Discontinuation for Iodinated Contrast Imaging Procedures: • GLUMETZA may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. ( 2.3 ) 2.1 Adult Dosage and Administration • The recommended starting dose of GLUMETZA is 500 mg orally once daily with the evening meal. • Increase the dose in increments of 500 mg every 1 to 2 weeks on the basis of glycemic control and tolerability, up to a maximum of 2,000 mg once daily with the evening meal. • Patients receiving metformin hydrochloride (HCl) may be switched to GLUMETZA once daily at the same total daily dose, up to 2,000 mg once daily. • Swallow GLUMETZA whole and never crush, cut or chew. • If a dose of GLUMETZA is missed, instruct patients not to take two doses the same day and to resume their usual dose of GLUMETZA with the next schedule dose. 2.2 Recommendations for Use in Renal Impairment • Assess renal function prior to initiation of GLUMETZA and periodically thereafter. • GLUMETZA is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m2. • Initiation of GLUMETZA in patients with an eGFR between 30 to 45 mL/minute/1.73 m2 is not recommended. • In patients taking GLUMETZA whose eGFR later falls below 45 mL/minute/1.73 m2, assess the benefit risk of continuing therapy. • Discontinue GLUMETZA if the patient’s eGFR later falls below 30 mL/minute/1.73 m2 [see Contraindications (4) and Warnings and Precautions ( 5.1 )]. 2.3 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue GLUMETZA at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/minute/1.73 m2; 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 GLUMETZA if renal function is stable [see Warnings and Precautions ( 5.1 )].

1 INDICATIONS AND USAGE GLUMETZA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. GLUMETZA is 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 HCl has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases. [see Warnings and Precautions ( 5.1 ).] Metformin is dialyzable with a clearance of up to 170 mL/minute under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

7 DRUG INTERACTIONS Table 2 presents clinically significant drug interactions with GLUMETZA. Table 2: Clinically Significant Drug Interactions with GLUMETZA 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 GLUMETZA may increase the risk for lactic acidosis. Intervention: Consider more frequent monitoring of these patients. Examples: Topiramate, zonisamide, acetazolamide or dichlorphenamide. Drugs that Reduce GLUMETZA 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 GLUMETZA. 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 GLUMETZA. Insulin Secretagogues or Insulin Clinical Impact: Coadministration of GLUMETZA 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 GLUMETZA, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving GLUMETZA, 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 a biguanide that improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease. 12.3 Pharmacokinetics Absorption Following a single oral dose of 1,000 mg (2x500 mg tablets) GLUMETZA after a meal, the time to reach maximum plasma metformin concentration (Tmax) is achieved at approximately 7-8 hours. In both single- and multiple-dose studies in healthy subjects, once daily 1,000 mg (2x500 mg tablets) dosing provides equivalent systemic exposure, as measured by area under the curve (AUC), and up to 35% higher Cmax, of metformin relative to the immediate-release given as 500 mg twice daily. At usual clinical doses and dosing schedules of metformin, steady state plasma concentrations of metformin are reached within 24-48 hours and are generally <1 mcg/mL. Single oral doses of GLUMETZA from 500 mg to 2,500 mg resulted in less than proportional increase in both AUC and C max . Effect of food: Low-fat and high-fat meals increased the systemic exposure (as measured by AUC) from GLUMETZA tablets by about 38% and 73%, respectively, relative to fasting. Both meals prolonged metformin T max by approximately 3 hours but C max was not affected. In a two-way, single-dose, crossover study in healthy volunteers, the 1,000 mg tablet was found to be similar to two 500 mg tablets under fed conditions based on equivalent C max and AUCs for the two formulations. Distribution The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg metformin HCl averaged 654±358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. Metabolism Intravenous, single-dose studies in healthy subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans), nor biliary excretion. Excretion Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. Special Populations Renal Impairment Following a single-dose administration of GLUMETZA 500 mg in subjects with mild and moderate renal impairment, the oral and renal clearance of metformin were decreased by 33% and 50% and 16% and 53%, respectively . Metformin peak and systemic exposure was 27% and 61% greater, respectively in subjects with mild renal impairment and 74% and 2.36-fold greater in subjects with moderate renal impairment as compared to healthy subjects. [see Dosage and Administration ( 2.2 ), Contraindications ( 4 ), and Warnings and Precautions ( 5.1 ).] Hepatic Impairment No pharmacokinetic studies of GLUMETZA have been conducted in subjects with hepatic impairment, [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.7 )] Geriatrics Limited data from controlled pharmacokinetic studies of metformin HCl in healthy elderly subjects suggest that total plasma clearance of metformin is decreased by 35%, the half-life is prolonged by 64% and C max is increased by 76%, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function. [see Dosage and Administration ( 2 ) and Warnings and Precautions ( 5.1 ).] Gender In the pharmacokinetic studies in healthy volunteers, there were no important differences between male and female subjects with respect to metformin AUC and t1/2. However, Cmax for metformin was 40% higher in female subjects as compared to males. In controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin HCl tablets was comparable in males and females. The gender differences for Cmax are unlikely to be clinically important. Race A trend towards 10% higher metformin C max and AUC values for metformin are obtained in Asian subjects when compared to Caucasian, Hispanic and Black subjects. The differences between the Asian and Caucasian groups are unlikely to be clinically important. In controlled clinical studies of metformin HCl in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51) and Hispanics (n=24). Pediatrics There are no available pharmacokinetic data with GLUMETZA in pediatric patients. Drug Interactions Specific pharmacokinetic drug interaction studies with GLUMETZA have not been performed except for one with glyburide. However, such studies have been performed on metformin HCl tablets. Table 3: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure Coadministered Drug Dose of Coadministered Drug All metformin HCl and coadministered drugs were given as single doses. Dose of Metformin HCl Geometric Mean Ratio (ratio with/without coadministered drug) No Effect=1.00 AUC AUC=AUC 0−inf C max No dosing adjustments required for the following: Glyburide 5 mg 500 mg 0.98 0.99 Furosemide 40 mg 850 mg 1.09 1.22 Nifedipine 10 mg 850 mg 1.16 1.21 Propranolol 40 mg 850 mg 0.90 0.94 Ibuprofen 400 mg 850 mg 1.05 1.07 Cationic drugs that are eliminated by renal tubular secretion may increase the accumulation of metformin: [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7 )]. Cimetidine 400 mg 850 mg 1.40 1.61 Carbonic anhydrase inhibitors may cause metabolic acidosis: [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7 )]. Topiramate 100 mg GLUMETZA (metformin HCl extended-release tablets) 500 mg 500 mg 1.25 1.17 Table 4: Effect of Metformin on Coadministered Drug Systemic Exposure Coadministered Drug Dose of Coadministered Drug All metformin HCl and coadministered drugs were given as single doses. Dose of Metformin HCl Geometric Mean Ratio (ratio with/without coadministered drug) No effect=1.00 AUC AUC=AUC0–inf unless otherwise noted C max No dosing adjustments required for the following: Glyburide 5 mg 500 mg 0.78 0.63 Furosemide 40 mg 850 mg 0.87 0.69 Nifedipine 10 mg 850 mg 1.10 1.08 Propranolol 40 mg 850 mg 1.01 0.94 Ibuprofen 400 mg 850 mg 0.97 Ratio of arithmetic means 1.01 Cimetidine 400 mg 850 mg 0.95 1.01

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

12.3 Pharmacokinetics Absorption Following a single oral dose of 1,000 mg (2x500 mg tablets) GLUMETZA after a meal, the time to reach maximum plasma metformin concentration (Tmax) is achieved at approximately 7-8 hours. In both single- and multiple-dose studies in healthy subjects, once daily 1,000 mg (2x500 mg tablets) dosing provides equivalent systemic exposure, as measured by area under the curve (AUC), and up to 35% higher Cmax, of metformin relative to the immediate-release given as 500 mg twice daily. At usual clinical doses and dosing schedules of metformin, steady state plasma concentrations of metformin are reached within 24-48 hours and are generally <1 mcg/mL. Single oral doses of GLUMETZA from 500 mg to 2,500 mg resulted in less than proportional increase in both AUC and C max . Effect of food: Low-fat and high-fat meals increased the systemic exposure (as measured by AUC) from GLUMETZA tablets by about 38% and 73%, respectively, relative to fasting. Both meals prolonged metformin T max by approximately 3 hours but C max was not affected. In a two-way, single-dose, crossover study in healthy volunteers, the 1,000 mg tablet was found to be similar to two 500 mg tablets under fed conditions based on equivalent C max and AUCs for the two formulations. Distribution The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg metformin HCl averaged 654±358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. Metabolism Intravenous, single-dose studies in healthy subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans), nor biliary excretion. Excretion Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. Special Populations Renal Impairment Following a single-dose administration of GLUMETZA 500 mg in subjects with mild and moderate renal impairment, the oral and renal clearance of metformin were decreased by 33% and 50% and 16% and 53%, respectively . Metformin peak and systemic exposure was 27% and 61% greater, respectively in subjects with mild renal impairment and 74% and 2.36-fold greater in subjects with moderate renal impairment as compared to healthy subjects. [see Dosage and Administration ( 2.2 ), Contraindications ( 4 ), and Warnings and Precautions ( 5.1 ).] Hepatic Impairment No pharmacokinetic studies of GLUMETZA have been conducted in subjects with hepatic impairment, [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.7 )] Geriatrics Limited data from controlled pharmacokinetic studies of metformin HCl in healthy elderly subjects suggest that total plasma clearance of metformin is decreased by 35%, the half-life is prolonged by 64% and C max is increased by 76%, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function. [see Dosage and Administration ( 2 ) and Warnings and Precautions ( 5.1 ).] Gender In the pharmacokinetic studies in healthy volunteers, there were no important differences between male and female subjects with respect to metformin AUC and t1/2. However, Cmax for metformin was 40% higher in female subjects as compared to males. In controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin HCl tablets was comparable in males and females. The gender differences for Cmax are unlikely to be clinically important. Race A trend towards 10% higher metformin C max and AUC values for metformin are obtained in Asian subjects when compared to Caucasian, Hispanic and Black subjects. The differences between the Asian and Caucasian groups are unlikely to be clinically important. In controlled clinical studies of metformin HCl in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51) and Hispanics (n=24). Pediatrics There are no available pharmacokinetic data with GLUMETZA in pediatric patients. Drug Interactions Specific pharmacokinetic drug interaction studies with GLUMETZA have not been performed except for one with glyburide. However, such studies have been performed on metformin HCl tablets. Table 3: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure Coadministered Drug Dose of Coadministered Drug All metformin HCl and coadministered drugs were given as single doses. Dose of Metformin HCl Geometric Mean Ratio (ratio with/without coadministered drug) No Effect=1.00 AUC AUC=AUC 0−inf C max No dosing adjustments required for the following: Glyburide 5 mg 500 mg 0.98 0.99 Furosemide 40 mg 850 mg 1.09 1.22 Nifedipine 10 mg 850 mg 1.16 1.21 Propranolol 40 mg 850 mg 0.90 0.94 Ibuprofen 400 mg 850 mg 1.05 1.07 Cationic drugs that are eliminated by renal tubular secretion may increase the accumulation of metformin: [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7 )]. Cimetidine 400 mg 850 mg 1.40 1.61 Carbonic anhydrase inhibitors may cause metabolic acidosis: [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7 )]. Topiramate 100 mg GLUMETZA (metformin HCl extended-release tablets) 500 mg 500 mg 1.25 1.17 Table 4: Effect of Metformin on Coadministered Drug Systemic Exposure Coadministered Drug Dose of Coadministered Drug All metformin HCl and coadministered drugs were given as single doses. Dose of Metformin HCl Geometric Mean Ratio (ratio with/without coadministered drug) No effect=1.00 AUC AUC=AUC0–inf unless otherwise noted C max No dosing adjustments required for the following: Glyburide 5 mg 500 mg 0.78 0.63 Furosemide 40 mg 850 mg 0.87 0.69 Nifedipine 10 mg 850 mg 1.10 1.08 Propranolol 40 mg 850 mg 1.01 0.94 Ibuprofen 400 mg 850 mg 0.97 Ratio of arithmetic means 1.01 Cimetidine 400 mg 850 mg 0.95 1.01

20190801

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3 DOSAGE FORMS AND STRENGTHS GLUMETZA is available as: • Extended-release tablets: 500 mg white, film-coated, oval-shaped tablets with “M500” on one side. • Extended-release tablets: 1,000 mg white, film-coated, oval-shaped tablets with “M1000” on one side. GLUMETZA Extended-Release Tablets: 500 mg and 1,000 mg ( 3 )

Glumetza metformin hydrochloride METFORMIN HYDROCHLORIDE METFORMIN HYPROMELLOSE, UNSPECIFIED MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE POLYETHYLENE GLYCOL, UNSPECIFIED white oval M500 Glumetza metformin hydrochloride METFORMIN HYDROCHLORIDE METFORMIN HYPROMELLOSE, UNSPECIFIED MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE POLYETHYLENE GLYCOL, UNSPECIFIED blue oval GMZ;500 Glumetza metformin hydrochloride METFORMIN HYDROCHLORIDE METFORMIN SILICON DIOXIDE POLYVINYL ALCOHOL, UNSPECIFIED CROSPOVIDONE (15 MPA.S AT 5%) GLYCERYL DIBEHENATE HYPROMELLOSE, UNSPECIFIED TALC POLYETHYLENE GLYCOL, UNSPECIFIED TITANIUM DIOXIDE POLYSORBATE 80 white oval M1000

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

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

NDA021748

Glumetza

metformin hydrochloride

68012-004

HUMAN PRESCRIPTION DRUG

ORAL

Package/Label Display Panel – 500 mg NDC 68012-004-50 Rx only Glumetza ® (metformin hydrochloride extended-release tablets) 500 mg ONCE DAILY 100 Tablets Salix Label-500mg.jpg

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 GLUMETZA 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 GLUMETZA. Instruct patients to inform their doctor that they are taking GLUMETZA 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 GLUMETZA 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 GLUMETZA [see Warnings and Precautions ( 5.2 )]. Females of Reproductive Age: Inform females that treatment with GLUMETZA may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy [see Use in Specific Populations ( 8.3 )]. Administration Information: Inform patients that GLUMETZA must be swallowed whole and not crushed, cut, or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet. Distributed by: Salix Pharmaceuticals, a division of Bausch Health US, LLC Bridgewater, NJ 08807 USA Manufactured by: Bausch Health Companies Inc. Steinbach, MB R5G 1Z7, Canada U.S. Patent Numbers: 6,488,962; 6,723,340; 7,780,987 and 8,323,692 Glumetza is a trademark of Salix Pharmaceuticals, Inc. or its affiliates. © 2019 Salix Pharmaceuticals, Inc. or its affiliates 9618904 20002702

14 CLINICAL STUDIES In a multicenter, randomized, double-blind, active-controlled, dose-ranging, parallel group study conducted in patients type 2 diabetes mellitus, GLUMETZA 1,500 mg once daily, GLUMETZA 1,500 per day in divided doses (500 mg in the morning and 1,000 mg in the evening), and GLUMETZA 2,000 mg once daily were compared to immediate-release metformin HCl tablets 1,500 mg per day in divided doses (500 mg in the morning and 1,000 mg in the evening). This study included patients (n=338) who were newly diagnosed with diabetes, patients treated only with diet and exercise, patients treated with a single antidiabetic medication (sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, or meglitinides), and patients (n=368) receiving metformin HCl tablets up to 1,500 mg/day plus a sulfonylurea at a dose equal to or less than one-half the maximum dose. Patients who were enrolled on monotherapy or combination antidiabetic therapy underwent a 6-week washout. Patients randomized to GLUMETZA began titration from 1,000 mg/day up to their assigned treatment dose over 3 weeks. Patients randomized to immediate-release metformin initiated 500 mg twice daily for 1 week followed by 500 mg with breakfast and 1,000 mg with dinner for the second week. The 3-week treatment period was followed by an additional 21-week period at the randomized dose. The results are presented in Table 5. Table 5: Mean Changes from Baseline in HbA1c and Fasting Plasma Glucose at Week 24 Comparing GLUMETZA versus Metformin HCl Tablets in Patients with Type 2 Diabetes Mellitus GLUMETZA Metformin HCl Tablets 1,500 mg in Divided Doses (n=174) 1,500 mg Once Daily (n=178) 1,500 mg in Divided Doses (n=182) 2,000 mg Once Daily (n=172) HbA 1c (%), N 169 175 159 170 Baseline 8.2 8.5 8.3 8.7 Mean Change at Final Visit -0.7 -0.7 -1.1 -0.7 Mean Difference from Metformin HCl Tablets (98.4% CI) 0 (-0.3, 0.3) 0 (-0.3, 0.3) -0.4 (-0.7, -0.1) N/A Fasting Plasma Glucose (mg/dL), N 175 179 170 172 Baseline 190 192.3 184 197 Mean Change at Final Visit -39 -32 -42 -32 Mean Difference from Metformin HCl Tablets (95% CI) -6 (-15, 2) 0 (-8, 9) -10 (-19, -1) N/A Mean baseline body weight was 88.2 kg, 90.5 kg, 87.7 kg and 88.7 kg in the GLUMETZA 1,500 mg once daily, GLUMETZA 1,500 mg in divided doses, GLUMETZA 2,000 mg once daily and metformin HCl tablets 1,500 mg in divided doses arms, respectively. Mean change in body weight from baseline to week 24 was -0.9 kg, -0.7 kg, -1.1 kg, and -0.9 kg in the GLUMETZA 1,500 mg once daily, GLUMETZA 1,500 mg in divided doses, GLUMETZA 2,000 mg once daily and metformin HCl tablets 1,500 mg in divided doses arms, respectively. A double-blind, randomized, placebo-controlled (glyburide add-on) multicenter study enrolled patients with type 2 diabetes mellitus who were newly diagnosed or treated with diet and exercise (n=144), or who were receiving monotherapy with metformin, sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, or meglitinides, or treated with combination therapy consisting of metformin HCl/glyburide at doses up to 1,000 mg metformin + 10 mg glyburide per day (or equivalent doses of glipizide or glimepiride up to half the maximum therapeutic dose) (n=431). All patients were stabilized on glyburide for a 6-week run-in period, and then randomized to 1 of 4 treatments: placebo + glyburide (glyburide alone); GLUMETZA 1,500 mg once a day + glyburide, GLUMETZA 2,000 mg once a day + glyburide, or GLUMETZA 1,000 mg twice a day + glyburide. A 3-week GLUMETZA titration period was followed by a 21-week maintenance treatment period. Use of insulin and oral hypoglycemic agents other than the study drugs were prohibited. The results are presented in Table 6. Table 6: Mean Changes from Baseline in HbA1c and Fasting Plasma Glucose at Week 24 for the GLUMETZA + Glyburide Groups and Placebo+ Glyburide Treatment Group in Patients with Type 2 Diabetes Mellitus GLUMETZA + Glyburide Placebo + Glyburide (n=144) 1,500 mg Once Daily (n=144) 1,000 mg Twice Daily (n=141) 2,000 mg Once Daily (n=146) HbA 1c (%), N 136 136 144 141 Baseline 7.9 7.8 7.7 8.1 Mean Change at Final Visit -0.7 -0.8 -0.7 -0.1 Mean Difference from Glyburide Alone (95% CI) -0.8 (-1.0, -0.6) -0.9 (-1.1, -0.7) -0.8 (-1.0, -0.6) N/A Fasting Plasma Glucose (mg/dL), N 143 141 145 144 Baseline 163 163 159 164 Mean Change at Final Visit -14 -16 -9 16 Mean Difference from Glyburide Alone (95% CI) -29.2 (-39, -20) -31.2 (-41, -22) -24.9 (-35, -15) N/A Mean baseline body weight was 89.4 kg, 103.7 kg, 102.9 kg and 95.6 kg in the GLUMETZA 1,500 mg once daily, GLUMETZA 1,500 mg in divided doses, GLUMETZA 2,000 mg once daily and metformin HCl tablets 1,500 mg in divided doses arms, respectively. Mean change in body weight from baseline to week 24 was 0.3 kg, 0.1 kg, 0 kg, and 0.7 kg in the GLUMETZA 1,500 mg once daily, GLUMETZA 1,500 mg in divided doses, GLUMETZA 2,000 mg once daily and metformin HCl tablets 1,500 mg in divided doses arms, respectively.

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

8.4 Pediatric Use Safety and effectiveness of GLUMETZA in pediatric patients have not been established.

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

8 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 GLUMETZA in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy [see Clinical Considerations]. No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 3 and 1 times, respectively, a 2,000 mg clinical dose, based on body surface area [see Data]. The estimated background risk of major birth defects is 6–10% in women with pregestational diabetes mellitus with an HbA1c >7 and has been reported to be as high as 20–25% in women with an HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% 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 postmarketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. Animal Data Metformin HCl was not teratogenic or embyrolethal when administered to rats prior to pregnancy through the period of organogenesis at doses up to 900 mg/kg, or when administered to rabbits during the period of organogenesis at doses up to 90 mg/kg. 8.2 Lactation Risk Summary Limited published studies report that metformin is present in human milk [see Data]. However, there is insufficient information to determine the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for GLUMETZA and any potential adverse effects on the breastfed child from GLUMETZA 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 GLUMETZA may result in ovulation in some anovulatory women. 8.4 Pediatric Use Safety and effectiveness of GLUMETZA in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of GLUMETZA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients. [see Dosage and Administration ( 2.2 ) and Warnings and Precautions ( 5.1 ).] 8.6 Renal Impairment Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. GLUMETZA is contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m2. [see Dosage and Administration ( 2.2 ), Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), and Clinical Pharmacology ( 12.3 ).] 8.7 Hepatic Impairment Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. GLUMETZA is not recommended in patients with hepatic impairment. [see Warnings and Precautions ( 5.1 ).]

16 HOW SUPPLIED/STORAGE AND HANDLING GLUMETZA is supplied as: 500 mg Bottles of 100 NDC 68012-004-50 white, film-coated, oval-shaped, extended-release tablets with “M500” on one side. 1,000 mg Bottles of 90 NDC 68012-003-16 white, film-coated, oval-shaped, extended-release tablets with “M1000” on one side. 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].

WARNING: LACTIC ACIDOSIS Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio, and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions ( 5.1 )] . Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information [see Dosage and Administration ( 2.2 ), Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), and Drug Interactions ( 7 )]. If metformin-associated lactic acidosis is suspected, immediately discontinue GLUMETZA 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 GLUMETZA and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. ( 5.1 )