NATEGLINIDE

6 ADVERSE REACTIONS The following serious adverse reaction is also described elsewhere in the labeling: Hypoglycemia [see Warnings and Precautions (5. 1) ] 6.1 Clinical Trials 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 clinical trials, approximately 2,600 patients with type 2 diabetes mellitus were treated with nateglinide. Of these, approximately 1,335 patients were treated for 6 months or longer and approximately 190 patients for one year or longer. Table 1 shows the most common adverse reactions associated with nateglinide. Table 1: Adverse Reactions other than Hypoglycemia (%) occurring Greater than or Equal to 2% in Nateglinide -Treated Patients from Pool of 12 to 64 week Placebo Controlled Trials Placebo N=458 Nateglinide N=1,441 Preferred Term Upper Respiratory Infection 8.1 10.5 Back Pain 3.7 4.0 Flu Symptoms 2.6 3.6 Dizziness 2.2 3.6 Arthropathy 2.2 3.3 Diarrhea 3.1 3.2 Accidental Trauma 1.7 2.9 Bronchitis 2.6 2.7 Coughing 2.2 2.4 Hypoglycemia Episodes of severe hypoglycemia (plasma glucose less than 36 mg/dl) were reported in two patients treated with nateglinide tablets. Non-severe hypoglycemia occurred in 2.4 % of nateglinide tablets treated patients and 0.4 % of placebo treated patients [see Warnings and Precautions (5.1) ]. Weight Gain Patients treated with nateglinide tablets had statistically significant mean increases in weight compared to placebo. In clinical trials, the mean weight increases with nateglinide tablets 60 mg (3 times daily) and nateglinide tablets 120 mg (3 times daily) compared to placebo were 1.0 kg and 1.6 kg respectively. Laboratory Test Increases in Uric Acid: There were increases in mean uric acid levels for patients treated with nateglinide tablets alone, nateglinide tablets in combination with metformin, metformin alone, and glyburide alone. The respective differences from placebo were 0.29 mg/dl, 0.45 m9/dl, 0.28 m9/dl, and 0.19 mg/dl. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of nateglinide tablets. 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. Hypersensitivity reactions: Rash, itching, and urticaria Hepatobiliary Disorders: Jaundice, cholestatic hepatitis, and elevated liver enzymes

4 CONTRAINDICATIONS Nateglinide is contraindicated in patients with a history of hypersensitivity to nateglinide or its inactive ingredients. History of hypersensitivity to nateglinide or its inactive ingredients ( 4 )

11 DESCRIPTION Nateglinide, USP is an oral blood glucose-lowering drug of the glinide class. Nateglinide, USP (-)-N-[(trans-4-isopropylcyclohexane)carbonyl]-D-phenylalanine, is structurally unrelated to the oral sulfonylurea insulin secretagogues. The structural formula is as shown: Nateglinide is a white or almost white powder with a molecular weight of 317.42. It is freely soluble in methanol, methylene chloride and in alcohol, soluble in ether, sparingly soluble in acetonitrile and in octanol, practically insoluble in water. Nateglinide tablets contain 60 mg, or 120mg, of nateglinide for oral administration. Inactive ingredients: colloidal silicon dioxide, corn starch, croscarmellose sodium, hypromellose, mannitol, iron oxide (yellow and red), polyethylene glycol, povidone, pre-gelatinized starch, sodium lauryl sulphate, sodium starch glycolate, sodium stearyl fumarate, talc and titanium dioxide. Film-coating material contains opadry pink and opadry yellow for the 60 mg and 120 mg. Opadry pink contains hypromellose, iron oxide red, macrogol and titanium dioxide. Opadry yellow contains hypromellose, iron oxides (yellow and red), macrogol, titanium dioxide, and talc. Chemical Structure

2 DOSAGE AND ADMINISTRATION The recommended dose of nateglinide tablets is 120 mg orally three times daily before meals. The recommended dose of nateglinide tablets is 60 mg orally three times daily before meals in patients who are near glycemic goal when treatment is initiated. Instruct patients to take nateglinide tablets 1 to 30 minutes before meals. In patients who skip meals, instruct patients to skip the scheduled dose of nateglinide tablets to reduce the risk of hypoglycemia {see Warnings and Precautions (5.1) ]. Recommended dose is 120 mg three times daily. In patients who are near glycemic goal when treatment is initiated, 60 mg three times daily may be administered. ( 2 ) Administer 1 to 30 minutes before meals. ( 2 ) If a meal is skipped, skip the scheduled dose to reduce the risk of hypoglycemia. ( 2 , 5.1 )

1 INDICATIONS AND USAGE Nateglinide tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Nateglinide is a glinide indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 ) Limitations of Use: Not for treating type 1 diabetes mellitus or diabetes ketoacidosis ( 1 ) Limitations of Use: Nateglinide tablets should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

10 OVERDOSAGE There have been no instances of overdose with nateglinide in clinical trials. However, an overdose may result in an exaggerated glucose-lowering effect with the development of hypoglycemic symptoms. Hypoglycemic symptoms without loss of consciousness or neurological findings should be treated with oral glucose and adjustments in dosage and/or meal patterns. Severe hypoglycemic reactions with coma, seizure, or other neurological symptoms should be treated with intravenous glucose. As nateglinide are highly protein bound, dialysis is not an efficient means of removing it from the blood.

7 DRUG INTERACTIONS Table 2 includes a list of drugs with clinically important drug interactions when concomitantly administered or withdrawn with nateglinide tablets and instructions for managing or preventing them. Table 2: Clinically Significant Drug Interactions with Nateglinide Drugs That May Increase the Blood-Glucose-Lowering Effect of Nateglinide and Susceptibility to Hypoglycemia Drugs: Nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates, monoamine oxidase inhibitors, non-selective beta-adrenergic-blocking agents, anabolic hormones (e.g. methandrostenolone), guanethidine, gymnema sylvestre, glucomannan, thioctic acid, and inhibitors of CYP2C9 (e.g. amiodarone, fluconazole, voriconazole, sulfinpyrazone) or in patients known to be poor metabolizers of CYP2C9 substrates, alcohol. Intervention: Dose increases and increased frequency of glucose monitoring may be required when nateglinide tablets are coadministered with these drugs. Drugs and Herbals That May Reduce the Blood-Glucose-Lowering Effect of Nateglinide and Increase Susceptibility to Hyperglycemia Drugs: Thiazides, corticosteroids, thyroid products, sympathomimetics, somatropin, somatostatin analogues (e.g. lanreotide, octreotide), and CYP inducers (e.g. rifampin, phenytoin and St John's Wort). Intervention: Dose increases and increased frequency of glucose monitoring may be required when nateglinide tablets are coadministered with these drugs. Drugs That May Blunt Signs and Symptoms of Hypoglycemia Drugs: beta-blockers, clonidine, guanethidine, and reserpine Intervention: Increased frequency of glucose monitoring may be required when nateglinide tablets are coadministered with these drugs.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Nateglinide lowers blood glucose levels by stimulating insulin secretion from the pancreas. This action is dependent upon functioning beta-cells in the pancreatic islets. Nateglinide interacts with the ATP-sensitive potassium (K + ATP ) channel on pancreatic beta-cells. The subsequent depolarization of the beta cell opens the calcium channel, producing calcium influx and insulin secretion. The extent of insulin release is glucose dependent and diminishes at low glucose levels. Nateglinide is highly tissue selective with low affinity for heart and skeletal muscle. 12.2 Pharmacodynamics Nateglinide tablets stimulates pancreatic insulin secretion within 20 minutes of oral administration. When nateglinide tablets are dosed before meals, the peak rise in plasma insulin occurs approximately 1 hour after dosing and falls to baseline by 4 hours after dosing. 12.3 Pharmacokinetics In patients with Type 2 diabetes, multiple dose administration of nateglinide over the dosage range of 60 mg to 240 mg shows linear pharmacokinetics for both AUC and C MAX . In patients with Type 2 diabetes, there is no apparent accumulation of nateglinide upon multiple dosing of up to 240 mg three times daily for 7 days. Absorption Absolute bioavailability of nateglinide is approximately 73%. Plasma profiles are characterized by multiple plasma concentration peaks when nateglinide is administered under fasting conditions. This effect is diminished when nateglinide is taken prior to a meal. Following oral administration immediately prior to a meal, the mean peak plasma nateglinide concentrations (C MAX ) generally occur within 1 hour (T MAX ) after dosing. T MAX is independent of dose. The pharmacokinetics of nateglinide are not affected by the composition of a meal (high protein, fat, or carbohydrate). However, peak plasma levels are significantly reduced when nateglinide tablets are administered 10 minutes prior to a liquid meal as compared to solid meal. When given with or after meals, the extent of nateglinide absorption (AUC) remains unaffected. However, there is a delay in the rate of absorption characterized by a decrease in C MAX and a delay in time to peak plasma concentration (T MAX ). Nateglinide tablets did not have any effect on gastric emptying in healthy subjects as assessed by acetaminophen testing. Distribution Following intravenous (IV) administration of nateglinide, the steady-state volume of distribution of nateglinide is estimated to be approximately 10 L in healthy subjects. Nateglinide is extensively bound (98%) to serum proteins, primarily serum albumin, and to a lesser extent a acid glycoprotein. The extent of serum protein binding is independent of drug concentration over the test range of 0.1 to 10 mcg/ml. Elimination In healthy volunteers and patients with type 2 diabetes mellitus, nateglinide plasma concentrations declined with an average elimination half-life of approximately 1.5 hours. Metabolism In vitro drug metabolism studies indicate that nateglinide tablets are predominantly metabolized by the cytochrome P450 isozyme CYP2C9 (70%) and to a lesser extent CYP3A4 (30%). The major routes of metabolism are hydroxylation followed by glucuronide conjugation. The major metabolites are less potent antidiabetic agents than nateglinide. The isoprene minor metabolite possesses potency similar to that of the parent compound nateglinide. Excretion Nateglinide and its metabolites are rapidly and completely eliminated following oral administration. Eighty-three percent of the 14c_nateglinide was excreted in the urine with an additional 10% eliminated in the feces. Approximately 16% of the 14c_Nateglinide was excreted in the urine as parent compound. Specific Populations Renal Impairment No pharmacokinetic data are available in subjects with mild renal impairment (CrCI 60 to 89 mL/min). Compared to healthy matched subjects, patients with type 2 diabetes mellitus and moderate and severe renal impairment (CrCl 15 to 50 mL/min) not on dialysis displayed similar apparent clearance, AUG, and C MAX . Patients with type 2 diabetes and renal failure on dialysis exhibited reduced overall drug exposure (C MAX decreased by 49%; not statistically significant). However, hemodialysis patients also experienced reductions in plasma protein binding compared to the matched healthy volunteers. In a cohort of 8 patients with type 2 diabetes and end-stage renal disease (ESRD) (eGFR < 15 mL/min/1.73m 2 ) M1 metabolite accumulation up to 1.2 ng/mL occurred with a dosage of 90 mg once daily for 1 to 3 months. In another cohort of 8 patients with type 2 diabetes on hemodialysis, M 1 concentration decreased after a single session of hemodialysis. Although the hypoglycemic activity of the M1 metabolite is approximately 5 times lower than nateglinide, metabolite accumulation may increase the hypoglycemic effect of the administered dose. Hepatic Impairment In patients with mild hepatic impairment, the mean increase in C MAX and AUC of nateglinide were 37% and 30 % respectively, as compared to healthy matched control subjects. There is no data on pharmacokinetics of nateglinide tablets in patients with moderate-to-severe hepatic impairment. Gender No clinically significant differences in nateglinide pharmacokinetics were observed between men and women. Race Results of a population pharmacokinetic analysis including subjects of Caucasian, Black, and other ethnic origins suggest that race has little influence on the pharmacokinetics of nateglinide. Age Age does not influence the pharmacokinetic properties of nateglinide. Drug Interactions: In vitro assessment of drug interactions Nateglinide is a potential inhibitor of the CYP2C9 isoenzyme in viva as indicated by its ability to inhibit the in vitro metabolism of tolbutamide. Inhibition of CYP3A4 metabolic reactions was not detected in in vitro experiments. In vitro displacement studies with highly protein-bound drugs such as furosemide, propranolol, captopril, nicardipine, pravastatin, glyburide, warfarin, phenytoin, acetylsalicylic acid, tolbutamide, and metformin showed no influence on the extent of nateglinide protein binding. Similarly, nateglinide had no influence on the serum protein binding of propranolol, glyburide, nicardipine, warfarin, phenytoin, acetylsalicylic acid, and tolbutamide in vitro. However, prudent evaluation of individual cases is warranted in the clinical setting. In vivo assessment of drug interactions The effect of coadministered drugs on the pharmacokinetics of nateglinide and the effect of nateglinide on pharmacokinetics of coadministered drugs are shown in Tables 3 and 4. No clinically relevant change in pharmacokinetic parameters of either agent was reported when nateglinide was coadministered with glyburide, metformin, digoxin, warfarin, and diclofenac. Table 3: Effect of Coadministered Drugs on Pharmacokinetics of Nateglinide Coadministered drug Dosing regimen of coadministered drug Dosing regimen of nateglinide Change in C max Change in AUC AM: after morning dose; PM: after evening dose; * after second dose; ↑: Increase in the parameter; ↓: decrease in the parameter Glyburide 10 mg once daily for 3 weeks 120 mg three times a day, single dose 8.78%↓ 3.53%↓ Metformin 500 mg three times a day for 3 weeks 120 mg three times a day, single dose AM:7.14%↑ PM:11.4%↓ AM:1.51%↑ PM:5.97%↑ Digoxin 1 mg, single dose 120 mg three times a day, single dose AM:2.17%↓ PM:3.19%↑ AM:7.62%↑ PM:2.22%↑ Warfarin 30 mg, single dose 120 mg three times a day for 4 days 2.65%↑ 3.72%↓ Diclofenac 75 mg, single dose 120 mg twice daily, single dose AM:13.23%↓ *PM: 3.76% ↑ AM:2.2%↓ *PM: 7.5% ↑ Table 4: Effect of Nateglinide on Pharmacokinetics of Coadministered Drugs Coadministered drug Dosing regimen of Coadministered drug Dosing regimen of nateglinide Change in C max Change in AUC AM: after morning dose; PM: after evening dose; SD: single dose; ↑: increase in the parameter; ↓: decrease in the parameter Glyburide 10 mg once daily for 3 weeks 120 mg three times a day, single dose 3.18%↓ 7.34%↓ Metformin 500 mg three times a day for 3 weeks 120 mg three times a day, single dose AM:10.7%↑ PM:0.40%↑ AM:13.3%↑ PM:2.27%↓ Digoxin 1 mg, single dose 120 mg three times a day, single dose 5.41%↓ 6.58%↑ Warfarin 30 mg, single dose 120 mg three times a day for 4 days R-warfarin:1.03%↓ S-warfarin:0.85%↓ R-warfarin:0.74%↑ S-warfarin:7.23%↑ Diclofenac 75 mg, single dose 120 mg twice daily, single dose 2.19%↑ 7.97%↑

12.1 Mechanism of Action Nateglinide lowers blood glucose levels by stimulating insulin secretion from the pancreas. This action is dependent upon functioning beta-cells in the pancreatic islets. Nateglinide interacts with the ATP-sensitive potassium (K + ATP ) channel on pancreatic beta-cells. The subsequent depolarization of the beta cell opens the calcium channel, producing calcium influx and insulin secretion. The extent of insulin release is glucose dependent and diminishes at low glucose levels. Nateglinide is highly tissue selective with low affinity for heart and skeletal muscle.

12.2 Pharmacodynamics Nateglinide tablets stimulates pancreatic insulin secretion within 20 minutes of oral administration. When nateglinide tablets are dosed before meals, the peak rise in plasma insulin occurs approximately 1 hour after dosing and falls to baseline by 4 hours after dosing.

12.3 Pharmacokinetics In patients with Type 2 diabetes, multiple dose administration of nateglinide over the dosage range of 60 mg to 240 mg shows linear pharmacokinetics for both AUC and C MAX . In patients with Type 2 diabetes, there is no apparent accumulation of nateglinide upon multiple dosing of up to 240 mg three times daily for 7 days. Absorption Absolute bioavailability of nateglinide is approximately 73%. Plasma profiles are characterized by multiple plasma concentration peaks when nateglinide is administered under fasting conditions. This effect is diminished when nateglinide is taken prior to a meal. Following oral administration immediately prior to a meal, the mean peak plasma nateglinide concentrations (C MAX ) generally occur within 1 hour (T MAX ) after dosing. T MAX is independent of dose. The pharmacokinetics of nateglinide are not affected by the composition of a meal (high protein, fat, or carbohydrate). However, peak plasma levels are significantly reduced when nateglinide tablets are administered 10 minutes prior to a liquid meal as compared to solid meal. When given with or after meals, the extent of nateglinide absorption (AUC) remains unaffected. However, there is a delay in the rate of absorption characterized by a decrease in C MAX and a delay in time to peak plasma concentration (T MAX ). Nateglinide tablets did not have any effect on gastric emptying in healthy subjects as assessed by acetaminophen testing. Distribution Following intravenous (IV) administration of nateglinide, the steady-state volume of distribution of nateglinide is estimated to be approximately 10 L in healthy subjects. Nateglinide is extensively bound (98%) to serum proteins, primarily serum albumin, and to a lesser extent a acid glycoprotein. The extent of serum protein binding is independent of drug concentration over the test range of 0.1 to 10 mcg/ml. Elimination In healthy volunteers and patients with type 2 diabetes mellitus, nateglinide plasma concentrations declined with an average elimination half-life of approximately 1.5 hours. Metabolism In vitro drug metabolism studies indicate that nateglinide tablets are predominantly metabolized by the cytochrome P450 isozyme CYP2C9 (70%) and to a lesser extent CYP3A4 (30%). The major routes of metabolism are hydroxylation followed by glucuronide conjugation. The major metabolites are less potent antidiabetic agents than nateglinide. The isoprene minor metabolite possesses potency similar to that of the parent compound nateglinide. Excretion Nateglinide and its metabolites are rapidly and completely eliminated following oral administration. Eighty-three percent of the 14c_nateglinide was excreted in the urine with an additional 10% eliminated in the feces. Approximately 16% of the 14c_Nateglinide was excreted in the urine as parent compound. Specific Populations Renal Impairment No pharmacokinetic data are available in subjects with mild renal impairment (CrCI 60 to 89 mL/min). Compared to healthy matched subjects, patients with type 2 diabetes mellitus and moderate and severe renal impairment (CrCl 15 to 50 mL/min) not on dialysis displayed similar apparent clearance, AUG, and C MAX . Patients with type 2 diabetes and renal failure on dialysis exhibited reduced overall drug exposure (C MAX decreased by 49%; not statistically significant). However, hemodialysis patients also experienced reductions in plasma protein binding compared to the matched healthy volunteers. In a cohort of 8 patients with type 2 diabetes and end-stage renal disease (ESRD) (eGFR < 15 mL/min/1.73m 2 ) M1 metabolite accumulation up to 1.2 ng/mL occurred with a dosage of 90 mg once daily for 1 to 3 months. In another cohort of 8 patients with type 2 diabetes on hemodialysis, M 1 concentration decreased after a single session of hemodialysis. Although the hypoglycemic activity of the M1 metabolite is approximately 5 times lower than nateglinide, metabolite accumulation may increase the hypoglycemic effect of the administered dose. Hepatic Impairment In patients with mild hepatic impairment, the mean increase in C MAX and AUC of nateglinide were 37% and 30 % respectively, as compared to healthy matched control subjects. There is no data on pharmacokinetics of nateglinide tablets in patients with moderate-to-severe hepatic impairment. Gender No clinically significant differences in nateglinide pharmacokinetics were observed between men and women. Race Results of a population pharmacokinetic analysis including subjects of Caucasian, Black, and other ethnic origins suggest that race has little influence on the pharmacokinetics of nateglinide. Age Age does not influence the pharmacokinetic properties of nateglinide. Drug Interactions: In vitro assessment of drug interactions Nateglinide is a potential inhibitor of the CYP2C9 isoenzyme in viva as indicated by its ability to inhibit the in vitro metabolism of tolbutamide. Inhibition of CYP3A4 metabolic reactions was not detected in in vitro experiments. In vitro displacement studies with highly protein-bound drugs such as furosemide, propranolol, captopril, nicardipine, pravastatin, glyburide, warfarin, phenytoin, acetylsalicylic acid, tolbutamide, and metformin showed no influence on the extent of nateglinide protein binding. Similarly, nateglinide had no influence on the serum protein binding of propranolol, glyburide, nicardipine, warfarin, phenytoin, acetylsalicylic acid, and tolbutamide in vitro. However, prudent evaluation of individual cases is warranted in the clinical setting. In vivo assessment of drug interactions The effect of coadministered drugs on the pharmacokinetics of nateglinide and the effect of nateglinide on pharmacokinetics of coadministered drugs are shown in Tables 3 and 4. No clinically relevant change in pharmacokinetic parameters of either agent was reported when nateglinide was coadministered with glyburide, metformin, digoxin, warfarin, and diclofenac. Table 3: Effect of Coadministered Drugs on Pharmacokinetics of Nateglinide Coadministered drug Dosing regimen of coadministered drug Dosing regimen of nateglinide Change in C max Change in AUC AM: after morning dose; PM: after evening dose; * after second dose; ↑: Increase in the parameter; ↓: decrease in the parameter Glyburide 10 mg once daily for 3 weeks 120 mg three times a day, single dose 8.78%↓ 3.53%↓ Metformin 500 mg three times a day for 3 weeks 120 mg three times a day, single dose AM:7.14%↑ PM:11.4%↓ AM:1.51%↑ PM:5.97%↑ Digoxin 1 mg, single dose 120 mg three times a day, single dose AM:2.17%↓ PM:3.19%↑ AM:7.62%↑ PM:2.22%↑ Warfarin 30 mg, single dose 120 mg three times a day for 4 days 2.65%↑ 3.72%↓ Diclofenac 75 mg, single dose 120 mg twice daily, single dose AM:13.23%↓ *PM: 3.76% ↑ AM:2.2%↓ *PM: 7.5% ↑ Table 4: Effect of Nateglinide on Pharmacokinetics of Coadministered Drugs Coadministered drug Dosing regimen of Coadministered drug Dosing regimen of nateglinide Change in C max Change in AUC AM: after morning dose; PM: after evening dose; SD: single dose; ↑: increase in the parameter; ↓: decrease in the parameter Glyburide 10 mg once daily for 3 weeks 120 mg three times a day, single dose 3.18%↓ 7.34%↓ Metformin 500 mg three times a day for 3 weeks 120 mg three times a day, single dose AM:10.7%↑ PM:0.40%↑ AM:13.3%↑ PM:2.27%↓ Digoxin 1 mg, single dose 120 mg three times a day, single dose 5.41%↓ 6.58%↑ Warfarin 30 mg, single dose 120 mg three times a day for 4 days R-warfarin:1.03%↓ S-warfarin:0.85%↓ R-warfarin:0.74%↑ S-warfarin:7.23%↑ Diclofenac 75 mg, single dose 120 mg twice daily, single dose 2.19%↑ 7.97%↑

20210115

2

3 DOSAGE FORMS AND STRENGTHS 60 mg tablets: Pink, round, beveled edge tablet with "C" debossed on one side and "123" on the other side 120 mg tablets: Yellow, ovaloid tablet with "C" debossed on one side and "125" on the other side Tablets: 60 mg and 120 mg ( 3 )

NATEGLINIDE NATEGLINIDE NATEGLINIDE NATEGLINIDE SILICON DIOXIDE STARCH, CORN CROSCARMELLOSE SODIUM HYPROMELLOSE, UNSPECIFIED MANNITOL FERRIC OXIDE RED POLYETHYLENE GLYCOL 6000 POVIDONE K30 SODIUM STARCH GLYCOLATE TYPE A POTATO SODIUM LAURYL SULFATE SODIUM STEARYL FUMARATE TALC TITANIUM DIOXIDE C123 NATEGLINIDE NATEGLINIDE NATEGLINIDE NATEGLINIDE SILICON DIOXIDE STARCH, CORN CROSCARMELLOSE SODIUM HYPROMELLOSE, UNSPECIFIED MANNITOL FERRIC OXIDE RED POLYETHYLENE GLYCOL 400 POVIDONE K30 SODIUM STARCH GLYCOLATE TYPE A POTATO SODIUM LAURYL SULFATE SODIUM STEARYL FUMARATE TALC TITANIUM DIOXIDE C125

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity: Nateglinide did not increase tumors in two year carcinogenicity studies conducted in mice and rats. Oral doses of nateglinide up to 900 mg/kg in rats and 400 mg/kg in mice were tested, which produced exposures in rats approximately 30 to 40 times and in mice 10 to 30 times the human therapeutic exposure of nateglinide at a dose of 120 mg three times daily, based on AUC. Mutagenesis: Nateglinide was not genotoxic in the in vM:ra Ames test, mouse lymphoma assay, chromosome aberration assay or in the in vivo mouse micronucleus test. Impairment of Fertility: Fertility was unaffected by administration of nateglinide to rats at doses up to 600 mg/kg (approximately 16 times the human therapeutic exposure with a recommended nateglinide tablets dose of 120 mg three times daily before meals).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity: Nateglinide did not increase tumors in two year carcinogenicity studies conducted in mice and rats. Oral doses of nateglinide up to 900 mg/kg in rats and 400 mg/kg in mice were tested, which produced exposures in rats approximately 30 to 40 times and in mice 10 to 30 times the human therapeutic exposure of nateglinide at a dose of 120 mg three times daily, based on AUC. Mutagenesis: Nateglinide was not genotoxic in the in vM:ra Ames test, mouse lymphoma assay, chromosome aberration assay or in the in vivo mouse micronucleus test. Impairment of Fertility: Fertility was unaffected by administration of nateglinide to rats at doses up to 600 mg/kg (approximately 16 times the human therapeutic exposure with a recommended nateglinide tablets dose of 120 mg three times daily before meals).

ANDA206432

NATEGLINIDE

NATEGLINIDE

75834-205

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL - 60 mg Tablet Bottle Label NDC 75834-205-01 NATEGLINIDE TABLETS, USP 60 mg 100 Tablets NIVAGEN Rx only PRINCIPAL DISPLAY PANEL - 60 mg Tablet Bottle Label

Manufactured by: Cadila Pharmaceuticals Limited 1389 Trasad Road, Dholka - 382225, District - Ahmedabad, Gujarat, INDIA Manufactured for: Nivagen Pharmaceuticals, Inc. Sacramento, CA 95827 Toll free number: 1-877-977-0687 May, 2019

17 PATIENT COUNSELING INFORMATION Administration Instruct patients to take nateglinide tablets 1 to 30 minutes before meals. Instruct patients that skip meals to skip their dose of nateglinide tablets [see Dosage and Administration (2) ]. Hypoglycemia Inform patients that nateglinide tablets can cause hypoglycemia and instruct patients and their caregivers on self-management procedures including glucose monitoring and management of hypoglycemia. Inform patients that their ability to concentrate and react may be impaired as a result of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended [see Warnings and Precautions (5.1) ]. Drug Interactions Discuss potential drug interactions with patients and inform them of potential drug-drug interactions with nateglinide tablets.

14 CLINICAL STUDIES 14.1 Monotherapy In a 24-week, double-blind, placebo-controlled study, patients with type 2 diabetes were randomized to receive either nateglinide tablets (60 mg or 120 mg three times daily before meals) or placebo. Patients previously treated with antidiabetic medications were required to discontinue that medication for at least 2 months before randomization. At Week 24, treatment with nateglinide tablets before meals resulted in statistically significant reductions in mean HbA1C and mean fasting plasma glucose (FPG) compared to placebo (see Table 5 ). The reductions in HbA1C and FPG were similar for patient's naive to, and those previously exposed to, antidiabetic medications. Table 5: Endpoint Results for a 24-week, Fixed Dose Study of Nateglinide Monotherapy Placebo Nateglinide Tablets 60 mg three times daily before meals Nateglinide Tablets 120 mg three times daily before meals HbA1C (%) N=168 N=167 N=168 Baseline (mean) 8.0 7.9 8.1 Change from baseline (mean) +0.2 -0.3 -0.5 Difference from placebo (mean) -0.5 p-value≤0.004 -0.7 FPG (mg/dL) N=172 N=171 N=169 Baseline (mean) 167.9 161.0 166.5 Change from baseline (mean) +9.1 +0.4 -4.5 Difference from placebo (mean) -8.7 -13.6 14.2 Monotherapy Compared to Glyburide In a 24-week, double-blind, active-controlled trial, patients with type 2 diabetes who had been on a sulfonylurea for 3 or more months and who had a baseline HbA 1 C greater than or equal to 6.5% were randomized to receive nateglinide tablets (60 mg or 120 mg three times daily before meals) or glyburide 10 mg once daily. Patients randomized to nateglinide tablets had statistically significant increases in mean HbA1C and mean FPG at endpoint compared to patients randomized to glyburide. Table 6: Endpoint Results for a 24-week Study of Nateglinide Monotherapy Compared to Glyburide Glyburide 10 mg Once daily Nateglinide 60 mg three times daily before meals Nateglinide 120 mg three times daily before meals HbA 1C (%) N=183 N=178 N=179 Baseline (mean) 7.8 8.0 7.9 Change from baseline (mean) 0.3 1.3 1.1 Difference from glyburide 1.0 p-value <0.001 0.9 FPG(mmol/L) N=184 N=182 N=180 Baseline (mean) 9.44 9.67 9.61 Change from baseline (mean) 0.19 3.06 2.84 Difference from glyburide 2.87 2.66 14.3 Monotherapy and In Combination With Metformin In a 24-week, double-blind, active- and placebo-controlled study, patients with type 2 diabetes were randomized to receive either nateglinide alone (120 mg three times daily before meals), metformin alone (500 mg three times daily), a combination of nateglinide tablets 120 mg (three times daily before meals) and metformin (500 mg three times daily), or placebo. Fifty-seven percent of patients were previously untreated with oral antidiabetic therapy. Patients previously treated with antidiabetic medications were required to discontinue medication for at least 2 months before randomization. At Week 24, statistically significant reductions in mean HbA1c and FPG were observed with metformin monotherapy compared to nateglinide tablets monotherapy, and the combination of nateglinide tablets and metformin compared to either nateglinide tablets or metformin monotherapy (see Table 7 ). Compared to placebo, nateglinide monotherapy was associated with a statistically significant increase in mean body weight, while no significant change in body weight was observed with metformin monotherapy or combination of nateglinide and metformin therapy (see Table 7 ). Among the subset of patients previously treated with other antidiabetic agents, primarily glyburide, HbA1C in the nateglinide monotherapy group increased slightly from baseline, whereas HbA1C was reduced in the metformin monotherapy group (see Table 7 ). Table 7: Endpoint results for a 24-week study of Nateglinide Monotherapy and Combination with Metformin Placebo Nateglinide 120 mg three times daily Metformin 500 mg three times daily Nateglinide 120 mg before meals plus Metformin Metformin was administered three times daily HbA1C(%) All N=160 N=171 N=172 N=162 Baseline (mean) 8.3 8.3 8.4 8.4 Change from baseline (mean) +0.4 -0.4 p-value≤0.03 vs. metformin p-value≤0.05 vs. combination -0.8 -1.5 Difference from placebo -0.8 p-value≤0.05 vs. placebo -1.2 -1.9 Naïve N=98 N=99 N=98 N=81 Baseline (mean) 8.2 8.1 8.3 8.2 Change from baseline (mean) +0.3 -0.7 -0.8 -1.6 Difference from placebo -1.0 -1.1 -1.9 Non-Naïve N=62 N=72 N=74 N=81 Baseline (mean) 8.3 8.5 8.7 8.7 Change from baseline (mean) +0.6 +0.004 -0.8 -1.4 Difference from placebo -0.6 -1.4a -2.0 FPG (mg/dL) All N=166 N=173 N=174 N=167 Baseline (mean) 194.0 196.5 196.0 197.7 Change from baseline (mean) +8.0 -13.1 -30.0 -44.9 Difference from placebo -21.1 -38.0 -52.9 In another 24-week, double-blind, placebo-controlled trial, patients with type 2 diabetes with HbA1C greater than or equal to 6.8% after treatment with metformin (greater than or equal to 1,500 mg daily for at least 1 month) were first entered into a four week run-in period of metformin monotherapy (2,000 mg daily) and then randomized to receive either nateglinide tablets (60 mg or 120 mg three limes daily before meals) or placebo as add-on to metformin. At the end of treatment, nateglinide tablets 60 mg and 120 mg three times daily resulted in a statistically significantly greater reductions in HbA1C compared to placebo when added to metformin (-0.4% and -0.6% for nateglinide tablets 60 mg and nateglinide tablets 120 mg plus metformin, respectively). Table 8: Endpoint Results for a 24-week Study of Nateglinide Monotherapy as Add-on to Metformin Placebo + 006Detformin Nateglinide 60 mg + metformin Nateglinide 120 mg + metformin HbA 1C (%) N=150 N=152 N=154 Baseline (mean) 8.2 8.0 8.2 Change from baseline (mean) 0.01 -0.4 -0.6 Difference from metformin -0.4 p-value 0.003 vs. metformin -0.6 p-value < 0.001 vs. metformin All nateglinide /placebo taken three times daily before meals; all metformin 1,000 mg twice daily. 14.4 Add-On Combination Therapy With Rosiglitazone A 24-week, double blind, multicenter, placebo-controlled trial was performed in patients with type 2 diabetes not adequately controlled on rosiglitazone 8 mg daily. The addition of nateglinide (120 mg three times per day with meals) was associated with statistically significantly greater reductions in HbA1C compared to placebo as add-on to rosiglitazone. The mean change in weight from baseline was +3 kg for patients treated with nateglinide tablets compared to +1 kg for patients treated with placebo when added to rosiglitazone. Table 9: Endpoint Results for a 24-week Study of the Effect of Adding Nategllnlde or Placebo to Rosiglitazone Placebo + roalglitazone 8 mg once daily Nateglinide 120 mg before meals + rosiglitazone 8 mg once daily HbA 1C (%) N=191 N=194 Baseline (mean) 8.4 8.3 Change from baseline (mean) 0.03 -0.7 Difference from rosiglitazone (mean) -0.7 p-value≤0.0001 14.5 Add-On Combination Therapy With Glyburide In a 12-week study of patients with type 2 diabetes inadequately controlled on glyburide 10 mg once daily, the addition of nateglinide (60 mg or 120 mg three times daily before meals) did not produce any additional benefit. Table 10: Endpoint Results for a 12-week Study of the Effect of Adding Nateglinide or Placebo to Glyburide Placebo + roalglitazone 8 mg once daily Nateglinide 120 mg before meals + rosiglitazone 8 mg once daily HbA 1C (%) N=191 N=194 Baseline (mean) 8.4 8.3 Change from baseline (mean) 0.03 -0.7 Difference from rosiglitazone (mean) -0.7 p-value≤0.0001

8.5 Geriatric Use 436 patients 65 years and older, and 80 patients 75 years and older were exposed to nateglinide in clinical studies. No differences were observed in safety or efficacy of nateglinide tablets between patients age 65 and over, and those under age 65. However, greater sensitivity of some older individuals to nateglinide tablets therapy cannot be ruled out.

8.3 Nursing Mothers It is not known whether nateglinide is excreted in human milk. Nateglinide is excreted in rat milk. Offspring of rats exposed to 1,000 mg/kg nateglinide (approximately 27 times the human therapeutic exposure of 120 mg three times daily, based on body surface area) had lower body weight. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made as to whether nateglinide should be discontinued in nursing mothers, or if mothers should discontinue nursing.

8.4 Pediatric Use The safety and effectiveness of nateglinide have not been established in pediatric patients.

8.1 Pregnancy There are no adequate and well-controlled studies of nateglinide in pregnant women. It is unknown whether nateglinide can cause fetal harm when administered to a pregnant woman. Nateglinide tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In the rabbit, embryonic development was adversely affected and the incidence of gall bladder agenesis or small gallbladder was increased at a dose of 500 mg/kg (approximately 27 times the human therapeutic exposure of 120 mg three times daily, based on body surface area). Nateglinide was not teratogenic in rats at doses up to 1,000 mg/kg (approximately 27 times the human therapeutic exposure based on body surface area).

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy There are no adequate and well-controlled studies of nateglinide in pregnant women. It is unknown whether nateglinide can cause fetal harm when administered to a pregnant woman. Nateglinide tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In the rabbit, embryonic development was adversely affected and the incidence of gall bladder agenesis or small gallbladder was increased at a dose of 500 mg/kg (approximately 27 times the human therapeutic exposure of 120 mg three times daily, based on body surface area). Nateglinide was not teratogenic in rats at doses up to 1,000 mg/kg (approximately 27 times the human therapeutic exposure based on body surface area). 8.3 Nursing Mothers It is not known whether nateglinide is excreted in human milk. Nateglinide is excreted in rat milk. Offspring of rats exposed to 1,000 mg/kg nateglinide (approximately 27 times the human therapeutic exposure of 120 mg three times daily, based on body surface area) had lower body weight. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made as to whether nateglinide should be discontinued in nursing mothers, or if mothers should discontinue nursing. 8.4 Pediatric Use The safety and effectiveness of nateglinide have not been established in pediatric patients. 8.5 Geriatric Use 436 patients 65 years and older, and 80 patients 75 years and older were exposed to nateglinide in clinical studies. No differences were observed in safety or efficacy of nateglinide tablets between patients age 65 and over, and those under age 65. However, greater sensitivity of some older individuals to nateglinide tablets therapy cannot be ruled out. 8.6 Renal Impairment No dosage adjustment is recommended in patients with mild to severe renal impairment [see Clinical Pharmacology (12.3) ]. 8. 7 Hepatic Impairment No dose adjustment is recommended for patients with mild hepatic impairment. Use of nateglinide in patients with moderate-to-severe hepatic impairment has not been studied and therefore, should be used with caution in these patients [see Clinical Pharmacology (12.3) ].

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied 60 mg Nateglinide tablets, USP 60 mg are supplied as pink, round, beveled edge tablet with "C" debossed on one side and "123" on the other side. NDC Number Size NDC 75834-205-01 bottle of 100 120 mg Nateglinide tablets, USP 120 mg are supplied as yellow, ovaloid tablet with "C" debossed on one side and "125" on the other side. NDC Number Size NDC 75834-206-01 bottle of 100 Storage and Handling 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.] Dispense in a tight container (USP).

Storage and Handling 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.] Dispense in a tight container (USP).