nateglinide

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. Limitations of Use : Nateglinide Tablets should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Nateglinide Tablets are 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 )

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 ( 2 ) 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 )

3 DOSAGE FORMS AND STRENGTHS 60 mg tablets: Pink color coated, round biconvex, beveled edge tablet debossed with "P 984" on one side and plain on the other side 120 mg tablets: Orange color coated, oval shaped biconvex, tablet debossed with "P 985" on one side and plain on the other side Tablets: 60 mg and 120 mg (3)

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

6 ADVERSE REACTIONS The following serious adverse reaction is also described elsewhere in the labeling: Hypoglycemia [see Warnings and Precautions (5.1) ] Common adverse reactions associated with Nateglinide Tablets (3% or greater incidence) were upper respiratory tract infection, back pain, flu symptoms, dizziness, arthropathy, diarrhea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharma Holdings, Inc. at 1-844-874-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 Tablets. 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 Tablets. Table 1: Adverse Reactions other than Hypoglycemia (%) occurring Greater than or Equal to 2% in Nateglinide Tablets-Treated Patients from Pool of 12 to 64 week Placebo Controlled Trials Placebo Nateglinide Tablets N=458 N=1441 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 mg/dL, 0.28 mg/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

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 Tablets Drugs That May Increase the Blood-Glucose-Lowering Effect of Nateglinide Tablets 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 reductions 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 Tablets 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. Drugs That May Increase the Potential for Hypoglycemia : Nateglinide Tablets dose reductions and increased frequency of glucose monitoring may be required when co-administered ( 7 ) Drugs That May Increase the Potential for Hyperglycemia : Nateglinide Tablets dose increases and increased frequency of glucose monitoring may be required when co-administered ( 7 ) Drugs That May Blunt Signs and Symptoms of Hypoglycemia : Increased frequency of glucose monitoring may be required when co-administered ( 7 )

8 USE IN SPECIFIC POPULATIONS Lactation : Nateglinide Tablets are not recommended when breastfeeding ( 8.2 ) 8.1 Pregnancy Risk Summary The available data from published literature and the applicant’s pharmacovigilance with use of Nateglinide Tablets in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy ( see Clinical Considerations ). Nateglinide Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In animal reproduction studies, there was no teratogenicity in rats and rabbits administered oral nateglinide during organogenesis at approximately 27 and 8 times the maximum recommended human dose (MRHD), respectively, based on body surface area (BSA). The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with a 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 in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Animal data In embryofetal development studies, nateglinide administered orally during the period of organogenesis was not teratogenic in rats at doses up to 1,000 mg/kg (corresponding to 27 times the MRHD of 120 mg three times per day, based on BSA). In rabbits, embryonic development was adversely affected at 500 mg/kg/day and the incidence of gallbladder agenesis or small gallbladder was increased at a dose of 300 and 500 mg/kg (corresponding to 16 and 27 times the MRHD). No such effects were observed at 150 mg/kg/day (corresponding to 8 times the MRHD). In a pre- and postnatal development study in rats, nateglinide administered by oral gavage at doses of 100, 300, and 1,000 mg/kg/day from gestation day 17 to lactation day 21 resulted in lower body weight in offspring of rats administered nateglinide at 1,000 mg/kg/day (corresponding to 27 times the MHRD). 8.2 Lactation Risk summary There are no data on the presence of nateglinide in human milk, the effects on the breastfeeding infant, or the effects on milk production. The drug is present in animal milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk ( see Data ). Because the potential for hypoglycemia in breast-fed infants, advise women that use of Nateglinide Tablets are not recommended while breastfeeding. Data In rat reproduction studies, nateglinide and its metabolite are excreted in the milk following oral dose (300 mg/kg). The overall milk: plasma (M/P) concentration ratio of the total radioactivity was approximately 1.4 based on AUC 0 to 48 values. The M/P ratio of unchanged nateglinide was approximately 2.2. 8.4 Pediatric Use The safety and effectiveness of Nateglinide Tablets 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 Tablets 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 rena …

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.

11 DESCRIPTION Nateglinide Tablets, USP are an oral blood glucose-lowering drug of the glinide class. Nateglinide, (-)-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 powder with a molecular weight of 317.43. It is freely soluble in methanol, ethanol, and chloroform, soluble in ether, sparingly soluble in acetonitrile and octanol, and practically insoluble in water. Nateglinide biconvex tablets contain 60 mg, or 120 mg, of nateglinide for oral administration. Inactive Ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch (starch 1500 ® ). Starch 1500 ® is partially pregelatinized maize starch. The 60 mg also contains iron oxide red, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. In addition, the 120 mg contains FD&C Yellow #6/Sunset Yellow Aluminum Lake, iron oxide yellow. Nateglinide structural formula

10 OVERDOSAGE There have been no instances of overdose with Nateglinide Tablets 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 Tablets are highly protein bound, dialysis is not an efficient means of removing it from the blood.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Nateglinide tablets USP are available as 60 mg white to off-white, round, biconvex tablets embossed with ‘RDY’ on one side and ‘328’ on other side and they are supplied in bottles of 30, 90, 100, 500 and unit dose package of 100 (10 x 10). Bottles of 30 NDC 55111-328-30 Bottles of 90 NDC 55111-328-90 Bottles of 100 NDC 55111-328-01 Bottles of 500 NDC 55111-328-05 Unit dose package of 100 (10 x 10) NDC 55111-328-78 Nateglinide tablets USP are available as 120 mg white to off-white, round, biconvex tablets embossed with ‘RDY’ on one side and ‘329’ on other side and they are supplied in bottles of 30, 90, 100, 500 and unit dose package of 100 (10 x 10). Bottles of 30 NDC 55111-329-30 Bottles of 90 NDC 55111-329-90 Bottles of 100 NDC 55111-329-01 Bottles of 500 NDC 55111-329-05 Unit dose package of 100 (10 x 10) NDC 55111-329-78 Storage and Handling Store at 20° to 25°C (68°-77°F); excursions permitted to 15° to 30°C (59°-86°F) [See USP Controlled Room Temperature]. Dispense in a tight container, USP.