NATEGLINIDE

Nateglinide Tablets, USP are an oral blood glucose-lowering drug of the glinide class. Nateglinide Tablets, (-)-N- [(trans-4-isopropylcyclohexane)carbonyl]-D-phenylalanine, are structurally unrelated to the oral sulfonylurea insulin secretagogues. The structural formula is as shown: Nateglinide, USP is a white powder with a molecular weight of 317.43 g/mol. It is freely soluble in methanol, ethanol, and chloroform, soluble in ether, sparingly soluble in acetonitrile and octanol, and practically insoluble in water. Nateglinide Tablets, USP biconvex tablets contain 60 mg, or 120 mg, of nateglinide for oral administration. Inactive Ingredients: colloidal silicon dioxide, corn starch, hypromellose, mannitol, polyethylene glycol, povidone, sodium starch glycolate, sodium stearyl fumarate, talc, titanium dioxide. In addition, the 60 mg contains iron oxide red and the 120 mg contains iron oxide yellow. nateglinide-structure

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 )

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 )

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 )

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

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 )