Nateglinide Drug Information

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

Limitations of Use : Not for treating type 1 diabetes mellitus or diabetes ketoacidosis

The recommended dose of nateglinide is 120 mg orally three times daily before meals. The recommended dose of nateglinide 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 1 to 30 minutes before meals.

In patients who skip meals, instruct patients to skip the scheduled dose of nateglinide to reduce the risk of hypoglycemia . 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. Administer 1 to 30 minutes before meals If a meal is skipped, skip the scheduled dose to reduce the risk of hypoglycemia.

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 = 1441 Preferred Term Upper Respiratory Infection 8.1

Back Pain 3.7 4.0 Flu Symptoms 2.6 3.6 Dizziness 2.2 3.6 Arthropathy

2.2

Hypoglycemia Episodes of severe hypoglycemia (plasma glucose less than 36 mg/dL) were

reported in two patients treated with nateglinide. Non-severe hypoglycemia occurred in 2.4 % of nateglinide treated patients and 0.4 % of placebo-treated patients . Weight Gain Patients treated with nateglinide had statistically significant mean increases in weight compared to placebo. In clinical trials, the mean weight increases with nateglinide 60 mg (3 times daily) and nateglinide 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 alone, nateglinide 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.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of nateglinide. 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 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 reductions and increased frequency of glucose monitoring may be required when nateglinide is 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 is 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 is coadministered with these drugs. Drugs That May Increase the Potential for Hypoglycemia : Nateglinide dose reductions and increased frequency of glucose monitoring may be required when co-administered Drugs That May Increase the Potential for Hyperglycemia : Nateglinide dose increases and increased frequency of glucose monitoring may be required when co-administered Drugs That May Blunt Signs and Symptoms of Hypoglycemia : Increased frequency of glucose monitoring may be required when co-administered

Pregnancy Risk Summary The available data from published literature and the applicant's pharmacovigilance with use of nateglinide 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 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 1000 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).

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

Nateglinide tablets are contraindicated in patients with a history of hypersensitivity to nateglinide or its inactive ingredients. History of hypersensitivity to nateglinide or its inactive ingredients

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 is highly protein bound, dialysis is not an efficient means of removing it from the blood.